Biology subjects

Sakai, S.

Publications and source records attributed to Sakai, S..

24 records · Page 2Linked to original sources

bioRxiv2020

Extracellular DJ-1 induces sterile inflammation in the ischemic brain

Inflammation is implicated in the onset and progression of various diseases, including cerebral pathologies. Here we report that DJ-1, which plays a role within cells as an antioxidant protein, functions as a damage-associated molecular pattern (DAMP), and triggers inflammation if released from dead cells into the extracellular space. We first found that recombinant DJ-1 protein induces the production of various inflammatory cytokines in bone marrow-derived macrophages (BMMs). We further identified a unique peptide sequence in the G and H helices of DJ-1 that activates Toll-like receptor 2 (TLR2) and TLR4. In the ischemic brain, DJ-1 is released into the extracellular space from necrotic neurons within 24 hours after stroke onset and makes direct contact with the surfaces of infiltrating myeloid cells. Administration of an antibody against DJ-1 suppresses the expression of inflammatory cytokines in infiltrating immune cells and attenuates ischemic neuronal damage. Our results demonstrate a previously unknown function of DJ-1 as a DAMP and suggest that extracellular DJ-1 could be a therapeutic target to prevent inflammation in tissue injuries and neurodegenerative diseases. Significance statementDJ-1 has been thoroughly investigated as a cytoprotective antioxidant protein in neurons. However, here we demonstrate that extracellularly released DJ-1 triggers neurotoxic inflammation after ischemic stroke. Intracellular DJ-1 increases in response to oxidative stress in ischemic neurons, but if ischemic stresses result in necrotic cell death, DJ-1 is released extracellularly. Released DJ-1 interacts with TLR2 and TLR4 on the surface of infiltrating myeloid cells and triggers post-ischemic inflammation, leading to the exacerbated pathologies of ischemic stroke. Thus, extracellular DJ-1 is a previously unknown inflammatogenic DAMP, and may be a putative target for therapeutic intervention to prevent progression of inflammatory and neurodegenerative diseases.

immunology↗

bioRxiv2020

PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques

Boosting immune cell function by targeting the co-inhibitory receptor PD-1 may have applications in the treatment of chronic infections. Here we examine the role of PD-1 during Mycobacterium tuberculosis (Mtb) infection of rhesus macaques. Animals treated with PD-1 mAb developed worse disease and higher granuloma bacterial loads compared to isotype control treated monkeys. PD-1 blockade increased the number and functionality of granuloma Mtb-specific CD8 T cells. In contrast, Mtb-specific CD4 T cells in PD-1 treated macaques were not increased in number or function in granulomas, upregulated high levels of CTLA-4 and exhibited reduced intralesional trafficking in live imaging studies. In granulomas of PD-1 treated animals, multiple pro-inflammatory cytokines were elevated, and more cytokines correlated with bacterial loads, leading to the identification of a role for caspase 1 in the exacerbation of tuberculosis after PD-1 blockade. Lastly, increased Mtb bacterial loads after PD-1 blockade were found to associate with the composition of the intestinal microbiota prior to infection in individual macaques. Therefore, PD-1-mediated co-inhibition is required for control of Mtb infection in macaques, perhaps due to its role in dampening detrimental inflammation as well as allowing for normal CD4 T cell responses.

immunology↗

bioRxiv2019

Maintenance of High Inbreeding Depression in Selfing Populations: Effects of Coupling of Early- and Late-Acting Mutations

High estimates of inbreeding depression have been obtained in many plant populations with high selfing rates. However, deleterious mutations might be purged from such populations as a result of selfing. I developed a simulation model assuming the presence of mutations at two sets of loci, namely, early- and late-acting loci, and the selective abortion of embryos coupled with ovule overproduction. In the model, early-acting loci are expressed during embryo initiation, and less vigorous embryos are aborted. Late-acting loci are expressed after selective abortion ends; the surviving embryos (seeds) compete, and some of them form the next generation. If mutations are allowed to occur in both early- and late-acting loci, they increase in frequency in populations with high selfing rates in both sets of loci. However, this phenomenon does not occur if mutations occur in only the early- or late-acting loci. Consistent results are observed even if the total number of loci in which mutations are allowed to occur is the same among simulations with both early- and late-acting loci or only early- or late-acting loci, indicating that the presence of both sets of loci is the causal factor. Thus, the coupling effects of early- and late-acting mutations promote the maintenance of these mutations in populations with high selfing rates.

