Distinct Modes Research Articles

P2X7R-primed keratinocytes are susceptible to apoptosis via GPCR-Gβγ-pERK signal pathways

BackgroundCell death constitutes a pivotal biological phenomenon essential for the preservation of homeostasis within living organisms. In the context of maintaining a functional skin barrier, keratinocytes exert positively and negatively control cell death signals. However, in patients with severe drug eruptions, anomalous overexpression of the formyl peptide receptor 1 (FPR1) in keratinocytes elicits a distinctive mode of cell death known as necroptosis, thereby suffering a loss of the skin barrier. The precise molecular mechanisms connecting FPR1 activation to this cell death remain unclear. ObjectiveWe have investigated the intracellular signal transduction cascade governing FPR1-mediated cell death in cultured keratinocytes. MethodsWe used HaCaT cells as a model keratinocyte. The expression of FPR1 was detected with qPCR. The presence of cell death events was monitored through live-cell fluorescent staining and LDH release assays. Furthermore, the phosphorylation of ERK was assessed via Western blot analysis. Intracellular signal pathways were investigated using specific inhibitors. ResultsLigand stimulation of an endogenous ion channel, purinergic receptor P2X7 (P2X7R), increased the FPR1 expression level. This upregulated FPR1 demonstrated functional competence in the phosphorylation of downstream MAP kinase and the initiation of cell death. Notably, this cell death was ameliorated upon the administration of inhibitors targeting Gβγ, ERK, and caspases. ConclusionThe induction and stimulation of FPR1 initiated apoptosis in keratinocytes via the Gβγ-pERK signaling pathway. Our findings postulate that the downstream components of FPR1 represent an alternative therapeutic target for preventing unintended keratinocyte cell death.

Enhanced Foreign Exchange Volatility Forecasting Using Ceemdan with Optuna-Optimized Ensemble Deep Learning Model

Foreign Exchange (FX) is the largest financial market in the world, with a daily trading volume that significantly exceeds that of stock and futures markets. The prediction of FX volatility is a critical financial concern that has garnered significant attention from researchers and practitioners due to its far-reaching implications in the financial markets. This paper presents a novel hybrid ensemble forecasting model integrating a decomposition strategy and three deep learning (DL) models: Long Short-Term Memory (LSTM), Bidirectional LSTM (BiLSTM), and Convolutional Neural Network (CNN). This combination addresses individual models' limitations and further improves the accuracy and stability of FX volatility forecasting. The proposed approach utilizes the CEEMDAN technique to decompose volatility into multiple distinct intrinsic mode functions (IMFs) and merges these IMFs with GARCH and EGARCH volatilities to form the input dataset for the DL models. In addition, we employed an attention mechanism to improve the effectiveness of the DL techniques. Furthermore, the hyperparameters for the DL models are optimized using the Optuna algorithm. Finally, a hybrid ensemble model for forecasting exchange rate volatility is developed by combining the predictions of three distinct DL models. The proposed approach is evaluated against various benchmark models using evaluation measures such as MSE, MAE, HMSE, HMAE, RMSE, Q-LIKE, and the model confidence set (MCS) approach. The results demonstrate that our proposed approach provides accurate and reliable forecasts of FX volatility under different forecasting regimes, making it a valuable tool for financial practitioners and researchers.

Deep Kinetic Energy Response to the Variability of the Kuroshio Extension

AbstractThe transfer of energy from the upper to deep oceans is a well‐known and challenging subject in physical oceanography. This research investigates the intricate relationship between surface and deep ocean currents. Utilizing nearly 2 years of observations from the Kuroshio Extension System Study (KESS), our study unveils the deep‐ocean kinetic energy response to the Kuroshio Extension (KE) variability. We introduce the Kuroshio Extension Jet Path Index (KEJPI), which identifies two distinct modes of the KE jet on an intra‐seasonal timescale. Our findings reveal a strong correlation (0.73) between KEJPI and the mean kinetic energy of deep‐ocean geostrophic circulation, suggesting that the KE jet's large amplitude meanders have a significant impact on deep‐ocean kinetic energy. Singular Value Decomposition (SVD) analysis further unveils a co‐evolving spatial pattern between upper and lower ocean kinetic energy. We investigate the dynamic vertical coupling (DVC) mechanism by examining the coherent variation among the sea surface height (SSH), 15°C isotherm (Z15), deep pressure anomaly, and abyssal flow. The KE jet migration can induce net divergence and convergence within the water column, which in turn generates deep‐ocean quasi‐geostrophic currents. These currents show a marked increase in kinetic energy, reaching levels three times higher than the background. This DVC‐driven kinetic energy can further cascade into near‐inertial and high‐frequency internal waves, contributing to abyssal mixing. Our study underscores the role of large current system instabilities in transferring energy to the deep ocean and facilitating deep mixing processes.

