Subjects -> BIOLOGY (Total: 3174 journals)
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    - BIOLOGY (1491 journals)
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    - ENTOMOLOGY (67 journals)
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    - ORNITHOLOGY (26 journals)
    - PHYSIOLOGY (73 journals)
    - ZOOLOGY (117 journals)

BIOLOGY (1491 journals)            First | 1 2 3 4 5 6 7 8 | Last

Showing 401 - 600 of 1720 Journals sorted alphabetically
Cryoletters     Full-text available via subscription   (Followers: 4)
Cuadernos de Neuropsicología     Open Access   (Followers: 1)
Current Applied Science and Technology     Open Access  
Current Bioinformatics     Hybrid Journal   (Followers: 13)
Current Biology     Full-text available via subscription   (Followers: 228)
Current Genomics     Hybrid Journal   (Followers: 8)
Current Landscape Ecology Reports     Hybrid Journal   (Followers: 2)
Current Medical Science     Hybrid Journal   (Followers: 1)
Current Molecular Medicine     Hybrid Journal   (Followers: 3)
Current Opinion in Cell Biology     Hybrid Journal   (Followers: 51)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 8)
Current Opinion in Neurobiology     Hybrid Journal   (Followers: 32)
Current Opinion in Structural Biology     Hybrid Journal   (Followers: 26)
Current Opinion in Systems Biology     Hybrid Journal   (Followers: 2)
Current Pharmacogenomics and Personalized Medicine     Hybrid Journal   (Followers: 3)
Current Protein and Peptide Science     Hybrid Journal   (Followers: 8)
Current Proteomics     Hybrid Journal   (Followers: 4)
Current Protocols in Bioinformatics     Hybrid Journal   (Followers: 1)
Current Protocols in Cell Biology     Hybrid Journal  
Current Protocols in Molecular Biology     Hybrid Journal  
Current Protocols in Mouse Biology     Hybrid Journal  
Current Protocols in Neuroscience     Hybrid Journal  
Current Protocols in Plant Biology     Hybrid Journal   (Followers: 2)
Current Protocols in Protein Science     Hybrid Journal   (Followers: 1)
Current Protocols in Stem Cell Biology     Hybrid Journal  
Current Research in Bacteriology     Open Access   (Followers: 3)
Current Research in Biostatistics     Open Access   (Followers: 8)
Current Research in Chemical Biology     Open Access  
Current Research in Neurobiology     Open Access  
Current Research in Parasitology & Vector-Borne Diseases     Open Access  
Current Research in Structural Biology     Open Access   (Followers: 1)
Current Research in Translational Medicine     Full-text available via subscription   (Followers: 1)
Current Research in Virological Science     Open Access   (Followers: 2)
Current Science     Open Access   (Followers: 115)
Current Stem Cell Reports     Hybrid Journal   (Followers: 4)
Current Stem Cell Research & Therapy     Hybrid Journal   (Followers: 8)
Current Topics in Developmental Biology     Full-text available via subscription   (Followers: 3)
Current Topics in Membranes     Full-text available via subscription   (Followers: 1)
Cytotechnology     Hybrid Journal   (Followers: 11)
Database : The Journal of Biological Databases and Curation     Open Access   (Followers: 10)
Dendrochronologia     Hybrid Journal   (Followers: 1)
Developing World Bioethics     Hybrid Journal   (Followers: 6)
Developmental & Comparative Immunology     Hybrid Journal   (Followers: 5)
Developmental Biology     Hybrid Journal   (Followers: 26)
Developmental Cell     Full-text available via subscription   (Followers: 46)
Developmental Dynamics     Hybrid Journal   (Followers: 4)
Developmental Neurobiology     Hybrid Journal   (Followers: 6)
Dhaka University Journal of Biological Sciences     Open Access  
Diatom Research     Hybrid Journal   (Followers: 3)
Differentiation     Hybrid Journal  
Digital Biomarkers     Open Access   (Followers: 1)
Disease Models and Mechanisms     Open Access   (Followers: 1)
Diseases of Aquatic Organisms     Hybrid Journal  
DNA and Cell Biology     Hybrid Journal   (Followers: 9)
DNA Repair     Hybrid Journal   (Followers: 3)
DNA Research     Open Access   (Followers: 4)
Doklady Physics     Hybrid Journal   (Followers: 1)
Drug Discovery Today: Technologies     Full-text available via subscription   (Followers: 13)
Drug Resistance Updates     Hybrid Journal   (Followers: 3)
e-Jurnal Rekayasa dan Teknologi Budidaya Perairan     Open Access  
Ecocycles     Open Access   (Followers: 4)
Ecohydrology & Hydrobiology     Full-text available via subscription   (Followers: 4)
Ecología en Bolivia     Open Access  
Ecological Engineering     Hybrid Journal   (Followers: 4)
Ecological Questions     Open Access   (Followers: 5)
Ecological Solutions and Evidence     Open Access   (Followers: 1)
Ecology and Society     Open Access   (Followers: 51)
Ecology Letters     Hybrid Journal   (Followers: 246)
Economics & Human Biology     Hybrid Journal   (Followers: 1)
Ecoprint : An International Journal of Ecology     Open Access   (Followers: 4)
Ecoscience     Hybrid Journal   (Followers: 2)
Ecosystem Health and Sustainability     Open Access   (Followers: 1)
Ecosystems and People     Open Access   (Followers: 2)
Educational Technology Research and Development     Partially Free   (Followers: 45)
EDUSAINS     Open Access  
EFB Bioeconomy Journal     Open Access  
Egyptian Journal of Basic and Applied Sciences     Open Access  
Egyptian Journal of Biology     Open Access  
Egyptian Journal of Natural History     Open Access   (Followers: 1)
EJNMMI Research     Open Access  
Ekologia     Open Access  
el-Hayah     Open Access  
Electromagnetic Biology and Medicine     Hybrid Journal  
eLife     Open Access   (Followers: 95)
Embo Molecular Medicine     Open Access   (Followers: 10)
EMBO reports     Full-text available via subscription   (Followers: 23)
Emotion Review     Hybrid Journal   (Followers: 20)
Endangered Species Research     Open Access   (Followers: 6)
Endocrine Connections     Open Access   (Followers: 4)
Endothelium: Journal of Endothelial Cell Research     Full-text available via subscription   (Followers: 3)
Engineering & Technology     Hybrid Journal   (Followers: 22)
Engineering Economist, The     Hybrid Journal   (Followers: 4)
Engineering in Life Sciences     Hybrid Journal   (Followers: 3)
Engineering Optimization     Hybrid Journal   (Followers: 19)
Ensaios e Ciência : Ciências Biológicas, Agrárias e da Saúde     Open Access  
Environmental Biology of Fishes     Hybrid Journal   (Followers: 4)
