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  • Articles  (22)
  • Latest Papers from Table of Contents or Articles in Press  (22)
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  • 1
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    Growth-dependent signals drive an increase in early G1 cyclin concentration to link cell cycle entry with cell growth (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-29
    Description: Entry into the cell cycle occurs only when sufficient growth has occurred. In budding yeast, the cyclin Cln3 is thought to initiate cell cycle entry by inactivating a transcriptional repressor called Whi5. Growth-dependent changes in the concentrations of Cln3 or Whi5 have been proposed to link cell cycle entry to cell growth. However, there are conflicting reports regarding the behavior and roles of Cln3 and Whi5. Here, we found no evidence that changes in the concentration of Whi5 play a major role in controlling cell cycle entry. Rather, the data suggest that cell growth triggers cell cycle entry by driving an increase in the concentration of Cln3. We further found that accumulation of Cln3 is dependent upon homologs of mammalian SGK kinases that control cell growth and size. Together, the data are consistent with models in which Cln3 is a crucial link between cell growth and the cell cycle.
    Electronic ISSN: 2050-084X
    Topics: Biology , Medicine , Natural Sciences in General
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  • 2
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    A single synonymous nucleotide change impacts the male-killing phenotype of prophage WO gene wmk (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-22
    Description: Wolbachia are the most widespread bacterial endosymbionts in animals. Within arthropods, these maternally transmitted bacteria can selfishly hijack host reproductive processes to increase the relative fitness of their transmitting females. One such form of reproductive parasitism called male killing, or the selective killing of infected males, is recapitulated to degrees by transgenic expression of the prophage WO-mediated killing (wmk) gene. Here, we characterize the genotype-phenotype landscape of wmk-induced male killing in D. melanogaster using transgenic expression. While phylogenetically distant wmk homologs induce no sex-ratio bias, closely-related homologs exhibit complex phenotypes spanning no death, male death, or death of all hosts. We demonstrate that alternative start codons, synonymous codons, and notably a single synonymous nucleotide in wmk can ablate killing. These findings reveal previously unrecognized features of transgenic wmk-induced killing and establish new hypotheses for the impacts of post-transcriptional processes in male killing variation. We conclude that synonymous sequence changes are not necessarily silent in nested endosymbiotic interactions with life-or-death consequences.
    Electronic ISSN: 2050-084X
    Topics: Biology , Medicine , Natural Sciences in General
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  • 3
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    Sequence features of retrotransposons allow for epigenetic variability (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-20
    Description: Transposable elements (TEs) are mobile genetic elements that make up a large fraction of mammalian genomes. While select TEs have been co-opted in host genomes to have function, the majority of these elements are epigenetically silenced by DNA methylation in somatic cells. However, some TEs in mice, including the Intracisternal A-particle (IAP) subfamily of retrotransposons, have been shown to display interindividual variation in DNA methylation. Recent work has revealed that IAP sequence differences and strain-specific KRAB zinc finger proteins (KZFPs) may influence the methylation state of these IAPs. However, the mechanisms underlying the establishment and maintenance of interindividual variability in DNA methylation still remain unclear. Here, we report that sequence content and genomic context influence the likelihood that IAPs become variably methylated. IAPs that differ from consensus IAP sequences have altered KZFP recruitment that can lead to decreased KAP1 recruitment when in proximity of constitutively expressed genes. These variably methylated loci have a high CpG density, similar to CpG islands, and can be bound by ZF-CxxC proteins, providing a potential mechanism to maintain this permissive chromatin environment and protect from DNA methylation. These observations indicate that variably methylated IAPs escape silencing through both attenuation of KZFP binding and recognition by ZF-CxxC proteins to maintain a hypomethylated state.