An intelligent sensing platform for detecting and identifying biochemical substances based on terahertz spectra

This paper presents the development of an intelligent sensing platform dedicated to accurately identifying terahertz (THz) spectra obtained from various biochemical substances. The platform currently has two distinct identification modes, which focus on identifying five amino acids, namely phenylalanine, methionine, lysine, leucine, and threonine, and five carbohydrates, namely aspartame, fructose, glucose, lactose monohydrate, and sucrose based on their THz spectra. The first mode, called One-dimensional THz Spectrum Identification (OTSI), combines THz time-domain spectroscopy (THz-TDS) with the proposed mini convolutional neural network (MCNN) model. THz-TDS detects biochemical substances, while the MCNN model identifies the THz spectra. The MCNN model has a simple structure and only needs to deal with the THz absorption coefficients of biochemical substances, which are less computationally intensive and easily converged. The model can achieve 99.07 % accuracy in identifying one-dimensional THz spectra of the ten biochemical substances. The second mode, THz Spectrum Image-based Identification (TSII), applies the YOLO-v5 target detection model to THz spectral image recognition. The YOLO-v5 model uses THz absorption peaks as identification features and can identify biochemical substances based on only one or several THz absorption peaks. The overall identifying accuracy of the YOLO-v5 model for ten biochemical substances is 96.20 %. We also compared the MCNN and YOLO-v5 models with other deep learning and machine learning models, which demonstrate that they have better performance. This feature broadens the platform's utility in biomolecular analysis and paves the way for further research and development in detecting and analyzing diverse biological compounds.

High discrimination ratio, broadband circularly polarized light photodetector using dielectric achiral nanostructures

The on-chip measurement of polarization states plays an increasingly crucial role in modern sensing and imaging applications. While high-performance monolithic linearly polarized photodetectors have been extensively studied, integrated circularly polarized light (CPL) photodetectors are still hindered by inadequate discrimination capability. This study presents a broadband CPL photodetector utilizing achiral all-dielectric nanostructures, achieving an impressive discrimination ratio of ~107 at a wavelength of 405 nm. Our device shows outstanding CPL discrimination capability across the visible band without requiring intensity calibration. It functions based on the CPL-dependent near-field modes within achiral structures: under left or right CPL illumination, distinct near-field modes are excited, resulting in asymmetric irradiation of the two electrodes and generating a photovoltage with directions determined by the chirality of the incident light field. The proposed design strategy facilitates ultra-compact CPL detection across diverse materials, structures, and spectral ranges, presenting a novel avenue for achieving high-performance monolithic CPL detection.

Potent and selective ‘genetic zipper’ method for DNA-programmable plant protection: innovative oligonucleotide insecticides against Trioza alacris Flor

Chemical insecticides increased the chemical burden on natural ecosystems posing environmental health risk factor. The urgent need for a more sustainable and ecological approach has produced many innovative ideas, including eco-friendly ‘genetic zipper’ method (or CUAD platform) based on contact oligonucleotide insecticides. Oligonucleotide insecticides have enjoyed success recently on many sternorrhynchans showing highly adaptable structure for distinct insect pest species and selective mode of action. In this article, we describe the efficiency of the oligonucleotide insecticides (briefly, olinscides or DNA insecticides) Alacris-11 and Laura-11, as well as their combined use in mixture (1:1), designed for control of bay sucker (Trioza alacris Flor), an important psyllid pest of noble laurel (Laurus nobilis L.). These olinscides are based on short unmodified antisense DNA oligonucleotides that target ITS2 between 5.8S rRNA and 28S rRNA in pre-rRNA (Laura-11) and 28S rRNA region in mature 28S rRNA and pre-rRNA (Alacris-11). The maximum pest mortality, observed on the 14th day of the experiment, comprised 95.01 ± 4.42% for Alacris-11, 97.16 ± 2.48% for Laura-11, and 98.72 ± 1.14% for their mixture (1:1). The control oligonucleotide CTGA-11 did not cause any significant mortality (9.38 ± 0.57%), emphasizing selectivity in the action of oligonucleotide insecticides. The results show potent and specific nature of oligonucleotide insecticides for pest control and open up new frontiers in control of economically important psyllids in agriculture and forestry, including Asian citrus psyllid (Diaphorina citri Kuwayama) and many others. Scientists can easily adopt ‘genetic zipper’ method for plethora of insect pests because DNA is a programmable molecule and provides game-changing characteristics for plant protection.Graphical

A kalihinol analog disrupts apicoplast function and vesicular trafficking in P. falciparum malaria.