Environmental DNA     Open Access  
Environmental Dynamics and Global Climate Change     Open Access   (Followers: 21)
Environmental Epigenetics     Open Access   (Followers: 2)
Environmental Microbiology     Hybrid Journal   (Followers: 27)
Environmental Microbiome     Open Access  
Environmental Science & Technology     Hybrid Journal   (Followers: 181)
Enzyme and Microbial Technology     Hybrid Journal   (Followers: 12)
Enzyme Research     Open Access   (Followers: 4)
Epidemiology & Infection     Open Access   (Followers: 23)
Epigenomes     Open Access  
EPMA Journal     Open Access  
Ethiopian Journal of Biological Sciences     Open Access   (Followers: 3)
Ethnobiology and Conservation     Open Access   (Followers: 3)
Ethnobiology Letters     Open Access  
Ethnobotany Research & Applications : a journal of plants, people and applied research     Open Access   (Followers: 2)
Ethnoscientia : Brazilian Journal of Ethnobiology and Ethnoecology     Open Access  
Ethology     Hybrid Journal   (Followers: 11)
Ethology Ecology & Evolution     Hybrid Journal   (Followers: 16)
EuPA Open Proteomics     Open Access   (Followers: 2)
EUREKA : Life Sciences     Open Access  
European Journal of Biological Research     Open Access   (Followers: 1)
European Journal of Biology     Open Access   (Followers: 1)
European Journal of Cell Biology     Hybrid Journal   (Followers: 6)
European Journal of Ecology     Open Access   (Followers: 1)
European Journal of Neuroscience     Hybrid Journal   (Followers: 36)
European Journal of Obstetrics & Gynecology and Reproductive Biology     Hybrid Journal   (Followers: 19)
European Journal of Obstetrics & Gynecology and Reproductive Biology : X     Open Access  
European Journal of Phycology     Hybrid Journal   (Followers: 4)
European Journal of Protistology     Hybrid Journal   (Followers: 5)
European Journal of Soil Biology     Hybrid Journal   (Followers: 3)
European Online Journal of Natural and Social Sciences     Open Access   (Followers: 4)
European Scientific Journal     Open Access   (Followers: 1)
Evidência - Ciência e Biotecnologia - Interdisciplinar     Open Access  
EvoDevo     Open Access   (Followers: 4)
Evolution     Partially Free   (Followers: 129)
Evolution and Human Behavior     Hybrid Journal   (Followers: 22)
Evolution Letters     Open Access   (Followers: 8)
Evolutionary Applications     Open Access   (Followers: 6)
Evolutionary Bioinformatics     Open Access   (Followers: 12)
Evolutionary Biology     Hybrid Journal   (Followers: 25)
Evolutionary Computation     Hybrid Journal   (Followers: 11)
Evolutionary Systematics     Open Access   (Followers: 2)
EXCLI Journal : Experimental and Clinical Sciences     Open Access  
Experimental & Molecular Medicine     Open Access  
Experimental and Applied Acarology     Hybrid Journal   (Followers: 1)
Experimental Parasitology     Hybrid Journal   (Followers: 1)
Expert Opinion on Biological Therapy     Hybrid Journal   (Followers: 4)
Expert Opinion on Environmental Biology     Hybrid Journal  
Expert Review of Proteomics     Hybrid Journal   (Followers: 4)
ExRNA     Open Access  
Extreme Life, Biospeology & Astrobiology - International Journal of the Bioflux Society     Full-text available via subscription   (Followers: 4)
Extremophiles     Hybrid Journal   (Followers: 1)
F&S Science : Official journal of the American Society for Reproductive Medicine     Open Access  
Facta Universitatis, Series : Medicine and Biology     Open Access  
Familial Cancer     Hybrid Journal   (Followers: 2)
FASEB BioAdvances     Open Access  
Fauna Norvegica     Open Access  
Fauna of New Zealand     Open Access  
Febs Journal     Hybrid Journal   (Followers: 29)
Feddes Repertorium     Hybrid Journal  
Fems Yeast Research     Hybrid Journal   (Followers: 11)
FIGEMPA : Investigación y Desarrollo     Open Access   (Followers: 1)
Fire Ecology     Open Access   (Followers: 2)
Fish & Shellfish Immunology     Hybrid Journal   (Followers: 10)
Fish and Shellfish Immunology Reports     Open Access   (Followers: 1)
Fishes     Open Access  
Fitoterapia     Hybrid Journal   (Followers: 4)
Florea : Jurnal Biologi dan Pembelajarannya     Open Access  
Fly     Full-text available via subscription  
Folia Biologica     Free   (Followers: 1)
Folia Histochemica et Cytobiologica     Open Access  
Folia Microbiologica     Hybrid Journal   (Followers: 2)
Folia Primatologica     Full-text available via subscription   (Followers: 4)
Food and Bioproducts Processing     Hybrid Journal   (Followers: 3)
Food and Ecological Systems Modelling Journal     Open Access  
Food and Waterborne Parasitology     Open Access  
Food Webs     Hybrid Journal   (Followers: 1)
Forensic Genomics     Full-text available via subscription   (Followers: 4)
Forest Pathology     Hybrid Journal   (Followers: 1)
Forschung     Hybrid Journal   (Followers: 1)
Foundations of Physics     Hybrid Journal   (Followers: 40)
Free Radical Biology and Medicine     Hybrid Journal   (Followers: 6)
Free Radical Research     Hybrid Journal   (Followers: 2)
Freshwater Science     Full-text available via subscription   (Followers: 14)
Frontiers in Ecology and Evolution     Open Access   (Followers: 45)
Frontiers in Evolutionary Neuroscience     Open Access   (Followers: 7)
Frontiers in Life Science     Hybrid Journal   (Followers: 1)
Frontiers in Marine Science     Open Access   (Followers: 13)
Frontiers in Network Physiology     Open Access   (Followers: 2)
Frontiers in Neurogenesis     Open Access   (Followers: 2)
Frontiers in Neuroprosthetics     Open Access   (Followers: 6)
Frontiers of Biogeography     Open Access   (Followers: 4)
Frontiers of Biology     Hybrid Journal   (Followers: 2)
Frontiers of Environmental Science & Engineering     Hybrid Journal   (Followers: 3)
Frontiers of Medical and Biological Engineering     Hybrid Journal  
Functional & Integrative Genomics     Hybrid Journal   (Followers: 7)
Fundamental and Applied Limnology / Archiv für Hydrobiologie     Full-text available via subscription   (Followers: 3)
Fundamental Research     Open Access  
Fungal Biology     Hybrid Journal   (Followers: 6)
Fungal Biology and Biotechnology     Open Access   (Followers: 2)
Fungal Biology Reviews     Full-text available via subscription   (Followers: 9)
Fungal Diversity     Hybrid Journal   (Followers: 2)
Fungal Ecology     Hybrid Journal   (Followers: 6)
Fungal Genetics Reports     Open Access  

