eLife
Latest Publications


TOTAL DOCUMENTS

12017
(FIVE YEARS 8763)

H-INDEX

150
(FIVE YEARS 81)

Published By "Elife Sciences Publications, Ltd."

2050-084x

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
David Dahmen ◽  
Moritz Layer ◽  
Lukas Deutz ◽  
Paulina Anna Dąbrowska ◽  
Nicole Voges ◽  
...  

Modern electrophysiological recordings simultaneously capture single-unit spiking activities of hundreds of neurons spread across large cortical distances. Yet, this parallel activity is often confined to relatively low-dimensional manifolds. This implies strong coordination also among neurons that are most likely not even connected. Here, we combine in vivo recordings with network models and theory to characterize the nature of mesoscopic coordination patterns in macaque motor cortex and to expose their origin: We find that heterogeneity in local connectivity supports network states with complex long-range cooperation between neurons that arises from multi-synaptic, short-range connections. Our theory explains the experimentally observed spatial organization of covariances in resting state recordings as well as the behaviorally related modulation of covariance patterns during a reach-to-grasp task. The ubiquity of heterogeneity in local cortical circuits suggests that the brain uses the described mechanism to flexibly adapt neuronal coordination to momentary demands.


eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Thomas S McAlear ◽  
Susanne Bechstedt

Cells increase microtubule dynamics to make large rearrangements to their microtubule cytoskeleton during cell division. Changes in microtubule dynamics are essential for the formation and function of the mitotic spindle, and misregulation can lead to aneuploidy and cancer. Using in vitro reconstitution assays we show that the mitotic spindle protein Cytoskeleton-Associated Protein 2 (CKAP2) has a strong effect on nucleation of microtubules by lowering the critical tubulin concentration 100-fold. CKAP2 increases the apparent rate constant ka of microtubule growth by 50-fold and increases microtubule growth rates. In addition, CKAP2 strongly suppresses catastrophes. Our results identify CKAP2 as the most potent microtubule growth factor to date. These finding help explain CKAP2's role as an important spindle protein, proliferation marker, and oncogene.


eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Andreas Kolbeck ◽  
Peter Marhavý ◽  
Damien De Bellis ◽  
Baohai Li ◽  
Takehiro Kamiya ◽  
...  

Efficient uptake of nutrients in both animal and plant cells requires tissue-spanning diffusion barriers separating inner tissues from the outer lumen/soil. However, we poorly understand how such contiguous three-dimensional superstructures are formed in plants. Here, we show that correct establishment of the plant Casparian Strip (CS) network relies on local neighbor communication. We show that positioning of Casparian Strip membrane domains (CSDs) is tightly coordinated between neighbors in wild-type and that restriction of domain formation involves the putative extracellular protease LOTR1. Impaired domain restriction in lotr1 leads to fully functional CSDs at ectopic positions, forming 'half strips'. LOTR1 action in the endodermis requires its expression in the stele. LOTR1 endodermal expression cannot complement, while cortex expression causes a dominant-negative phenotype. Our findings establish LOTR1 as a crucial player in CSD positioning acting in a directional, non-cell-autonomous manner to restrict and coordinate CS positioning.


eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
James A Timmons ◽  
Andrew Anighoro ◽  
Robert J Brogan ◽  
Jack Stahl ◽  
Claes Wahlestedt ◽  
...  

Insulin resistance (IR) contributes to the pathophysiology of diabetes, dementia, viral infection, and cardiovascular disease. Drug repurposing (DR) may identify treatments for IR; however, barriers include uncertainty whether in vitro transcriptomic assays yield quantitative pharmacological data, or how to optimise assay design to best reflect in vivo human disease. We developed a clinical-based human tissue IR signature by combining lifestyle-mediated treatment responses (>500 human adipose and muscle biopsies) with biomarkers of disease status (fasting IR from >1200 biopsies). The assay identified a chemically diverse set of >130 positively acting compounds, highly enriched in true positives, that targeted 73 proteins regulating IR pathways. Our multi-gene RNA assay score reflected the quantitative pharmacological properties of a set of epidermal growth factor receptor-related tyrosine kinase inhibitors, providing insight into drug target specificity; an observation supported by deep learning-based genome-wide predicted pharmacology. Several drugs identified are suitable for evaluation in patients, particularly those with either acute or severe chronic IR.


eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Daniel W Belsky ◽  
Avshalom Caspi ◽  
David L Corcoran ◽  
Karen Sugden ◽  
Richie Poulton ◽  
...  

Background: Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Previously we showed that quantification of the pace of biological aging from a DNA-methylation blood test was possible (Belsky et al. 2020). Here we report a next-generation DNA-methylation biomarker of Pace of Aging, DunedinPACE (for Pace of Aging Calculated from the Epigenome).Methods: We used data from the Dunedin Study 1972-3 birth cohort tracking within-individual decline in 19 indicators of organ-system integrity across four time points spanning two decades to model Pace of Aging. We distilled this two-decade Pace of Aging into a single-time-point DNA-methylation blood-test using elastic-net regression and a DNA-methylation dataset restricted to exclude probes with low test-retest reliability. We evaluated the resulting measure, named DunedinPACE, in five additional datasets.Results: DunedinPACE showed high test-retest reliability, was associated with morbidity, disability, and mortality, and indicated faster aging in young adults with childhood adversity. DunedinPACE effect-sizes were similar to GrimAge Clock effect-sizes. In analysis of incident morbidity, disability, and mortality, DunedinPACE and added incremental prediction beyond GrimAge.Conclusions: DunedinPACE is a novel blood biomarker of the pace of aging for gerontology and geroscience.Funding: This research was supported by US-National Institute on Aging grants AG032282, AG061378, AG066887, and UK Medical Research Council grant MR/P005918/1.


eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Minyan Zheng ◽  
Olga Zueva ◽  
Veronica Hinman

The ability to restore lost body parts following traumatic injury is a fascinating area of biology that challenges current understanding of the ontogeny of differentiation. The origin of new cells needed to regenerate lost tissue, and whether they are pluripotent stem cells, tissue-specific stem cells or have de- or trans- differentiated, remains one of the most important open questions in regeneration. Additionally, it is not clearly known whether developmental gene regulatory networks (GRNs) are reused to direct specification in these cells or whether regeneration specific networks are deployed. Echinoderms, including sea stars, have extensive ability for regeneration and have therefore been the subject of many thorough studies on the ultrastructural and molecular properties of cells needed for regeneration. However, the technologies for obtaining transgenic echinoderms are limited and tracking cells involved in regeneration, and thus identifying the cellular sources and potencies has proven challenging. In this study we develop new transgenic tools to follow the fate of populations of cells in the regenerating bipinnaria larva of the sea star Patira minaita. We show that the larval serotonergic nervous system can regenerate following decapitation. Using a BAC-transgenesis approach with photoconvertible fluorescent proteins, we show that expression of the pan ectodermal marker, sox2, is induced in previously sox2 minus cells at the wound site, even when cell division is inhibited. sox2+ cells give rise to new sox4+ neural precursors that then proceed along an embryonic neurogenesis pathway to reform the anterior nervous systems. sox2+ cells contribute to only neural and ectoderm lineages, indicating that these progenitors maintain their normal, embryonic lineage restriction. This indicates that sea star larval regeneration uses a combination of existing lineage restricted stem cells, as well as respecification of cells into neural lineages, and at least partial reuse of developmental GRNs to regenerate their nervous system.


eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Sarah E Westrick ◽  
Mara Laslo ◽  
Eva Fischer

The Puerto Rican coquí frog Eleutherodactylus coqui (E. coqui) is both a cultural icon and a species with an unusual natural history that has attracted attention from researchers in a number of different fields within biology. Unlike most frogs, the coquí frog skips the tadpole stage, which makes it of interest to developmental biologists. The frog is best known in Puerto Rico for its notoriously loud mating call, which has allowed researchers to study aspects of social behavior such as vocal communication and courtship, while the ability of coquí to colonize new habitats has been used to explore the biology of invasive species. This article reviews research on the natural history of E. coqui and opportunities for future research.


eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Iga Kucharska ◽  
Lamia Hossain ◽  
Danton Ivanochko ◽  
Qiren Yang ◽  
John L Rubinstein ◽  
...  

Malaria is a global health burden, with Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) responsible for the majority of infections worldwide. Circumsporozoite protein (CSP) is the most abundant protein on the surface of Plasmodium sporozoites, and antibodies targeting the central repeat region of CSP can prevent parasite infection. Although much has been uncovered about the molecular basis of antibody recognition of the PfCSP repeats, data remains scarce for PvCSP. Here, we performed molecular dynamics simulations for peptides comprising the PvCSP repeats from strains VK210 and VK247 to reveal how the PvCSP central repeats are highly disordered, with minor propensities to adopt turn conformations. Next, we solved eight crystal structures to unveil the interactions of two inhibitory monoclonal antibodies (mAbs), 2F2 and 2E10.E9, with PvCSP repeats. Both antibodies can accommodate subtle sequence variances in the repeat motifs and recognize largely coiled peptide conformations that also contain isolated turns. Our structural studies uncover various degrees of Fab-Fab homotypic interactions upon recognition of the PvCSP central repeats by these two inhibitory mAbs, similar to potent mAbs against PfCSP. These findings augment our understanding of host-Plasmodium interactions, and contribute molecular details of Pv inhibition by mAbs to unlock structure-based engineering of PvCSP-based vaccines.


eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Ananya Chakravarti ◽  
Heshani N Thirimanne ◽  
Savanna Brown ◽  
Brian R Calvi

p53 gene family members in humans and other organisms encode a large number of protein isoforms whose functions are largely undefined. Using Drosophila as a model, we find that a p53B isoform is expressed predominantly in the germline where it colocalizes with p53A into subnuclear bodies. It is only p53A, however, that mediates the apoptotic response to ionizing radiation in the germline and soma. In contrast, p53A and p53B are both required for the normal repair of meiotic DNA breaks, an activity that is more crucial when meiotic recombination is defective. We find that in oocytes with persistent DNA breaks p53A is also required to activate a meiotic pachytene checkpoint. Our findings indicate that Drosophila p53 isoforms have DNA lesion and cell type-specific functions, with parallels to the functions of mammalian p53 family members in the genotoxic stress response and oocyte quality control.


eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Lucas C Pantaleao ◽  
Isabella Inzani ◽  
Samuel Furse ◽  
Elena Loche ◽  
Antonia Hufnagel ◽  
...  

Maternal obesity during pregnancy has immediate and long-term detrimental effects on the offspring heart. In this study, we characterized the cardiac and circulatory lipid profiles in late gestation E18.5 fetuses of diet-induced obese pregnant mice and established the changes in lipid abundance and fetal cardiac transcriptomics. We used untargeted and targeted lipidomics and transcriptomics to define changes in the serum and cardiac lipid composition and fatty acid metabolism in male and female fetuses. From these analyses we observed: (1) maternal obesity affects the maternal and fetal serum lipidome distinctly; (2) female fetal heart lipidomes are more sensitive to maternal obesity than males; (3) changes in lipid supply might contribute to early expression of lipolytic genes in mouse hearts exposed to maternal obesity. These results highlight the existence of sexually dimorphic responses of the fetal heart to the same in utero obesogenic environment and identify lipids species that might mediate programming of cardiovascular health.


Sign in / Sign up

Export Citation Format

Share Document