We report the discovery of MED6-189, an analog of the kalihinol family of isocyanoterpene natural products that is effective against drug-sensitive and drug-resistant Plasmodium falciparum strains, blocking both asexual replication and sexual differentiation. In vivo studies using a humanized mouse model of malaria confirm strong efficacy of the compound in animals with no apparent hemolytic activity or toxicity. Complementary chemical, molecular, and genomics analyses revealed that MED6-189 targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses revealed that a mutation in PfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. Its high potency, excellent therapeutic profile, and distinctive mode of action make MED6-189 an excellent addition to the antimalarial drug pipeline.

Investigating dehumidification and heating performance in a dual evaporator heat pump system for electric vehicles

In cold, moisture-rich winter environments, window fogging represents a substantial safety hazard for drivers. Electric vehicles often incorporate heat pump systems to address challenges such as dehumidification and heating specific to cold weather. Therefore, it is essential to evaluate the dehumidification and heating efficiency of these systems through focused research. This study presents a dual-evaporator heat pump system designed specifically for electric vehicles, equipped with two distinct modes for dehumidification and heating. The research examines how factors such as inlet air volume and the degree of opening of the electronic expansion valve affect the system's dehumidification and heating performance. Experimental analyses were conducted to explore the system's response under various conditions of inlet air humidity and compressor speed in both modes. Results suggest that increasing inlet air volume improves dehumidification effectiveness but may reduce heating performance. Likewise, a wider opening of the electronic expansion valve enhances heating but could decrease dehumidification efficiency. Importantly, the study indicates that when the relative humidity of the inlet air exceeds 70 %, a single evaporator mode is more effective for dehumidification. However, when the relative humidity is below 70 %, the dual evaporator mode is more advantageous, showing better heating performance.

Reliability modeling and analysis of uncertain competing failure systems

The competing failure system is quite common in real life, such as automotive system and aerospace system. Two distinct failure modes usually coexist in this type of system: gradual internal degradation and sudden external shock, where the occurrence of any failure mode can lead to the system failure. The system failure such as aircraft accident may cause a terrible loss of human life and property. Hence, it is worth reducing the rate of system failure by improving the system reliability. While, reliability model is the foundation of any research of reliability and epistemic uncertainty exists in the process of modeling and estimating. Therefore, we introduce uncertainty theory to investigate the competing failure system with epistemic uncertainty. The internal degradation and external shock of the system are characterized by an uncertain differential equation and an uncertain renewal process, respectively. The system reliability is defined as the uncertain measure that neither internal degradation nor external shock surpass corresponding thresholds. In addition, some reliability formulas are derived for the systems subjected to extreme shock, cumulative shock, running shock and δ-shock, respectively. Finally, a case study with respect to micro-electro-mechanical system is given to show how the proposed model is implemented.

A Meso Butterfly-Like Ce(III)-Containing Antimonotungstate with Catalytic Activity for Synthesizing Isoindolinones.

A unique meso Ce(III)-containing antimonotungstate, {Na(OAc)(H2O)2[Ce4(tar)(Htar)2(Sb2W21O72)2(H2O)7]}244- (Ce4tar3; H4tar = tartaric acid), consisting of two enantiomeric parts with a butterfly-like configuration, was successfully synthesized by a one-pot in situ method and characterized. The coordination of d- or l-tar ligands induced the formation of Dawson-like {Ce2Sb2W21} with right or left configurations, thereby determining the d/l configurations of {Na(OAc)(H2O)2[Ce4(tar)(Htar)2(Sb2W21O72)2(H2O)7]}22-. Carboxyl groups link these two enantiomeric parts with Ce(III) ions from each other around the symmetric center of the P1̅ space group. The three types of tar ligands exhibit distinct coordination modes, and all coordinate with at least one W(VI) atom using one carboxylate oxygen atom and one α-OH. Ce4tar3 represents the largest case among those meso-dl-tar-functionalized polyoxometalates. Furthermore, Ce4tar3 exhibits excellent catalytic activity for synthesizing isoindolinones via the three-component reaction of 2-acetylbenzoic acids, amines, and phosphine oxides.