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Similar Journals
Journal Cover
eLife
Journal Prestige (SJR): 7.121
Citation Impact (citeScore): 7
Number of Followers: 95  

  This is an Open Access Journal Open Access journal
ISSN (Online) 2050-084X
Published by eLife Sciences Publications Homepage  [1 journal]
  • Canonical Wnt signaling and the regulation of divergent mesenchymal Fgf8
           expression in Axolotl limb development and regeneration

    • Authors: Elly M Tanaka, Giacomo Leon Glotzer, Pietro Tardivo
      Abstract: The expression of Fibroblast growth factors (Fgf) ligands in a specialized epithelial compartment, the Apical Ectodermal Ridge (AER), is a conserved feature of limb development across vertebrate species. In vertebrates, Fgf 4, 8, 9, and 17 are all expressed in the AER. An exception to this paradigm is the salamander (axolotl) developing and regenerating limb, where key Fgf ligands are expressed in the mesenchyme. The mesenchymal expression of Amex.Fgf8 in axolotl has been suggested to be critical for regeneration. To date, there is little knowledge regarding what controls Amex.Fgf8 expression in the axolotl limb mesenchyme. A large body of mouse and chick studies have defined a set of transcription factors and canonical Wnt signaling as the main regulators of epidermal Fgf8 expression in these organisms. In this study, we address the hypothesis that alterations to one or more of these components during evolution has resulted in mesenchymal Amex.Fgf8 expression in the axolotl. To sensitively quantify gene expression with spatial precision, we combined optical clearing of whole-mount axolotl limb tissue with single molecule fluorescen in situ hybridization and a semi-automated quantification pipeline. Several candidate upstream components were found expressed in the axolotl ectoderm, indicating that they are not direct regulators of Amex.Fgf8 expression. We found that Amex.Wnt3a is expressed in axolotl limb epidermis, similarly to chicken and mouse. However, unlike in amniotes, Wnt target genes are activated preferentially in limb mesenchyme rather than in epidermis. Inhibition and activation of Wnt signaling results in downregulation and upregulation of mesenchymal Amex.Fgf8 expression respectively. These results implicate a shift in tissue responsiveness to canonical Wnt signaling from epidermis to mesenchyme as one step contributing to the unique mesenchymal Amex.Fgf8 expression seen in the axolotl.
      PubDate: 2022-05-19T00:00:00Z
      DOI: 10.7554/eLife.79762
       
  • Redoxing PTPN22 activity

    • Authors: Ivan Bogeski, Magdalena Shumanska
      Abstract: The oxidative state of a critical cysteine residue determines the enzymatic activity of a phosphatase involved in T-cell immune responses.
      PubDate: 2022-05-19T00:00:00Z
      DOI: 10.7554/eLife.79125
       
  • Brucella activates the host RIDD pathway to subvert BLOS1-directed
           immune defense

    • Authors: Allison Ficht, Ana Cabello, Aseem Pandey, Cameron Lee Martin, Charles D Johnson, Dongmei Zhang, Gabriel Gomez, Haowu Chang, Hao Zhang, Jianxun Song, Jill Skrobarczyk, Jing Yang, Julian Leibowitz, Kai He, Kelsey Michelle Wells, Kristin L Patrick, Luciana Fachini da Costa, Luc R Berghman, Paul de Figueiredo, Qing-Ming Qin, Richard Metz, Sing-Hoi Sze, Thomas A Ficht, Xiaoning Qian, Xuehuang Feng, Xueqiang Li, Yue Liu
      Abstract: The phagocytosis and destruction of pathogens in lysosomes constitute central elements of innate immune defense. Here, we show that Brucella, the causative agent of brucellosis, the most prevalent bacterial zoonosis globally, subverts this immune defense pathway by activating regulated IRE1α-dependent decay (RIDD) of Bloc1s1 mRNA encoding BLOS1, a protein that promotes endosome–lysosome fusion. RIDD-deficient cells and mice harboring a RIDD-incompetent variant of IRE1α were resistant to infection. Inactivation of the Bloc1s1 gene impaired the ability to assemble BLOC-1-related complex (BORC), resulting in differential recruitment of BORC-related lysosome trafficking components, perinuclear trafficking of Brucella-containing vacuoles (BCVs), and enhanced susceptibility to infection. The RIDD-resistant Bloc1s1 variant maintains the integrity of BORC and a higher-level association of BORC-related components that promote centrifugal lysosome trafficking, resulting in enhanced BCV peripheral trafficking and lysosomal destruction, and resistance to infection. These findings demonstrate that host RIDD activity on BLOS1 regulates Brucella intracellular parasitism by disrupting BORC-directed lysosomal trafficking. Notably, coronavirus murine hepatitis virus also subverted the RIDD–BLOS1 axis to promote intracellular replication. Our work establishes BLOS1 as a novel immune defense factor whose activity is hijacked by diverse pathogens.
      PubDate: 2022-05-19T00:00:00Z
      DOI: 10.7554/eLife.73625
       
  • SARS-CoV-2 host-shutoff impacts innate NK cell functions, but
           antibody-dependent NK activity is strongly activated through non-spike
           antibodies

    • Authors: Blair Merrick, B Paul Morgan, Carl Graham, Ceri Alan Fielding, David A Price, Eddie CY Wang, Edward JD Greenwood, Ian R Humphreys, Isabella Huettner, James C Williamson, Jeffrey Seow, Jonathan D Edgeworth, Katie Doores, Kristin Ladell, Matthias Eberl, Paul J Lehner, Pragati Sabberwal, Richard J Stanton, Sam J Wilson, Thomas WM Crozier, Wioleta Zelek
      Abstract: The outcome of infection is dependent on the ability of viruses to manipulate the infected cell to evade immunity, and the ability of the immune response to overcome this evasion. Understanding this process is key to understanding pathogenesis, genetic risk factors, and both natural and vaccine-induced immunity. SARS-CoV-2 antagonises the innate interferon response, but whether it manipulates innate cellular immunity is unclear. An unbiased proteomic analysis determined how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells, showing downregulation of activating NK ligands B7-H6, MICA, ULBP2, and Nectin1, with minimal effects on MHC-I. This occurred at the level of protein synthesis, could be mediated by Nsp1 and Nsp14, and correlated with a reduction in NK cell activation. This identifies a novel mechanism by which SARS-CoV-2 host-shutoff antagonises innate immunity. Later in the disease process, strong antibody-dependent NK cell activation (ADNKA) developed. These responses were sustained for at least 6 months in most patients, and led to high levels of pro-inflammatory cytokine production. Depletion of spike-specific antibodies confirmed their dominant role in neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.
      PubDate: 2022-05-19T00:00:00Z
      DOI: 10.7554/eLife.74489
       
