The surface of bovine serum‐derived exosomes (EXOs) are modified with α‐d‐mannose for facile interaction with mannose receptors on dendritic cells (DCs) and for efficient delivery of immune ...stimulators to the DCs. The surface of the EXOs is modified with polyethylene glycol (PEG) without particle aggregation (≈50 nm) via the incorporation of 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine (DSPE) into the lipid layer of the EXO, compared to chemical conjugation by N‐hydroxysuccinimide activated PEG (NHS‐PEG). PEG modification onto the exosomal surface significantly decreases the non‐specific cellular uptake of the EXOs into the DCs. However, the EXOs with mannose‐conjugated PEG‐DSPE (EXO‐PEG‐man) exhibit excellent intracellular uptake into the DCs and boost the immune response by the incorporation of adjuvant, monophosphoryl lipid A (MPLA) within the EXO. After an intradermal injection, a higher retention of EXO‐PEG‐man is observed in the lymph nodes, which could be used for the efficient delivery of immune stimulators and antigens to the lymph nodes in vivo.
Bovine serum‐derived exosome (EXO) is successfully modified with α‐d‐mannose (EXO‐PEG‐man) via the incorporation of 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine (DSPE). EXO‐PEG‐man demonstrates efficient uptake into dendritic cells (DC), which allows effective delivery of monophosphoryl lipid A; to dendritic cells via mannose receptor CD206. After an intradermal injection, a higher retention of EXO‐PEG‐man is observed in the lymph nodes, compared to PEG‐biotin modified EXOs (EXO‐PEG‐bio).
Summary
Plants possess hundreds of intracellular immune receptors encoding nucleotide‐binding domain leucine‐rich repeat (NLR) proteins. Full‐length NLRs or a specific domain of NLRs often induce ...plant cell death in the absence of pathogen infection.
In this study we used genome‐wide transient expression analysis to identify a group of NLRs (ANLs; ancient and autonomous NLRs) carrying autoactive coiled‐coil (CCA) domains in pepper (Capsicum annuum). CCA‐mediated cell death mimics hypersensitive cell death triggered by the interaction between NLRs and pathogen effectors.
Sequence alignment and mutagenesis analyses revealed that the intact α1 helix of CCAs is critical for both CCA‐ and ANL‐mediated cell death. Cell death induced by CCAs does not require NRG1/ADR1 or NRC type helper NLRs, suggesting ANLs may function as singleton NLRs. We also found that CCAs localize to the plasma membrane, as demonstrated for Arabidopsis singleton NLR ZAR1. Extended studies revealed that autoactive CCAs are well conserved in other Solanaceae plants as well as in rice, a monocot plant. Further phylogenetic analyses revealed that ANLs are present in all tested seed plants (spermatophytes).
Our study not only uncovers the autonomous NLR clade in plants but also provides powerful resources for dissecting the underlying molecular mechanism of NLR‐mediated cell death in plants.
Categorizing people with late-onset Alzheimer's disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n = 4050, of whom 2431 ...had genome-wide single-nucleotide polymorphism (SNP) data). We assigned people to cognitively defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer's disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p < 10
and odds ratios more extreme than those previously reported for Alzheimer's disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had ≥1 APOE ε4 allele than any other subgroup (overall p = 1.5 × 10
). Across subgroups, there were 33 novel suggestive loci across the genome with p < 10
and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively defined subgroups and nominate novel genetic loci.
Summary
Transient and rapid increase in cytosolic Ca2+ plays a crucial role in plant–pathogen‐associated molecular pattern (PAMP)‐triggered immunity (PTI). Cyclic nucleotide‐gated channels (CNGCs) ...have been implicated in mediating this Ca2+ influx; however, their regulatory mechanisms remain poorly understood.
Here, we have found that AVRblb2 requires the calmodulin (CaM) and calmodulin‐like (CML) proteins as co‐factors to interact with the NbCNGCs, resulting in the formation of AVRblb2‐CaM/CML‐NbCNGCs complex. Furthermore, CaM and CML are dissociated from NbCNGC18 during PTI response to increase Ca2+ influx; however, Avrblb2 inhibits calcium channel activation by disrupting the release of CaM and CML from NbCNGC18.
Following recognition of PAMP, NbCNGC18 forms active heteromeric channels with other NbCNGCs, which may give selectivity of CNGC complex against diverse signals for fine‐tuning of cytosolic Ca2+ level to mediate appropriate responses. Silencing of multiple NbCNGCs compromised the function of AVRblb2 on the pathogenicity of Phytophthora infestans, confirming that AVRblb2 contributes to pathogen virulence by targeting CNGCs.
Our findings provide new insights into the regulation of CNGCs in PTI and the role of pathogen effectors in manipulating host cell physiology to promote infection.
Invariant natural killer T (iNKT), mucosal-associated invariant T (MAIT), and γδ T cells are innate T cells that acquire memory phenotype in the thymus and share similar biological characteristics. ...However, how their effector differentiation is developmentally regulated is still unclear. Here, we identify analogous effector subsets of these three innate T cell types in the thymus that share transcriptional profiles. Using single-cell RNA sequencing, we show that iNKT, MAIT and γδ T cells mature via shared, branched differentiation rather than linear maturation or TCR-mediated instruction. Simultaneous TCR clonotyping analysis reveals that thymic maturation of all three types is accompanied by clonal selection and expansion. Analyses of mice deficient of TBET, GATA3 or RORγt and additional in vivo experiments corroborate the predicted differentiation paths, while human innate T cells from liver samples display similar features. Collectively, our data indicate that innate T cells share effector differentiation processes in the thymus.