    Electronic ISSN: 2050-084X
    Topics: Biology , Medicine , Natural Sciences in General
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  • 4
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    Humans use forward thinking to exploit social controllability (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-29
    Description: The controllability of our social environment has a profound impact on our behavior and mental health. Nevertheless, neurocomputational mechanisms underlying social controllability remain elusive. Here, 48 participants performed a task where their current choices either did (Controllable), or did not (Uncontrollable), influence partners’ future proposals. Computational modeling revealed that people engaged a mental model of forward thinking (FT; i.e., calculating the downstream effects of current actions) to estimate social controllability in both Controllable and Uncontrollable conditions. A large-scale online replication study (n=1342) supported this finding. Using functional magnetic resonance imaging (n=48), we further demonstrated that the ventromedial prefrontal cortex (vmPFC) computed the projected total values of current actions during forward planning, supporting the neural realization of the forward-thinking model. These findings demonstrate that humans use vmPFC-dependent FT to estimate and exploit social controllability, expanding the role of this neurocomputational mechanism beyond spatial and cognitive contexts.
    Electronic ISSN: 2050-084X
    Topics: Biology , Medicine , Natural Sciences in General
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  • 5
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    Paths and pathways that generate cell-type heterogeneity and developmental progression in hematopoiesis (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-29
    Description: Mechanistic studies of Drosophila lymph gland hematopoiesis are limited by the availability of cell-type specific markers. Using a combination of bulk RNA-Seq of FACS-sorted cells, single cell RNA-Seq, and genetic dissection, we identify new blood cell subpopulations along a developmental trajectory with multiple paths to mature cell types. This provides functional insights into key developmental processes and signaling pathways. We highlight metabolism as a driver of development, show that graded Pointed expression allows distinct roles in successive developmental steps, and that mature crystal cells specifically express an alternate isoform of Hypoxia-inducible factor (Hif/Sima). Mechanistically, the Musashi-regulated protein Numb facilitates Sima-dependent non-canonical, and inhibits canonical, Notch signaling. Broadly, we find that prior to making a fate choice, a progenitor selects between alternative, biologically relevant, transitory states allowing smooth transitions reflective of combinatorial expressions rather than stepwise binary decisions. Increasingly, this view is gaining support in mammalian hematopoiesis.
    Electronic ISSN: 2050-084X
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  • 6
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    Genetically engineered mice for combinatorial cardiovascular optobiology (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-29
    Description: Optogenetic effectors and sensors provide a novel real-time window into complex physiological processes, enabling determination of molecular signaling processes within functioning cellular networks. However, the combination of these optical tools in mice is made practical by construction of genetic lines that are optically compatible and genetically tractable. We present a new toolbox of 21 mouse lines with lineage-specific expression of optogenetic effectors and sensors for direct biallelic combination, avoiding the multiallelic requirement of Cre recombinase -mediated DNA recombination, focusing on models relevant for cardiovascular biology. Optogenetic effectors (11 lines) or Ca2+ sensors (10 lines) were selectively expressed in cardiac pacemaker cells, cardiomyocytes, vascular endothelial and smooth muscle cells, alveolar epithelial cells, lymphocytes, glia, and other cell types. Optogenetic effector and sensor function was demonstrated in numerous tissues. Arterial/arteriolar tone was modulated by optical activation of the second messengers InsP3 (optoα1AR) and cAMP (optoß2AR), or Ca2+-permeant membrane channels (CatCh2) in smooth muscle (Acta2) and endothelium (Cdh5). Cardiac activation was separately controlled through activation of nodal/conducting cells or cardiac myocytes. We demonstrate combined effector and sensor function in biallelic mouse crosses: optical cardiac pacing and simultaneous cardiomyocyte Ca2+ imaging in Hcn4BAC-CatCh2/Myh6-GCaMP8 crosses. These experiments highlight the potential of these mice to explore cellular signaling in vivo, in complex tissue networks.