  • Lighting up protein design

    • Authors: Grzegorz Kudla, Marcin Plech
      Abstract: Using a neural network to predict how green fluorescent proteins respond to genetic mutations illuminates properties that could help design new proteins.
      PubDate: 2022-05-19T00:00:00Z
      DOI: 10.7554/eLife.79310
       
  • Redox regulation of PTPN22 affects the severity of T-cell-dependent
           autoimmune inflammation

    • Authors: Amir A Saei, Annika Åstrand, Bernard Malissen, Clara M Hernandez, Elias SJ Arnér, Florian Forster, Gonzalo Fernandez Lahore, Hassan Gharibi, Jaime James, Markus Dagnell, Qing Cheng, Rajneesh Malhotra, Rikard Holmdahl, Roman A Zubarev, Yifei Chen
      Abstract: Chronic autoimmune diseases are associated with mutations in PTPN22, a modifier of T cell receptor (TCR) signaling. As with all protein tyrosine phosphatases, the activity of PTPN22 is redox regulated, but if or how such regulation can modulate inflammatory pathways in vivo is not known. To determine this, we created a mouse with a cysteine-to-serine mutation at position 129 in PTPN22 (C129S), a residue proposed to alter the redox regulatory properties of PTPN22 by forming a disulfide with the catalytic C227 residue. The C129S mutant mouse showed a stronger T-cell-dependent inflammatory response and development of T-cell-dependent autoimmune arthritis due to enhanced TCR signaling and activation of T cells, an effect neutralized by a mutation in Ncf1, a component of the NOX2 complex. Activity assays with purified proteins suggest that the functional results can be explained by an increased sensitivity to oxidation of the C129S mutated PTPN22 protein. We also observed that the disulfide of native PTPN22 can be directly reduced by the thioredoxin system, while the C129S mutant lacking this disulfide was less amenable to reductive reactivation. In conclusion, we show that PTPN22 functionally interacts with Ncf1 and is regulated by oxidation via the noncatalytic C129 residue and oxidation-prone PTPN22 leads to increased severity in the development of T-cell-dependent autoimmunity.
      PubDate: 2022-05-19T00:00:00Z
      DOI: 10.7554/eLife.74549
       
  • Single-cell transcriptome reveals insights into the development and
           function of the zebrafish ovary

    • Authors: Bruce W Draper, Caramai N Kamei, Celina E Juliano, Iain A Drummond, Lana N Christensen, Matthew E McFaul, Michelle E Kassack, Nayeli Arroyo, Samuel Horst, Stefan Siebert, Sydney R Wyatt, Yulong Liu
      Abstract: Zebrafish are an established research organism that has made many contributions to our understanding of vertebrate tissue and organ development, yet there are still significant gaps in our understanding of the genes that regulate gonad development, sex, and reproduction. Unlike the development of many organs, such as the brain and heart that form during the first few days of development, zebrafish gonads do not begin to form until the larval stage (≥5 dpf). Thus, forward genetic screens have identified very few genes required for gonad development. In addition, bulk RNA sequencing studies which identify genes expressed in the gonads do not have the resolution necessary to define minor cell populations that may play significant roles in development and function of these organs. To overcome these limitations, we have used single-cell RNA sequencing to determine the transcriptomes of cells isolated from juvenile zebrafish ovaries. This resulted in the profiles of 10,658 germ cells and 14,431 somatic cells. Our germ cell data represents all developmental stages from germline stem cells to early meiotic oocytes. Our somatic cell data represents all known somatic cell types, including follicle cells, theca cells and ovarian stromal cells. Further analysis revealed an unexpected number of cell subpopulations within these broadly defined cell types. To further define their functional significance, we determined the location of these cell subpopulations within the ovary. Finally, we used gene knockout experiments to determine the roles of foxl2l and wnt9b for oocyte development and sex determination and/or differentiation, respectively. Our results reveal novel insights into zebrafish ovarian development and function and the transcriptome profiles will provide a valuable resource for future studies.
      PubDate: 2022-05-19T00:00:00Z
      DOI: 10.7554/eLife.76014
       
  • Correction: The recycling endosome protein Rab25 coordinates collective
           cell movements in the zebrafish surface epithelium

    • PubDate: 2022-05-19T00:00:00Z
      DOI: 10.7554/eLife.79841
       
  • T cells discriminate between groups C1 and C2 HLA-C

    • Authors: Eric O Long, Jinghua Lu, Malcolm JW Sim, Paul Brennan, Peter D Sun, Zachary Stotz
      Abstract: Dimorphic amino acids at positions 77 and 80 delineate HLA-C allotypes into two groups, C1 and C2, which associate with disease through interactions with C1 and C2-specific natural killer cell receptors. How the C1/C2 dimorphism affects T cell recognition is unknown. Using HLA-C allotypes that differ only by the C1/C2-defining residues, we found that KRAS-G12D neoantigen-specific T cell receptors (TCR) discriminated between C1 and C2 presenting the same KRAS-G12D peptides. Structural and functional experiments, and immunopeptidomics analysis revealed that Ser77 in C1 and Asn77 in C2 influence amino acid preference near the peptide C-terminus (pW), including the pW-1 position, in which C1 favors small and C2 prefers large residues. This resulted in weaker TCR affinity for KRAS-G12D-bound C2-HLA-C despite conserved TCR contacts. Thus, the C1/C2 dimorphism on its own impacts peptide presentation and HLA-C restricted T cell responses, with implications in disease, including adoptive T cell therapy targeting KRAS-G12D-induced cancers.
      PubDate: 2022-05-19T00:00:00Z
      DOI: 10.7554/eLife.75670
       
  • Selection for infectivity profiles in slow and fast epidemics, and the
           rise of SARS-CoV-2 variants

    • Authors: Benjamin John Cowling, Florence Débarre, François Blanquart, Nathanaël Hozé, Simon Cauchemez
      Abstract: Evaluating the characteristics of emerging SARS-CoV-2 variants of concern is essential to inform pandemic risk assessment. A variant may grow faster if it produces a larger number of secondary infections ('R advantage') or if the timing of secondary infections (generation time) is better. So far, assessments have largely focused on deriving the R advantage assuming the generation time was unchanged. Yet, knowledge of both is needed to anticipate impact. Here we develop an analytical framework to investigate the contribution of both the R advantage and generation time to the growth advantage of a variant. It is known that selection on a variant with larger R increases with levels of transmission in the community. We additionally show that variants conferring earlier transmission are more strongly favoured when the historical strains have fast epidemic growth, while variants conferring later transmission are more strongly favoured when historical strains have slow or negative growth. We develop these conceptual insights into a new statistical framework to infer both the R advantage and generation time of a variant. On simulated data, our framework correctly estimates both parameters when it covers time periods characterized by different epidemiological contexts. Applied to data for the Alpha and Delta variants in England and in Europe, we find that Alpha confers a +54% [95% CI, 45-63%] R advantage compared to previous strains, and Delta +140% [98-182%] compared to Alpha, and mean generation times are similar to historical strains for both variants. This work helps interpret variant frequency dynamics and will strengthen risk assessment for future variants of concern.
      PubDate: 2022-05-19T00:00:00Z
      DOI: 10.7554/eLife.75791
       