•It is unclear if particulate matter (PM) directly goes into the skin.•We provide visual images of PM penetrating into epidermis in the barrier-disrupted skin.•Repeated PM application leads to ...cutaneous inflammation via ROS-dependent manner.•It may have clinical implications especially for patients with deficient skin barrier including atopic dermatitis, diabetics.
Particulate matter (PM) is an integral part of air pollution, which is a mixture of particles suspended in the air. Recently, it has been reported that PM is associated with increased risks of skin diseases, especially atopic dermatitis in children. However, it is unclear if PM directly goes into the skin and what mechanisms are involved in response to PM.
To see whether PM could penetrate into the barrier-disrupted skin, produce reactive oxygen species (ROS), and elicit an inflammatory response.
We collected PMs during a winter in Seoul and used cultured keratinocytes for in vitro study and tape-stripped BALB/c mice for in vivo study.
Keratinocyte cytotoxicity increased in a dose-dependent manner by PM treatment. IL-8 and MMP-1 mRNA expression and protein levels were significantly increased compared to control by qPCR and ELISA, respectively. Cellular ROS production was increased by PM treatment, and antioxidant N-acetyl cysteine pretreatment prevented induction of inflammatory cytokines IL-8 and MMP-1. In PM-treated keratinocytes, electron-dense subcellular particles were observed by transmission electron microscopy. PM was observed inside hair follicles in both intact and barrier-disrupted skin in vivo. Additionally, intercellular penetration of PM was seen in the barrier-disrupted skin. Repeated PM application induced epidermal thickening and dermal inflammation with neutrophil infiltration. Finally, N-acetyl cysteine could ameliorate skin inflammation induced by PM application.
PM penetrates into the barrier-disrupted skin, causing inflammation, demonstrating detrimental effects in the skin.
Aim
The present study investigated the effects of two types of lingual exercise (tongue‐hold swallowing and tongue‐pressure resistance training) on oral muscle strength, salivary flow rate and ...subjective oral health of the elderly.
Methods
We randomly assigned 74 elderly adults (≥65 years) to three groups (tongue‐hold swallowing, tongue‐pressure resistance training and control groups). Each group participated in 8 weeks of their appropriately prescribed intervention. We measured anterior tongue strength, posterior tongue strength, lip strength, salivary flow rate and Oral Health Impact Profile‐14 score before and after 8 weeks. Differences before and after intervention were observed with a paired sample t‐test. Moreover, analyses of covariance and variance were performed to determine the differences in the measured values between the groups.
Results
The tongue‐hold swallowing group showed improvement in both anterior and posterior tongue strength, while the tongue‐pressure resistance training group showed a significant increase in only anterior tongue strength. Both the tongue‐hold swallowing and tongue‐pressure resistance training groups showed increased salivary secretion, with the tongue‐pressure resistance training group showing a higher level of salivary secretion. However, the difference in the subjective oral health scores before and after the intervention was not significant.
Conclusions
The two lingual exercises strengthened some aspects of tongue muscles and increased the salivary flow rate, with more salivary secretion in the tongue‐pressure resistance training group than in the tongue‐hold swallowing group. Any evidence of the lingual exercises being able to enhance subjective oral health could not be found. Geriatr Gerontol Int 2020; ••: ••–••.
Background
Practice effects (PEs) are improvements in performance after repeated exposure to test materials, and typically viewed as a source of bias in repeated cognitive assessments. We aimed to ...determine whether characterizing PEs could also provide a useful marker of early cognitive decline.
Methods
We conducted a systematic review of the literature, searching PsycInfo (Ebsco) and PubMed databases for articles studying PEs in aging and dementia populations. Articles published between 1920 and 2019 were included.
Result
We identified 259 articles, of which 27 studied PEs as markers of cognitive performance. These studies consistently showed that smaller, less‐robust PEs were associated with current diagnostic status and/or future cognitive decline. In addition, lower PEs were associated with Alzheimer's disease risk factors and neurodegeneration biomarkers.
Conclusion
PEs provide a potentially useful marker of cognitive decline, and could prove valuable as part of a cost‐effective strategy to select individuals who are at‐risk for dementia for future interventions.
Summary
The hypersensitive response (HR) is a robust immune response mediated by nucleotide‐binding, leucine‐rich repeat receptors (NLRs). However, the early molecular event that links activated NLRs ...to cell death is unclear.
Here, we demonstrate that NLRs target plasma membrane H+‐ATPases (PMAs) that generate electrochemical potential, an essential component of living cells, across the plasma membrane. CCA309, an autoactive N‐terminal domain of a coiled‐coil NLR (CNL) in pepper, is associated with PMAs. Silencing or overexpression of PMAs reversibly affects cell death induced by CCA309 in Nicotiana benthamiana.
CCA309‐induced extracellular alkalization causes plasma membrane depolarization, followed by cell death. Coimmunoprecipitation analyses suggest that CCA309 inhibits PMA activation by preoccupying the dephosphorylated penultimate threonine residue of PMA. Moreover, pharmacological experiments using fusicoccin, an irreversible PMA activator, showed that inhibition of PMAs contributes to CNL‐type (but not Toll interleukin‐1 receptor NLR‐type) resistance protein‐induced cell death.
We suggest PMAs as primary targets of plasma membrane‐associated CNLs leading to HR‐associated cell death by disturbing the electrochemical gradient across the membrane. These results provide new insight into NLR‐mediated cell death in plants, as well as innate immunity in higher eukaryotes.
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