Cellulose binding and the timing of expression influence protein targeting to the double-layered cyst wall of Acanthamoeba.

The cyst wall of the eye pathogen Acanthamoeba castellanii contains cellulose and has ectocyst and endocyst layers connected by conical ostioles. Cyst walls contain families of lectins that localize to the ectocyst layer (Jonah) or the endocyst layer and ostioles (Luke and Leo). How lectins and an abundant laccase bind cellulose and why proteins go to locations in the wall are not known and are the focus of the studies here. Structural predictions identified β-jelly-roll folds (BJRFs) of Luke and sets of four disulfide knots (4DKs) of Leo, each of which contains linear arrays of aromatic amino acids, also present in carbohydrate-binding modules of bacterial and plant endocellulases. Ala mutations showed that these aromatics are necessary for cellulose binding and proper localization of Luke and Leo in the Acanthamoeba cyst wall. BJRFs of Luke, 4DKs of Leo, a single β-helical fold (BHF) of Jonah, and a copper oxidase domain of the laccase each bind to glycopolymers in both layers of deproteinated cyst walls. Promoter swaps showed that ectocyst localization does not just correlate with but is caused by early encystation-specific expression, while localization in the endocyst layer and ostioles is caused by later expression. Evolutionary studies showed distinct modes of assembly of duplicated domains in Luke, Leo, and Jonah lectins and suggested Jonah BHFs originated from bacteria, Luke BJRFs share common ancestry with slime molds, while 4DKs of Leo are unique to Acanthamoeba.IMPORTANCEAcanthamoebae is the only human parasite with cellulose in its cyst wall and conical ostioles that connect its inner and outer layers. Cyst walls are important virulence factors because they make Acanthamoebae resistant to surface disinfectants, hand sanitizers, contact lens sterilizers, and antibiotics applied to the eye. The goal here was to understand better how proteins are targeted to specific locations in the cyst wall. To this end, we identified three new proteins in the outer layer of the cyst wall, which may be targets for diagnostic antibodies in corneal scrapings. We used structural predictions and mutated proteins to show linear arrays of aromatic amino acids of two unrelated wall proteins are necessary for binding cellulose and proper wall localization. We showed early expression during encystation causes proteins to localize to the outer layer, while later expression causes proteins to localize to the inner layer and the ostioles.

Novel non-peptide uracil-derived human gonadotropin-releasing hormone receptor antagonists

Gonadotropin-releasing hormone (GnRH) is the main regulator of the reproductive system, acting on gonadotropic cells by binding to the GnRH1 receptor (GnRH1R). Traditionally, therapies targeting this receptor have relied on peptide modulators, which required subcutaneous or intramuscular injections. Due to the limitations of the parenteral administrations, there is a growing interest in developing oral small molecule modulators of GnRH1R as more convenient therapeutic alternatives.In this study, we examined the potential of chemically modifying elagolix, the first approved non-peptide, orally active GnRH1R antagonist, to increase its atropisomeric properties by introducing new moieties. We designed and synthesized the thio-uracil (1) and cytosine (2) derivatives of elagolix, both demonstrating GnRH1R antagonistic activities, with EC50 values of 39 and 110 nM, respectively. The atropisomers of 1 and 2 were efficiently separated using silica gel chromatography, and extensive NMR investigation, supported by Density Functional Theory (DFT) calculations, allowed us to define their conformations and rotational barriers. Docking and Molecular Dynamics (MD) studies revealed that 1 and 2 bind to GnRH1R with ΔG values comparable to elagolix, but through distinct binding modes. These results highlight the potential of non-peptide modulators to effectively modulate GnRH1R activity and pave the way for developing novel modulators.

Unleashing Nature's Allies: Comparing the Vertical Transmission Dynamics of Insect-Specific and Vertebrate-Infecting Flaviviruses in Mosquitoes.