  • A crowd of BashTheBug volunteers reproducibly and accurately measure the
           minimum inhibitory concentrations of 13 antitubercular drugs from
           photographs of 96-well broth microdilution plates

    • Authors: Ana L Gibertoni Cruz, A Sarah Walker, Aysha Roohi, Carla Wright, Chris Lintott, David Clifton, Derrick W Crook, Elisabeth ML Baeten, Grant Miller, Helen Spiers, Philip W Fowler, Samaneh Kouchaki, Sarah W Hoosdally, Timothy EA Peto, Timothy M Walker, Tingting Zhu
      Abstract: Tuberculosis is a respiratory disease that is treatable with antibiotics. An increasing prevalence of resistance means that to ensure a good treatment outcome it is desirable to test the susceptibility of each infection to different antibiotics. Conventionally this is done by culturing a clinical sample and then exposing aliquots to a panel of antibiotics, Using 96-well broth micro dilution plates with each well containing a lyophilised predetermined amount of an antibiotic is a convenient and cost-effective way to measure the MICs of several drugs at once for a clinical sample. Although accurate, this is still an expensive and slow process that requires highly skilled and experienced laboratory scientists. Here we show that, through the BashTheBug project hosted on the Zooniverse citizen science platform, a crowd of volunteers can reproducibly and accurately determine the MICs for 13 drugs and that simply taking the median or mode of 11-17 independent classifications is sufficient. There is therefore a potential role for crowds to support (but not supplant) the role of experts in antibiotic susceptibility testing.
      PubDate: 2022-05-19T00:00:00Z
      DOI: 10.7554/eLife.75046
       
  • Notch-dependent and -independent transcription are modulated by tissue
           movements at gastrulation

    • Authors: Julia Falo-Sanjuan, Sarah Bray
      Abstract: Cells sense and integrate external information from diverse sources that include mechanical cues. Shaping of tissues during development may thus require coordination between mechanical forces from morphogenesis and cell-cell signalling to confer appropriate changes in gene expression. By live-imaging Notch-induced transcription in real time we have discovered that morphogenetic movements during Drosophila gastrulation bring about an increase in activity-levels of a Notch responsive enhancer. Mutations that disrupt the timing of gastrulation resulted in concomitant delays in transcription up-regulation that correlated with the start of mesoderm invagination. As a similar gastrulation-induced effect was detected when transcription was elicited by the intracellular domain NICD, it cannot be attributed to forces exerted on Notch receptor activation. A Notch independent vnd enhancer also exhibited a modest gastrulation-induced activity increase in the same stripe of cells. Together, these observations argue that gastrulation-associated forces act on the nucleus to modulate transcription levels. This regulation was uncoupled when the complex linking the nucleoskeleton and cytoskeleton (LINC) was disrupted, indicating a likely conduit. We propose that the coupling between tissue level mechanics, arising from gastrulation, and enhancer activity represents a general mechanism for ensuring correct tissue specification during development and that Notch dependent enhancers are highly sensitive to this regulation.
      PubDate: 2022-05-18T00:00:00Z
      DOI: 10.7554/eLife.73656
       
  • Correction: Disease consequences of higher adiposity uncoupled from its
           adverse metabolic effects using Mendelian randomisation

    • PubDate: 2022-05-18T00:00:00Z
      DOI: 10.7554/eLife.80233
       
  • Seipin transmembrane segments critically function in triglyceride
           nucleation and lipid droplet budding from the membrane

    • Authors: Alexander J Pak, Gregory A Voth, Henning Arlt, Jeeyun Chung, Robert V Farese Jnr, Siyoung Kim, Tobias C Walther
      Abstract: Lipid droplets (LDs) are organelles formed in the endoplasmic reticulum (ER) to store triacylglycerol (TG) and sterol esters. The ER protein seipin is key for LD biogenesis. Seipin forms a cage-like structure, with each seipin monomer containing a conserved hydrophobic helix and two transmembrane (TM) segments. How the different parts of seipin function in TG nucleation and LD budding is poorly understood. Here, we utilized molecular dynamics simulations of human seipin, along with cell-based experiments, to study seipin’s functions in protein–lipid interactions, lipid diffusion, and LD maturation. An all-atom simulation indicates that seipin TM segment residues and hydrophobic helices residues located in the phospholipid tail region of the bilayer attract TG. Simulating larger, growing LDs with coarse-grained models, we find that the seipin TM segments form a constricted neck structure to facilitate conversion of a flat oil lens into a budding LD. Using cell experiments and simulations, we also show that conserved, positively charged residues at the end of seipin’s TM segments affect LD maturation. We propose a model in which seipin TM segments critically function in TG nucleation and LD growth.
      PubDate: 2022-05-18T00:00:00Z
      DOI: 10.7554/eLife.75808
       
  • Residual force enhancement is affected more by quadriceps muscle length
           than stretch amplitude

    • Authors: Brent James Raiteri, Daniel Hahn, Patrick Bakenecker, Tobias Weingarten
      Abstract: Little is known about how muscle length affects residual force enhancement (rFE) in humans. We therefore investigated rFE at short, long, and very long muscle lengths within the human quadriceps and patellar tendon (PT) using conventional dynamometry with motion capture (rFETQ) and a new, non-invasive shear-wave tensiometry technique (rFEWS). Eleven healthy male participants performed submaximal (50% max.) EMG-matched fixed-end reference and stretch-hold contractions across these muscle lengths while muscle fascicle length changes of the vastus lateralis (VL) were captured using B-mode ultrasound. We found significant rFETQ at long (7±5%) and very long (12±8%), but not short (2±5%) muscle lengths, whereas rFEWS was only significant at the very long (38±27%), but not short (8±12%) or long (6±10%) muscle lengths. We also found significant relationships between VL fascicle length and rFETQ (r=0.63, p=.001) and rFEWS (r=0.52, p=.017), but relationships were not significant between VL fascicle stretch amplitude and rFETQ (r=0.33, p=.126) or rFEWS (r=0.29, p=.201). PT shear-wave speed-angle relationships did not agree with estimated PT force-angle relationships, which indicates that estimating PT loads from shear-wave tensiometry might be inaccurate. We conclude that increasing muscle length rather than stretch amplitude contributes more to rFE during submaximal voluntary contractions of the human quadriceps.
      PubDate: 2022-05-17T00:00:00Z
      DOI: 10.7554/eLife.77553
       