evolutionary biology↗

bioRxiv2019

Isolation of an archaeon at the prokaryote-eukaryote interface

The origin of eukaryotes remains enigmatic. Current data suggests that eukaryotes may have risen from an archaeal lineage known as \"Asgard archaea\". Despite the eukaryote-like genomic features found in these archaea, the evolutionary transition from archaea to eukaryotes remains unclear due to the lack of cultured representatives and corresponding physiological insight. Here we report the decade-long isolation of a Lokiarchaeota-related Asgard archaeon from deep marine sediment. The archaeon, \"Candidatus Prometheoarchaeum syntrophicum strain MK-D1\", is an anaerobic, extremely slow-growing, small cocci ([~]550 nm), that degrades amino acids through syntrophy. Although eukaryote-like intracellular complexities have been proposed for Asgard archaea, the isolate has no visible organella-like structure. Ca. P. syntrophicum instead displays morphological complexity - unique long, and often, branching protrusions. Based on cultivation and genomics, we propose an \"Entangle-Engulf-Enslave (E3) model\" for eukaryogenesis through archaea-alphaproteobacteria symbiosis mediated by the physical complexities and metabolic dependency of the hosting archaeon.

microbiology↗

bioRxiv2019

Dynamic and synergistic influences of air temperature and rainfall on general flowering in a Bornean lowland tropical forest

Supra-annually synchronized flowering events occurring in tropical forests in Southeast Asia, known as general flowering (GF), are \"spectacular and mysterious\" forest events. Recently, studies that combined novel molecular techniques and model-based theoretical approaches suggested that cool temperature and drought synergistically drove GF. Although the novel approaches advanced our understanding of GF, it is usually difficult to know whether the mathematical formulation reasonably well represents the complex and dynamic processes involved in GF. In the present study, we collected a 17-year set of community-wide phenology data during 1993 to 2011 from Lambir Hills National Park in Borneo, Malaysia, and analyzed it using a model-free approach, empirical dynamic modeling (EDM), that does not rely on specific assumptions about the underlying mechanisms, to overcome and complement the previous limitations. By using EDM, we found that GF in the forest in Lambir Hills National Park is synergistically driven by cool air temperature and drought, which is consistent with the previous studies. Also, we found that cumulative meteorological variables, rather than instantaneous values, drive GF with delayed effects, which is also consistent with the previous studies. Interestingly, the present study showed that effects of cumulative meteorological variables on GF changed through time, which implies that the relationship between GF and meteorological variables may be influenced by other factors such as plant/soil nutrient resource dynamics. Future studies integrating novel mathematical/statistical frameworks, long-term and large spatial scale ecosystem monitoring and molecular phenology data are promising for better understanding and fore-casting of GF events in tropical forests in Southeast Asia.

ecology↗

bioRxiv2018

Evolutionary stability of plant-pollinator networks: efficient communities, hysteresis, and a pollination dilemma

Mutualistic interactions between species such as pollination and plant-mycorrhiza interactions are ubiquitous in nature and essential for ecosystem functioning. Often dozens or even hundreds of species with different degree of specialization form complex networks of interdependence. How the complexity evolved and is maintained are fundamental questions in ecology. Here, we present a new game theoretical approach to model complex mutualistic interactions, which we apply to pollination networks. The theoretical analysis revealed multiple evolutionary stable network structures that form a gradient from generalism toward specialism with increasing availability of pollination service. In particular, we found that efficient communities evolve only under pollination oversupply, but that pollination shortage selects for inefficient network structures due to a pollination dilemma. These results suggest that availability of pollination services is a key factor structuring pollination networks and offer a new explanation for the geographical differences in pollination faunas that have long been recognized by ecologists. The study bridges the gap between network studies, game theory, and the natural history of pollination, which have hitherto been studied largely independently.

ecology↗