Insect-specific viruses (ISVs) include viruses that are restricted to the infection of mosquitoes and are spread mostly through transovarial transmission. Despite using a distinct mode of transmission, ISVs are often phylogenetically related to arthropod-borne viruses (arboviruses) that are responsible for human diseases and able to infect both mosquitoes and vertebrates. ISVs can also induce a phenomenon called "superinfection exclusion", whereby a primary ISV infection in an insect inhibits subsequent viral infections of the insect. This has sparked interest in the use of ISVs for the control of pathogenic arboviruses transmitted by mosquitoes. In particular, insect-specific flaviviruses (ISFs) have been shown to inhibit infection of vertebrate-infecting flaviviruses (VIFs) both in vitro and in vivo. This has shown potential as a new and ecologically friendly biological approach to the control of arboviral disease. For this intervention to have lasting impacts for biological control, it is imperative that ISFs are maintained in mosquito populations with high rates of vertical transmission. Therefore, these strategies will need to optimise vertical transmission of ISFs in order to establish persistently infected mosquito lines for sustainable arbovirus control. This review compares recent observations of vertical transmission of arboviral and insect-specific flaviviruses and potential determinants of transovarial transmission rates to understand how the vertical transmission of ISFs may be optimised for effective arboviral control.

Protrusion force and cell-cell adhesion play a critical role in collective tumor cluster migration.

While collective migration is shown to enhance invasive and metastatic potential in cancer, the mechanisms driving this behavior and regulating tumor migration plasticity remain poorly understood. This study provides a mechanistic framework explaining the emergence of different modes of collective migration under hypoxia-induced secretome. We focus on the interplay between cellular protrusion force and cell-cell adhesion using collectively migrating three-dimensional microtumors as models with well-defined microenvironment. Large microtumors show directional migration due to intrinsic hypoxia, while small microtumors exhibit radial migration in response to hypoxic secretome. Here, we developed the minimal multi-scale microtumor model (MSMM) to elucidate underlying mechanisms. We identified distinct migration modes within specific regions of protrusion force and cell-cell adhesion parameter space. We show that sufficient cellular protrusion force is crucial for both, radial and directional collective microtumor migration. Radial migration emerges when sufficient cellular protrusion force is generated, driving neighboring cells to move collectively in diverse directions. Within migrating tumors, strong cell-cell adhesion enhances the alignment of cell polarity, breaking the symmetric angular distribution of protrusion forces, and leading to directional microtumor migration. The integrated results from the experimental and computational models provide fundamental insights into collective migration in response to different microenvironment stimuli.

Investigation of additively manufactured metamaterials for load-bearing structural applications

The study explores the potential application of Triply Periodic Minimal Surface (TPMS) metamaterials in structural engineering and architecture. It evaluates parametric design possibilities and analysis approaches while examining the mechanical properties of five TPMS structures (Gyroid, Schwarz, Diamond, Split, and Neovius). Comparisons are made between Additively Manufactured (AM) samples and numerical simulations. Gyroid and Diamond structures, which display advantageous properties, undergo further investigation with parametric design for uniform and non-uniform lattices. The study proposes simplified analytical formulations for metamaterial design, along with Homogenization analysis and detailed FEM analysis. Compression tests reveal distinct failure modes and stress-strain behaviors for each TPMS. The research suggests further investigation into the influence of the 3D printing process, void detection, and thermomechanical analysis. Finally, the study provides insights into tailored applications of these lattice metamaterials in structural engineering.

Comprehensive maps of material stock dynamics reveal increasingly coordinated urban development in the Yangtze River Delta of China

Sustainable urban development critically depends on effectively managing the interplay between material stock (MS) and economic growth. This study combined convolutional neural network model and nighttime lights data to map building MS of Yangtze River Delta (YRD) urban agglomeration in China from 2000 to 2020 across 1 km × 1 km pixel scale, then uncovered the spatiotemporal dynamics of MS and its correlation with economic development. Our findings indicate that the model performed robustly on the test set (R2 > 0.88). YRD's MS surged over tenfold, reaching 20,772 teragram, primarily expanding along northwest-southeast developmental axes. Most YRD cities exhibited synchronized growth in material stock and GDP, suggesting an emergent pattern of sustainable urban expansion. However, cities at the developmental extremes highlighted the need for optimizing urban development strategies. By categorizing YRD cities into four distinct development modes, our study offers deep insights into the dynamics of urban development, underpinning targeted strategies that could guide cities towards more sustainable and resource-efficient growth trajectories.