  • Prefrontal-amygdalar oscillations related to social behavior in mice

    • Authors: Kotomi Takano, Nahoko Kuga, Reimi Abe, Takuya Sasaki, Yuji Ikegaya
      Abstract: The medial prefrontal cortex and amygdala are involved in the regulation of social behavior and associated with psychiatric diseases but their detailed neurophysiological mechanisms at a network level remain unclear. We recorded local field potentials (LFPs) from the dorsal medial prefrontal cortex (dmPFC) and basolateral amygdala (BLA) while male mice engaged on social behavior. We found that in wild-type mice, both the dmPFC and BLA increased 4–7 Hz oscillation power and decreased 30–60 Hz power when they needed to attend to another target mouse. In mouse models with reduced social interactions, dmPFC 4–7 Hz power further increased especially when they exhibited social avoidance behavior. In contrast, dmPFC and BLA decreased 4–7 Hz power when wild-type mice socially approached a target mouse. Frequency-specific optogenetic manipulations replicating social approach-related LFP patterns restored social interaction behavior in socially deficient mice. These results demonstrate a neurophysiological substrate of the prefrontal cortex and amygdala related to social behavior and provide a unified pathophysiological understanding of neuronal population dynamics underlying social behavioral deficits.
      PubDate: 2022-05-17T00:00:00Z
      DOI: 10.7554/eLife.78428
       
  • Multi-tract multi-symptom relationships in pediatric concussion

    • Authors: Alain Ptito, Anne L Wheeler, Danilo Bzdok, Eman Nishat, Guido I Guberman, Maxime Descoteaux, Sonja Stojanovski
      Abstract: Background: The heterogeneity of white matter damage and symptoms in concussion has been identified as a major obstacle to therapeutic innovation. In contrast, most diffusion MRI (dMRI) studies on concussion have traditionally relied on group-comparison approaches that average out heterogeneity. To leverage, rather than average out, concussion heterogeneity, we combined dMRI and multivariate statistics to characterize multi-tract multi-symptom relationships.
      PubDate: 2022-05-17T00:00:00Z
      DOI: 10.7554/eLife.70450
       
  • Mitotically heritable, RNA polymerase II-independent H3K4 dimethylation
           stimulates INO1 transcriptional memory

    • Authors: Agustina D'Urso, Bethany Sump, Donna G Brickner, Jason H Brickner, Seo Hyun Kim
      Abstract: For some inducible genes, the rate and molecular mechanism of transcriptional activation depends on the prior experiences of the cell. This phenomenon, called epigenetic transcriptional memory, accelerates reactivation and requires both changes in chromatin structure and recruitment of poised RNA Polymerase II (RNAPII) to the promoter. Memory of inositol starvation in budding yeast involves a positive feedback loop between transcription factor-dependent interaction with the nuclear pore complex and histone H3 lysine 4 dimethylation (H3K4me2). While H3K4me2 is essential for recruitment of RNAPII and faster reactivation, RNAPII is not required for H3K4me2. Unlike RNAPII-dependent H3K4me2 associated with transcription, RNAPII-independent H3K4me2 requires Nup100, SET3C, the Leo1 subunit of the Paf1 complex and, upon degradation of an essential transcription factor, is inherited through multiple cell cycles. The writer of this mark (COMPASS) physically interacts with the potential reader (SET3C), suggesting a molecular mechanism for the spreading and re-incorporation of H3K4me2 following DNA replication.
      PubDate: 2022-05-17T00:00:00Z
      DOI: 10.7554/eLife.77646
       
  • A Permian fish reveals widespread distribution of neopterygian-like jaw
           suspension

    • Authors: Matt Friedman, Sam Giles, Thodoris Argyriou
      Abstract: The actinopterygian crown group (comprising all living ray-finned fishes) originated by the end of the Carboniferous. However, most late Paleozoic taxa are stem actinopterygians, and broadly resemble stratigraphically older taxa. The early Permian †Brachydegma caelatum is notable for its three-dimensional preservation and past phylogenetic interpretations as a nested member of the neopterygian crown. Here, we use computed microtomography to redescribe †Brachydegma, uncovering an unanticipated combination of primitive (e.g., aortic canal; immobile maxilla) and derived (e.g., differentiated occipital ossifications; posterior stem of parasphenoid; two accessory hyoidean ossifications; double jaw joint) dermal and endoskeletal features relative to most other Paleozoic actinopterygians. Some of these features were previously thought to be restricted to the neopterygian crown. The precise phylogenetic position of †Brachydegma is unclear, with placements either on the polypterid stem, or as an early-diverging stem neopterygian. However, our analyses decisively reject previous placements of †Brachydegma in the neopterygian crown. Critically, we demonstrate that key-endoskeletal components of the hyoid portion of the suspensorium of crown neopterygians appeared deeper in the tree than previously thought.
      PubDate: 2022-05-17T00:00:00Z
      DOI: 10.7554/eLife.58433
       
  • Integrative analysis of scRNA-seq and scATAC-seq revealed
           transit-amplifying thymic epithelial cells expressing autoimmune regulator
           

    • Authors: Aki Minoda, Asako Sakaue-Sawano, Atsushi Miyawaki, Azusa Inoue, Eugene Oh, Haruka Yabukami, Hiroto Ishii, Houko Ohki, Kenta Horie, Maki Miyauchi, Masafumi Muratani, Masaki Yoshida, Mio Hayama, Nobuko Akiyama, Sotaro Hirai, S Thomas Kelly, Taishin Akiyama, Takahisa MIyao, Takao Seki, Tatsuya Ishikawa, Tommy W Terooatea, Yuki Takakura, Yuya Maruyama
      Abstract: Medullary thymic epithelial cells (mTECs) are critical for self-tolerance induction in T cells via promiscuous expression of tissue-specific antigens (TSAs), which are controlled by the transcriptional regulator, AIRE. Whereas AIRE-expressing (Aire+) mTECs undergo constant turnover in the adult thymus, mechanisms underlying differentiation of postnatal mTECs remain to be discovered. Integrative analysis of single-cell assays for transposase-accessible chromatin (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) suggested the presence of proliferating mTECs with a specific chromatin structure, which express high levels of Aire and co-stimulatory molecules, CD80 (Aire+CD80hi). Proliferating Aire+CD80hi mTECs detected using Fucci technology express a minimal number of Aire-dependent TSAs and are converted into quiescent Aire+CD80hi mTECs expressing high levels of TSAs after a transit amplification. These data provide evidence for the existence of transit-amplifying Aire+mTEC precursors during the Aire+mTEC differentiation process of the postnatal thymus.
      PubDate: 2022-05-17T00:00:00Z
      DOI: 10.7554/eLife.73998
       