    Electronic ISSN: 2050-084X
    Topics: Biology , Medicine , Natural Sciences in General
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  • 7
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    Neuronal activity in dorsal anterior cingulate cortex during economic choices under variable action costs (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-13
    Description: The role of the dorsal anterior cingulate cortex (ACCd) in decision making has often been discussed but remains somewhat unclear. On the one hand, numerous studies implicated this area in decisions driven by effort or action cost. On the other hand, work on economic choices between goods (under fixed action costs) found that neurons in ACCd encoded only post-decision variables. To advance our understanding of the role played by this area in decision making, we trained monkeys to choose between different goods (juice types) offered in variable amounts and with different action costs. Importantly, the task design dissociated computation of the action cost from planning of any particular action. Neurons in ACCd encoded the chosen value and the binary choice outcome in several reference frames (chosen juice, chosen cost, chosen action). Thus, this area provided a rich representation of post-decision variables. In contrast to the OFC, neurons in ACCd did not represent pre-decision variables such as individual offer values in any reference frame. Hence, ongoing decisions are unlikely guided by ACCd. Conversely, neuronal activity in this area might inform subsequent actions.
    Electronic ISSN: 2050-084X
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  • 8
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    The decoy SNARE Tomosyn sets tonic versus phasic release properties and is required for homeostatic synaptic plasticity (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-29
    Description: Synaptic vesicle release probability (Pr) is a key presynaptic determinant of synaptic strength established by cell intrinsic properties and further refined by plasticity. To characterize mechanisms that generate Pr heterogeneity between distinct neuronal populations, we examined glutamatergic tonic (Ib) and phasic (Is) motoneurons in Drosophila with stereotyped differences in Pr and synaptic plasticity. We found the decoy SNARE Tomosyn is differentially expressed between these motoneuron subclasses and contributes to intrinsic differences in their synaptic output. Tomosyn expression enables tonic release in Ib motoneurons by reducing SNARE complex formation and suppressing Pr to generate decreased levels of synaptic vesicle fusion and enhanced resistance to synaptic fatigue. In contrast, phasic release dominates when Tomosyn expression is low, enabling high intrinsic Pr at Is terminals at the expense of sustained release and robust presynaptic potentiation. In addition, loss of Tomosyn disrupts the ability of tonic synapses to undergo presynaptic homeostatic potentiation (PHP).
    Electronic ISSN: 2050-084X
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  • 9
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    An experimental test of the effects of redacting grant applicant identifiers on peer review outcomes (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-19
    Description: Background:Blinding reviewers to applicant identity has been proposed to reduce bias in peer review.Methods:This experimental test used 1200 NIH grant applications, 400 from Black investigators, 400 matched applications from White investigators, and 400 randomly selected applications from White investigators. Applications were reviewed by mail in standard and redacted formats.Results:Redaction reduced, but did not eliminate, reviewers’ ability to correctly guess features of identity. The primary, preregistered analysis hypothesized a differential effect of redaction according to investigator race in the matched applications. A set of secondary analyses (not preregistered) used the randomly selected applications from White scientists and tested the same interaction. Both analyses revealed similar effects: Standard format applications from White investigators scored better than those from Black investigators. Redaction cut the size of the difference by about half (e.g. from a Cohen’s d of 0.20–0.10 in matched applications); redaction caused applications from White scientists to score worse but had no effect on scores for Black applications.Conclusions:Grant-writing considerations and halo effects are discussed as competing explanations for this pattern. The findings support further evaluation of peer review models that diminish the influence of applicant identity.Funding:Funding was provided by the NIH.