Performance investigation of UOWC system based on OAM beams for various Jerlov water types

This paper introduces a novel high-speed underwater optical wireless communication (UOWC) system employing three distinct orbital angular momentum (OAM) beams. A single green laser source operating at 532 nm generates these beams: LG0,0,LG0,20,andLG0,50, each transmitting data at 10 Gbps. The paper provides a comprehensive analysis of absorption and scattering coefficients for five Jerlov water types: I (JI), IA (JIA), IB (JIB), II (JII), and III (JIII). Simulation results demonstrate the system ability to transmit multiple data streams simultaneously using distinct OAM modes, achieving an overall capacity of 30 Gbps. The longest underwater (UW) transmission distance of 22 m is achieved in JI water as it exhibits the lowest attenuation. This range decreases by 9.09 %, 31.82 %, 59.09 %, and 80.91 % in JIA, JIB, JII, and JIII, respectively, due to increased attenuation in these water types. These results are obtained with a log (BER) below −5 and a Q-factor above 4, indicating successful data reception. The findings highlight the potential of OAM multiplexing for enhancing data capacity in challenging underwater environments.

Two Bond-Exchange modes in sodium silicate liquids

Because of their network structure, the diffusion mechanism of network-forming elements, namely silicon and oxygen, remains unclear. Several diffusion mechanisms have been proposed based on molecular dynamics simulations; however, the bond-exchange motion has not been quantitatively analyzed. This study introduces the concept of bond-breaking/forming particles. By treating the bond-breaking/forming events as instant particles, the bond-exchange event can be interpreted as a pair-correlation function of these particles. Here, examples of sodium silicate liquids at various pressures are presented using the results of force-field molecular dynamics simulations. Analyses of the pair correlation of bond-breaking/forming particles revealed two distinct bond-exchange modes. Only the short mode contributed to the diffusion of the network-forming elements based on comparative analysis of the pressure dependence of the integrated peaks of the pair-correlation functions and the self-diffusion coefficients of silicon.

Cell-type-specific origins of locomotor rhythmicity at different speeds in larval zebrafish

Different speeds of locomotion require heterogeneous spinal populations, but a common mode of rhythm generation is presumed to exist. Here, we explore the cellular versus synaptic origins of spinal rhythmicity at different speeds by performing electrophysiological recordings from premotor excitatory interneurons in larval zebrafish. Chx10-labeled V2a neurons are divided into at least two morphological subtypes proposed to play distinct roles in timing and intensity control. Consistent with distinct rhythm generating and output patterning functions within the spinal V2a population, we find that descending subtypes are recruited exclusively at slow or fast speeds and exhibit intrinsic cellular properties suitable for rhythmogenesis at those speeds, while bifurcating subtypes are recruited more reliably at all speeds and lack appropriate rhythmogenic cellular properties. Unexpectedly, however, phasic firing patterns during locomotion in rhythmogenic and non-rhythmogenic V2a neurons alike are best explained by distinct modes of synaptic inhibition linked to cell type and speed. At fast speeds reciprocal inhibition in descending V2a neurons supports phasic firing, while recurrent inhibition in bifurcating V2a neurons helps pattern motor output. In contrast, at slow speeds recurrent inhibition in descending V2a neurons supports phasic firing, while bifurcating V2a neurons rely on reciprocal inhibition alone to pattern output. Our findings suggest cell-type-specific, not common, modes of rhythmogenesis generate and coordinate different speeds of locomotion.

Striking a balance: new perspectives on homeostatic dendritic cell maturation.

Dendritic cells (DCs) are crucial gatekeepers of the balance between immunity and tolerance. They exist in two functional states, immature or mature, that refer to an information-sensing versus an information-transmitting state, respectively. Historically, the term DC maturation was used to describe the acquisition of immunostimulatory capacity by DCs following their triggering by pathogens or tissue damage signals. As such, immature DCs were proposed to mediate tolerance, whereas mature DCs were associated with the induction of protective T cell immunity. Later studies have challenged this view and unequivocally demonstrated that two distinct modes of DC maturation exist, homeostatic and immunogenic DC maturation, each with a distinct functional outcome. Therefore, the mere expression of maturation markers cannot be used to predict immunogenicity. How DCs become activated in homeostatic conditions and maintain tolerance remains an area of intense debate. Several recent studies have shed light on the signals driving the homeostatic maturation programme, especially in the conventional type 1 DC(cDC1) compartment. Here, we highlight our growing understanding of homeostatic DC maturation and the relevance of this process for immune tolerance.