  • Comparative multi-tissue profiling reveals extensive tissue-specificity in
           transcriptome reprogramming during thermal adaptation

    • Authors: Claire Chevalier, Doron Merkler, Gabriela Salinas, Karin Steinbach, Martina Spiljar, Melis Çolakoğlu, Mirko Trajkovski, Noushin Hadadi
      Abstract: Thermal adaptation is an extensively used intervention for enhancing or suppressing thermogenic and mitochondrial activity in adipose tissues. As such, it has been suggested as a potential lifestyle intervention for body weight maintenance. While the metabolic consequences of thermal acclimation are not limited to the adipose tissues, the impact on the rest of the tissues in context of their gene expression profile remains unclear. Here, we provide a systematic characterization of the effects in a comparative multi-tissue RNA sequencing approach following exposure of mice to 10 °C, 22 °C, or 34 °C in a panel of organs consisting of spleen, bone marrow, spinal cord, brain, hypothalamus, ileum, liver, quadriceps, subcutaneous-, visceral- and brown adipose tissues. We highlight that transcriptional responses to temperature alterations exhibit a high degree of tissue-specificity both at the gene level and at GO enrichment gene sets, and show that the tissue-specificity is not directed by the distinct basic gene expression pattern exhibited by the various organs. Our study places the adaptation of individual tissues to different temperatures in a whole-organism framework and provides integrative transcriptional analysis necessary for understanding the temperature-mediated biological programming.
      PubDate: 2022-05-17T00:00:00Z
      DOI: 10.7554/eLife.78556
       
  • A tonic nicotinic brake controls spike timing in striatal spiny projection
           neurons

    • Authors: Gilad Silberberg, Jeffrey M Malgady, Jennifer Wilking, Joshua A Goldberg, Joshua L Plotkin, Lior Matityahu, Meital Schirelman, Yvonne Johansson
      Abstract: Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can disynaptically inhibit SPNs by activating α4β2 nicotinic acetylcholine receptors (nAChRs) on various GINs. Measurements of this disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feed-forward inhibition. Moreover, functional nAChRs are also present on populations of GINs that respond only weakly to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices from mice we show that upon synchronous optogenetic activation of corticostriatal projections blockade of α4β2 nAChRs shortened SPN spike latencies and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond strongly to phasic CIN activation. In particular, the observed decrease in spike latency caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, a parallel hyperpolarization of PV-FSIs, and was occluded by pharmacologically preventing cortical activation of PV-FSIs. Taken together, we describe a role for tonic (as opposed to phasic) activation of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs maintains a GABAergic brake on cortically-driven striatal output by 'priming' feedforward inhibition, a process that may shape SPN spike timing, striatal processing and synaptic plasticity.
      PubDate: 2022-05-17T00:00:00Z
      DOI: 10.7554/eLife.75829
       
  • Development and evaluation of a machine learning-based in-hospital
           COvid-19 disease outcome predictor (CODOP): a multicontinental
           retrospective study

    • Authors: Antonio Lalueza Blanco, Benjamin Leiding, Bruno Boietti, Carlos Lumbreras, David Gómez-Varela, Disha Purohit, Estela Edith Titto Omonte, Florencia Pugliese, Francisco Rivas-Ruiz, Ivan Huesped, Javier A Pollan, Jesus Millan Nunez-Cortes, José Manuel Casas-Rojo, Jose Manuel Ramos-Rincon, Juan Ignacio Ramirez, Juan Miguel Antón-Santos, Magdy Teresa Canales Beltrán, María Dolores Martin-Escalante, Mari Ángeles Onieva-Garcia, Miguel Pedrera Jimenez, Nico Funke, Noelia Garcia Barrio, Pablo Young, Pascual Ruben Valdez, Ricardo Gómez-Huelgas, Riku Klén, Rosa Castagna, Rosmery Gross Artega
      Abstract: New SARS-CoV-2 variants, breakthrough infections, waning immunity, and sub-optimal vaccination rates account for surges of hospitalizations and deaths. There is an urgent need for clinically valuable and generalizable triage tools assisting the allocation of hospital resources, particularly in resource-limited countries. We developed and validate CODOP, a machine learning-based tool for predicting the clinical outcome of hospitalized COVID-19 patients. CODOP was trained, tested and validated with six cohorts encompassing 29223 COVID-19 patients from more than 150 hospitals in Spain, the USA and Latin America during 2020-22. CODOP uses 12 clinical parameters commonly measured at hospital admission for reaching high discriminative ability up to nine days before clinical resolution (AUROC: 0·90-0·96), it is well calibrated, and it enables an effective dynamic risk stratification during hospitalization. Furthermore, CODOP maintains its predictive ability independently of the virus variant and the vaccination status. To reckon with the fluctuating pressure levels in hospitals during the pandemic, we offer two online CODOP calculators, suited for undertriage or overtriage scenarios, validated with a cohort of patients from 42 hospitals in three Latin American countries (78-100% sensitivity and 89-97% specificity). The performance of CODOP in heterogeneous and geographically disperse patient cohorts and the easiness of use strongly suggest its clinical utility, particularly in resource-limited countries.
      PubDate: 2022-05-17T00:00:00Z
      DOI: 10.7554/eLife.75985
       
  • Structure of the IL-27 quaternary receptor signaling complex

    • Authors: Caleb R Glassman, K Christopher Garcia, Kevin M Jude, Naotaka Tsutsumi, Nathanael A Caveney
      Abstract: Interleukin 27 (IL-27) is a heterodimeric cytokine that functions to constrain T cell-mediated inflammation and plays an important role in immune homeostasis. Binding of IL-27 to cell surface receptors IL-27Rα and gp130 results in activation of receptor-associated Janus Kinases and nuclear translocation of Signal Transducer and Activator of Transcription 1 (STAT1) and STAT3 transcription factors. Despite the emerging therapeutic importance of this cytokine axis in cancer and autoimmunity, a molecular blueprint of the IL-27 receptor signaling complex, and its relation to other gp130/IL-12 family cytokines, is currently unclear. We used cryogenic-electron microscopy to determine the quaternary structure of IL-27, composed of p28 and Ebi3 subunits, bound to receptors, IL-27Rα and gp130. The resulting 3.47 Å resolution structure revealed a three-site assembly mechanism nucleated by the central p28 subunit of the cytokine. The overall topology and molecular details of this binding are reminiscent of IL-6 but distinct from related heterodimeric cytokines IL-12 and IL-23. These results indicate distinct receptor assembly mechanisms used by heterodimeric cytokines with important consequences for targeted agonism and antagonism of IL-27 signaling.
      PubDate: 2022-05-17T00:00:00Z
      DOI: 10.7554/eLife.78463
       