    Electronic ISSN: 2050-084X
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  • 10
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    Mechanical overstimulation causes acute injury and synapse loss followed by fast recovery in lateral-line neuromasts of larval zebrafish (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-19
    Description: Excess noise damages sensory hair cells, resulting in loss of synaptic connections with auditory nerves and, in some cases, hair-cell death. The cellular mechanisms underlying mechanically induced hair-cell damage and subsequent repair are not completely understood. Hair cells in neuromasts of larval zebrafish are structurally and functionally comparable to mammalian hair cells but undergo robust regeneration following ototoxic damage. We therefore developed a model for mechanically induced hair-cell damage in this highly tractable system. Free swimming larvae exposed to strong water wave stimulus for 2 hr displayed mechanical injury to neuromasts, including afferent neurite retraction, damaged hair bundles, and reduced mechanotransduction. Synapse loss was observed in apparently intact exposed neuromasts, and this loss was exacerbated by inhibiting glutamate uptake. Mechanical damage also elicited an inflammatory response and macrophage recruitment. Remarkably, neuromast hair-cell morphology and mechanotransduction recovered within hours following exposure, suggesting severely damaged neuromasts undergo repair. Our results indicate functional changes and synapse loss in mechanically damaged lateral-line neuromasts that share key features of damage observed in noise-exposed mammalian ear. Yet, unlike the mammalian ear, mechanical damage to neuromasts is rapidly reversible.
    Electronic ISSN: 2050-084X
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  • 11
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    Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-13
    Description: The gene regulatory networks that coordinate the development of the cardiac and pulmonary systems are essential for terrestrial life but poorly understood. The T-box transcription factor Tbx5 is critical for both pulmonary specification and heart development, but how these activities are mechanistically integrated remains unclear. Here using Xenopus and mouse embryos, we establish molecular links between Tbx5 and retinoic acid (RA) signaling in the mesoderm and between RA signaling and sonic hedgehog expression in the endoderm to unveil a conserved RA-Hedgehog-Wnt signaling cascade coordinating cardiopulmonary (CP) development. We demonstrate that Tbx5 directly maintains expression of aldh1a2, the RA-synthesizing enzyme, in the foregut lateral plate mesoderm via an evolutionarily conserved intronic enhancer. Tbx5 promotes posterior second heart field identity in a positive feedback loop with RA, antagonizing a Fgf8-Cyp regulatory module to restrict FGF activity to the anterior. We find that Tbx5/Aldh1a2-dependent RA signaling directly activates shh transcription in the adjacent foregut endoderm through a conserved MACS1 enhancer. Hedgehog signaling coordinates with Tbx5 in the mesoderm to activate expression of wnt2/2b, which induces pulmonary fate in the foregut endoderm. These results provide mechanistic insight into the interrelationship between heart and lung development informing CP evolution and birth defects.
    Electronic ISSN: 2050-084X
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  • 12
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    Intergenerational adaptations to stress are evolutionarily conserved, stress-specific, and have deleterious trade-offs (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-08
    Description: Despite reports of parental exposure to stress promoting physiological adaptations in progeny in diverse organisms, there remains considerable debate over the significance and evolutionary conservation of such multigenerational effects. Here, we investigate four independent models of intergenerational adaptations to stress in Caenorhabditis elegans – bacterial infection, eukaryotic infection, osmotic stress, and nutrient stress – across multiple species. We found that all four intergenerational physiological adaptations are conserved in at least one other species, that they are stress -specific, and that they have deleterious tradeoffs in mismatched environments. By profiling the effects of parental bacterial infection and osmotic stress exposure on progeny gene expression across species, we established a core set of 587 genes that exhibited a greater than twofold intergenerational change in expression in response to stress in C. elegans and at least one other species, as well as a set of 37 highly conserved genes that exhibited a greater than twofold intergenerational change in expression in all four species tested. Furthermore, we provide evidence suggesting that presumed adaptive and deleterious intergenerational effects are molecularly related at the gene expression level. Lastly, we found that none of the effects we detected of these stresses on C. elegans F1 progeny gene expression persisted transgenerationally three generations after stress exposure. We conclude that intergenerational responses to stress play a substantial and evolutionarily conserved role in regulating animal physiology and that the vast majority of the effects of parental stress on progeny gene expression are reversible and not maintained transgenerationally.
    Electronic ISSN: 2050-084X
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  • 13
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    β-Catenin-NF-κB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-05
    Description: Expansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic mouse knockouts of β-catenin, one with β-catenin loss is hepatocytes and BECs (KO1), and another with loss in only hepatocytes (KO2), we demonstrate disparate long-term repair after an initial injury by 2-week choline-deficient ethionine-supplemented diet. KO2 show gradual liver repopulation with BEC-derived β-catenin-positive hepatocytes and resolution of injury. KO1 showed persistent loss of β-catenin, NF-κB activation in BECs, progressive DR and fibrosis, reminiscent of CF histology. We identify interactions of β-catenin, NFκB, and CF transmembranous conductance regulator (CFTR) in BECs. Loss of CFTR or β-catenin led to NF-κB activation, DR, and inflammation. Thus, we report a novel β-catenin-NFκB-CFTR interactome in BECs, and its disruption may contribute to hepatic pathology of CF.
    Electronic ISSN: 2050-084X
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  • 14
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    DDK/Hsk1 phosphorylates and targets fission yeast histone deacetylase Hst4 for degradation to stabilize stalled DNA replication forks (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-05
    Description: In eukaryotes, paused replication forks are prone to collapse, which leads to genomic instability, a hallmark of cancer. Dbf4-dependent kinase (DDK)/Hsk1Cdc7 is a conserved replication initiator kinase with conflicting roles in replication stress response. Here, we show that fission yeast DDK/Hsk1 phosphorylates sirtuin, Hst4 upon replication stress at C-terminal serine residues. Phosphorylation of Hst4 by DDK marks it for degradation via the ubiquitin ligase SCFpof3. Phosphorylation-defective hst4 mutant (4SA-hst4) displays defective recovery from replication stress, faulty fork restart, slow S-phase progression and decreased viability. The highly conserved fork protection complex (FPC) stabilizes stalled replication forks. We found that the recruitment of FPC components, Swi1 and Mcl1 to the chromatin is compromised in the 4SA-hst4 mutant, although whole cell levels increased. These defects are dependent upon H3K56ac and independent of intra S-phase checkpoint activation. Finally, we show conservation of H3K56ac-dependent regulation of Timeless, Tipin, and And-1 in human cells. We propose that degradation of Hst4 via DDK increases H3K56ac, changing the chromatin state in the vicinity of stalled forks facilitating recruitment and function of FPC. Overall, this study identified a crucial role of DDK and FPC in the regulation of replication stress response with implications in cancer therapeutics.
    Electronic ISSN: 2050-084X
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  • 15
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    Two different cell-cycle processes determine the timing of cell division in Escherichia coli (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-06
    Description: Cells must control the cell cycle to ensure that key processes are brought to completion. In Escherichia coli, it is controversial whether cell division is tied to chromosome replication or to a replication-independent inter-division process. A recent model suggests instead that both processes may limit cell division with comparable odds in single cells. Here, we tested this possibility experimentally by monitoring single-cell division and replication over multiple generations at slow growth. We then perturbed cell width, causing an increase of the time between replication termination and division. As a consequence, replication became decreasingly limiting for cell division, while correlations between birth and division and between subsequent replication-initiation events were maintained. Our experiments support the hypothesis that both chromosome replication and a replication-independent inter-division process can limit cell division: the two processes have balanced contributions in non-perturbed cells, while our width perturbations increase the odds of the replication-independent process being limiting.
    Electronic ISSN: 2050-084X
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  • 16
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    Piezo1 ion channels inherently function as independent mechanotransducers (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-29
    Description: Piezo1 is a mechanically activated ion channel involved in sensing forces in various cell types and tissues. Cryo-electron microscopy has revealed that the Piezo1 structure is bowl-shaped and capable of inducing membrane curvature via its extended footprint, which indirectly suggests that Piezo1 ion channels may bias each other’s spatial distribution and interact functionally. Here, we use cell-attached patch-clamp electrophysiology and pressure-clamp stimulation to functionally examine large numbers of membrane patches from cells expressing Piezo1 endogenously at low levels and cells overexpressing Piezo1 at high levels. Our data, together with stochastic simulations of Piezo1 spatial distributions, show that both at endogenous densities (1–2 channels/μm2), and at non-physiological densities (10–100 channels/μm2) predicted to cause substantial footprint overlap, Piezo1 density has no effect on its pressure sensitivity or open probability in the nominal absence of membrane tension. The results suggest that Piezo channels, at densities likely to be physiologically relevant, inherently behave as independent mechanotransducers. We propose that this property is essential for cells to transduce forces homogeneously across the entire cell membrane.