  • Active site geometry stabilization of a presenilin homolog by the lipid
           bilayer promotes intramembrane proteolysis

    • Authors: Akio Fukumori, Harald Steiner, Lukas P Feilen, Martin Zacharias, Regina Feederle, Shu-Yu Chen
      Abstract: Cleavage of membrane proteins in the lipid bilayer by intramembrane proteases is crucial for health and disease. Although different lipid environments can potently modulate their activity, how this is linked to their structural dynamics is unclear. Here we show that the carboxy-peptidase-like activity of the archaeal intramembrane protease PSH, a homolog of the Alzheimer's disease-associated presenilin/γ-secretase is impaired in micelles and promoted in a lipid bilayer. Comparative molecular dynamics simulations revealed that important elements for substrate binding such as transmembrane domain 6a of PSH are more labile in micelles and stabilized in the lipid bilayer. Moreover, consistent with an enhanced interaction of PSH with a transition-state analog inhibitor, the bilayer promoted the formation of the enzyme´s catalytic active site geometry. Our data indicate that the lipid environment of an intramembrane protease plays a critical role in structural stabilization and active site arrangement of the enzyme-substrate complex thereby promoting intramembrane proteolysis.
      PubDate: 2022-05-17T00:00:00Z
      DOI: 10.7554/eLife.76090
       
  • Typhoid toxin sorting and exocytic transport from Salmonella Typhi
           infected cells

    • Authors: Jorge E Galan, Maria Lara-Tejero, Shu-Jung Chang, Yen-Yi Lin, Yun Chen, Yu-Ting Hsu
      Abstract: Typhoid toxin is an essential virulence factor for Salmonella Typhi, the cause of typhoid fever in humans. This toxin has an unusual biology in that it is produced by Salmonella Typhi only when located within host cells. Once synthesized, the toxin is secreted to the lumen of the Salmonella-containing vacuole from where it is transported to the extracellular space by vesicle carrier intermediates. Here we report the identification of the typhoid toxin sorting receptor and components of the cellular machinery that packages the toxin into vesicle carriers, and exports it to the extracellular space. We found that the cation-independent mannose-6-phosphate receptor serves as typhoid toxin sorting receptor and that the coat protein COPII and the GTPase Sar1 mediate its packaging into vesicle carriers. Formation of the typhoid toxin carriers requires the specific environment of the Salmonella Typhi-containing vacuole, which is determined by the activities of specific effectors of its type III protein secretion systems. We also found that Rab11B and its interacting protein Rip11 control the intracellular transport of the typhoid toxin carriers, and the SNARE proteins VAMP7, SNAP23, and Syntaxin 4 their fusion to the plasma membrane. Typhoid toxin's cooption of specific cellular machinery for its transport to the extracellular space illustrates the remarkable adaptation of an exotoxin to exert its function in the context of an intracellular pathogen.
      PubDate: 2022-05-17T00:00:00Z
      DOI: 10.7554/eLife.78561
       
  • Non-rapid eye movement sleep and wake neurophysiology in schizophrenia

    • Authors: Chenguang Jiang, Dara Manoach, Dimitrios Mylonas, Guanchen Gai, Guoqiang Wang, Hailiang Huang, James Coleman, Jen Q Pan, Jun Wang, Kai Zou, Lei A Wang, Lin Zhou, Lu Shen, Mei-Hua Hal, Michael Murphy, Nataliia Kozhemiako, Robert Law, Robert Stickgold, Shaun M Purcell, Shengying Qin, Shen Li, Shuping Tan, Wei Zhu, Xiaoman Yu, Zhenglin Guo, Zhenhe Zhou, Zhe Wang
      Abstract: Motivated by the potential of objective neurophysiological markers to index thalamocortical function in patients with severe psychiatric illnesses, we comprehensively characterized key non-rapid eye movement (NREM) sleep parameters across multiple domains, their interdependencies, and their relationship to waking event-related potentials and symptom severity. In 72 schizophrenia (SCZ) patients and 58 controls, we confirmed a marked reduction in sleep spindle density in SCZ and extended these findings to show that fast and slow spindle properties were largely uncorrelated. We also describe a novel measure of slow oscillation and spindle interaction that was attenuated in SCZ. The main sleep findings were replicated in a demographically distinct sample, and a joint model, based on multiple NREM components, statistically predicted disease status in the replication cohort. Although also altered in patients, auditory event-related potentials elicited during wake were unrelated to NREM metrics. Consistent with a growing literature implicating thalamocortical dysfunction in SCZ, our characterization identifies independent NREM and wake EEG biomarkers that may index distinct aspects of SCZ pathophysiology and point to multiple neural mechanisms underlying disease heterogeneity. This study lays the groundwork for evaluating these neurophysiological markers, individually or in combination, to guide efforts at treatment and prevention as well as identifying individuals most likely to benefit from specific interventions.
      PubDate: 2022-05-17T00:00:00Z
      DOI: 10.7554/eLife.76211
       
  • Aberrant causal inference and presence of a compensatory mechanism in
           Autism Spectrum Disorder

    • Authors: Dora E Angelaki, Jean-Paul Noel, Kalpana Dokka, Ralf M Haefner, Sabyasachi Shivkumar
      Abstract: Autism Spectrum Disorder (ASD) is characterized by a panoply of social, communicative, and sensory anomalies. As such, a central goal of computational psychiatry is to ascribe the heterogenous phenotypes observed in ASD to a limited set of canonical computations that may have gone awry in the disorder. Here, we posit causal inference - the process of inferring a causal structure linking sensory signals to hidden world causes - as one such computation. We show that audio-visual integration is intact in ASD and in line with optimal models of cue combination, yet multisensory behavior is anomalous in ASD because this group operates under an internal model favoring integration (vs. segregation). Paradoxically, during explicit reports of common cause across spatial or temporal disparities, individuals with ASD were less and not more likely to report common cause, particularly at small cue disparities. Formal model fitting revealed differences in both the prior probability for common cause (p-common) and choice biases, which are dissociable in implicit but not explicit causal inference tasks. Together, this pattern of results suggests (i) different internal models in attributing world causes to sensory signals in ASD relative to neurotypical individuals given identical sensory cues, and (ii) the presence of an explicit compensatory mechanism in ASD, with these individuals putatively having learned to compensate for their bias to integrate in explicit reports.
      PubDate: 2022-05-17T00:00:00Z
      DOI: 10.7554/eLife.71866
       
 
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