    Electronic ISSN: 2050-084X
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  • 17
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    Impaired HA-specific T follicular helper cell and antibody responses to influenza vaccination are linked to inflammation in humans (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-29
    Description: Antibody production following vaccination can provide protective immunity to subsequent infection by pathogens such as influenza viruses. However, circumstances where antibody formation is impaired after vaccination, such as in older people, require us to better understand the cellular and molecular mechanisms that underpin successful vaccination in order to improve vaccine design for at-risk groups. Here, by studying the breadth of anti-haemagglutinin (HA) IgG, serum cytokines, and B and T cell responses by flow cytometry before and after influenza vaccination, we show that formation of circulating T follicular helper (cTfh) cells was associated with high-titre antibody responses. Using Major Histocompatability Complex (MHC) class II tetramers, we demonstrate that HA-specific cTfh cells can derive from pre-existing memory CD4+ T cells and have a diverse T cell receptor (TCR) repertoire. In older people, the differentiation of HA-specific cells into cTfh cells was impaired. This age-dependent defect in cTfh cell formation was not due to a contraction of the TCR repertoire, but rather was linked with an increased inflammatory gene signature in cTfh cells. Together, this suggests that strategies that temporarily dampen inflammation at the time of vaccination may be a viable strategy to boost optimal antibody generation upon immunisation of older people.
    Electronic ISSN: 2050-084X
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  • 18
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    Different B cell subpopulations show distinct patterns in their IgH repertoire metrics (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-18
    Description: Several human B cell subpopulations are recognised in the peripheral blood, which play distinct roles in the humoral immune response. These cells undergo developmental and maturational changes involving VDJ recombination, somatic hypermutation and class switch recombination, altogether shaping their immunoglobulin heavy chain (IgH) repertoire. Here, we sequenced the IgH repertoire of naïve, marginal zone, switched and plasma cells from 10 healthy adults along with matched unsorted and in silico separated CD19+ bulk B cells. Using advanced bioinformatic analysis and machine learning, we show that sorted B cell subpopulations are characterised by distinct repertoire characteristics on both the individual sequence and the repertoire level. Sorted subpopulations shared similar repertoire characteristics with their corresponding in silico separated subsets. Furthermore, certain IgH repertoire characteristics correlated with the position of the constant region on the IgH locus. Overall, this study provides unprecedented insight over mechanisms of B cell repertoire control in peripherally circulating B cell subpopulations.
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  • 19
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    TAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiological states (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-08
    Description: The elucidation of the mechanisms whereby the liver maintains glucose homeostasis is crucial for the understanding of physiological and pathological states. Here, we show a novel role of hepatic transcriptional co-activator with PDZ-binding motif (TAZ) in the inhibition of glucocorticoid receptor (GR). TAZ is abundantly expressed in pericentral hepatocytes and its expression is markedly reduced by fasting. TAZ interacts via its WW domain with the ligand-binding domain of GR to limit the binding of GR to the GR response element in gluconeogenic gene promoters. Therefore, liver-specific TAZ knockout mice show increases in glucose production and blood glucose concentration. Conversely, the overexpression of TAZ in mouse liver reduces the binding of GR to gluconeogenic gene promoters and glucose production. Thus, our findings demonstrate that hepatic TAZ inhibits GR transactivation of gluconeogenic genes and coordinates gluconeogenesis in response to physiological fasting and feeding.
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  • 20
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    The consequences of group structure and efficiency benefits for the evolution of division of labour (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-29
    Description: Recent theory has overturned the assumption that accelerating returns from individual specialisation are required to favour the evolution of division of labour. Yanni et al. (2020) showed that topologically constrained groups, where cells cooperate with only direct neighbours such as for filaments or branching growths, can evolve a reproductive division of labour even with diminishing returns from individual specialisation. We develop a conceptual framework and specific models to investigate the factors that can favour the initial evolution of reproductive division of labour. We find that selection for division of labour in topologically constrained groups: (1) is not a single mechanism to favour division of labour - depending upon details of the group structure, division of labour can be favoured for different reasons; (2) always involves an efficiency benefit at the level of group fitness; and (3) requires a mechanism of coordination to determine which individuals perform which tasks. Given that such coordination must evolve prior to or concurrently with division of labour, this could limit the extent to which topological constraints favoured the initial evolution of division of labour. We conclude by suggesting experimental designs that could determine why division of labour is favoured in the natural world.
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  • 21
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    Genetic, cellular and structural characterization of the membrane potential-dependent cell-penetrating peptide translocation pore (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-29
    Description: Cell-penetrating peptides (CPPs) allow intracellular delivery of bioactive cargo molecules. The mechanisms allowing CPPs to enter cells are ill-defined. Using a CRISPR/Cas9-based screening, we discovered that KCNQ5, KCNN4, and KCNK5 potassium channels positively modulate cationic CPP direct translocation into cells by decreasing the transmembrane potential (Vm). These findings provide the first unbiased genetic validation of the role of Vm in CPP translocation in cells. In silico modeling and live cell experiments indicate that CPPs, by bringing positive charges on the outer surface of the plasma membrane, decrease the Vm to very low values (-150 mV or less), a situation we have coined megapolarization that then triggers formation of water pores used by CPPs to enter cells. Megapolarization lowers the free energy barrier associated with CPP membrane translocation. Using dyes of varying dimensions in CPP co-entry experiments, the diameter of the water pores in living cells was estimated to be 2(-5) nm, in accordance with the structural characteristics of the pores predicted by in silico modeling. Pharmacological manipulation to lower transmembrane potential boosted CPPs cellular internalization in zebrafish and mouse models. Besides identifying the first proteins that regulate CPP translocation, this work characterized key mechanistic steps used by CPPs to cross cellular membrane. This opens the ground for strategies aimed at improving the ability of cells to capture CPP-linked cargos in vitro and in vivo.
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  • 22
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    Causal roles of prefrontal cortex during spontaneous perceptual switching are determined by brain state dynamics (2021)
    eLife Sciences Publications
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    Publication Date: 2021-10-29
    Description: The prefrontal cortex (PFC) is thought to orchestrate cognitive dynamics. However, in tests of bistable visual perception, no direct evidence supporting such presumable causal roles of the PFC has been reported. Here, using a novel brain-state-dependent neural stimulation system, we identified causal effects on percept dynamics in three PFC activities-right frontal eye fields, dorsolateral PFC (DLPFC) and inferior frontal cortex (IFC)-. The causality is behaviourally detectable only when we track brain state dynamics and modulate the PFC activity in brain-state-/state-history-dependent manners. The behavioural effects are underpinned by transient neural changes in the brain state dynamics, and such neural effects are quantitatively explainable by structural transformations of the hypothetical energy landscapes. Moreover, these findings indicate distinct functions of the three PFC areas: in particular, the DLPFC enhances the integration of two PFC-active brain states, whereas IFC promotes the functional segregation between them. This work resolves the controversy over the PFC roles in spontaneous perceptual switching and underlines brain state dynamics in fine investigations of brain-behaviour causality.
    Electronic ISSN: 2050-084X
    Topics: Biology , Medicine , Natural Sciences in General
    Published by eLife Sciences Publications
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