Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells.

The major-histocompatibility-complex-(MHC)-class-I-related molecule MR1 can present activating and non-activating vitamin-B-based ligands to mucosal-associated invariant T cells (MAIT cells). Whether MR1 binds other ligands is unknown. Here we identified a range of small organic molecules, drugs, drug metabolites and drug-like molecules, including salicylates and diclofenac, as MR1-binding ligands. Some of these ligands inhibited MAIT cells ex vivo and in vivo, while others, including diclofenac metabolites, were agonists. Crystal structures of a T cell antigen receptor (TCR) from a MAIT cell in complex with MR1 bound to the non-stimulatory and stimulatory compounds showed distinct ligand orientations and contacts within MR1, which highlighted the versatility of the MR1 binding pocket. The findings demonstrated that MR1 was able to capture chemically diverse structures, spanning mono- and bicyclic compounds, that either inhibited or activated MAIT cells. This indicated that drugs and drug-like molecules can modulate MAIT cell function in mammals.

MAIT cell-MR1 reactivity is highly conserved across multiple divergent species.

Mucosal-associated invariant T (MAIT) cells are a subset of unconventional T cells that recognize small molecule metabolites presented by major histocompatibility complex class I related protein 1 (MR1), via an αß T cell receptor (TCR). MAIT TCRs feature an essentially invariant TCR α-chain, which is highly conserved between mammals. Similarly, MR1 is the most highly conserved major histocompatibility complex-I-like molecule. This extreme conservation, including the mode of interaction between the MAIT TCR and MR1, has been shown to allow for species-mismatched reactivities unique in T cell biology, thereby allowing the use of selected species-mismatched MR1-antigen (MR1-Ag) tetramers in comparative immunology studies. However, the pattern of cross-reactivity of species-mismatched MR1-Ag tetramers in identifying MAIT cells in diverse species has not been formally assessed. We developed novel cattle and pig MR1-Ag tetramers and utilized these alongside previously developed human, mouse, and pig-tailed macaque MR1-Ag tetramers to characterize cross-species tetramer reactivities. MR1-Ag tetramers from each species identified T cell populations in distantly related species with specificity that was comparable to species-matched MR1-Ag tetramers. However, there were subtle differences in staining characteristics with practical implications for the accurate identification of MAIT cells. Pig MR1 is sufficiently conserved across species that pig MR1-Ag tetramers identified MAIT cells from the other species. However, MAIT cells in pigs were at the limits of phenotypic detection. In the absence of sheep MR1-Ag tetramers, a MAIT cell population in sheep blood was identified phenotypically, utilizing species-mismatched MR1-Ag tetramers. Collectively, our results validate the use and define the limitations of species-mismatched MR1-Ag tetramers in comparative immunology studies.

Ultrahigh efficient emulsification with drag-reducing liquid gating interfacial behavior.

Emulsification is a crucial technique for mixing immiscible liquids into droplets in numerous areas ranging from food to medicine to chemical synthesis. Commercial emulsification methods are promising for high production, but suffer from high energy input. Here, we report a very simple and scalable emulsification method that employs the drag-reducing liquid gating structure to create a smooth liquid-liquid interface for the reduction of resistance and tunable generation of droplets with good uniformity. Theoretical modeling and experimental results demonstrate that our method exhibits ultrahigh efficiency, which can reach up to more than 4 orders of magnitude greater energy-saving compared to commercial methods. For temperature-sensitive biological components, such as enzymes, proteins, and bacteria, it can offer a comfortable environment to avoid exposure to high temperatures during emulsifying, and the interface also enables the suppression of fouling. This unique drag-reducing liquid gating interfacial emulsification mechanism promotes the efficiency of droplet generation and provides fresh insight into the innovation of emulsifications that can be applied in many fields, including the food industry, the daily chemical industry, biomedicine, material fabrication, the petrochemical industry, and beyond.

The balance of interleukin-12 and interleukin-23 determines the bias of MAIT1 versus MAIT17 responses during bacterial infection.

Mucosal-associated invariant T (MAIT) cells are a major subset of innate-like T cells mediating protection against bacterial infection through recognition of microbial metabolites derived from riboflavin biosynthesis. Mouse MAIT cells egress from the thymus as two main subpopulations with distinct functions, namely, T-bet-expressing MAIT1 and RORγt-expressing MAIT17 cells. Previously, we reported that inducible T-cell costimulator and interleukin (IL)-23 provide essential signals for optimal MHC-related protein 1 (MR1)-dependent activation and expansion of MAIT17 cells in vivo. Here, in a model of tularemia, in which MAIT1 responses predominate, we demonstrate that IL-12 and IL-23 promote MAIT1 cell expansion during acute infection and that IL-12 is indispensable for MAIT1 phenotype and function. Furthermore, we showed that the bias toward MAIT1 or MAIT17 responses we observed during different bacterial infections was determined and modulated by the balance between IL-12 and IL-23 and that these responses could be recapitulated by cytokine coadministration with antigen. Our results indicate a potential for tailored immunotherapeutic interventions via MAIT cell manipulation.

An immunochromatographic test strip for on-site detection of Ralstonia solanacearum in tobacco leaves and soil.

Tobacco bacterial wilt is one of the most devastating soil-borne diseases in tobacco-producing regions worldwide. It is often responsible for significant economic losses during tobacco production. A rapid, specific, and high-throughput on-site detection method is important for plant disease management. In this study, monoclonal antibody 3H3 and polyclonal antibody 0344 specific for Ralstonia solanacearum were used to prepare a colloidal gold-based immunochromatographic test strip (ITS). Under optimal conditions, the detection limit of the ITS was 105 CFU/mL. The ITS was able to detect different R. solanacearum strains collected from Shandong, Yunnan, Guizhou, and Sichuan provinces in China. Moreover, the ITS was highly specific for R. solanacearum, with no cross-reactivity with Alternaria alternata (Fries) Keissler, Pseudomonas syringae pv. angulata, and P. syringae pv. tabaci. Furthermore, R. solanacearum-spiked tobacco leaves and soil were used to evaluate the matrix interference of the developed ITS, which indicated the test strip was unaffected by leaf size or soil abundance.

The spatiotemporal response of China's vegetation greenness to human socio-economic activities.

Climate change and human socioeconomic activities both strongly impact long-term vegetation greenness. It is more a challenge to evaluate the impacts of socioeconomic activities on vegetative greenness than climate change, partially due to the lack of appropriate quantitative indicators of the former. Here we examined the relationship between the remote sensing nighttime light (NTL) data and the Normalized Difference Vegetation Index (NDVI), which in this study are used as the proxies of socioeconomic activities and vegetation greenness, respectively. We first eliminated the vegetation greenness changes in response to climate change and calculated the human-activities-induced NDVI (HNDVI). After explored the spatiotemporal patterns of the HNDVI and NTL data across China from 1998 to 2018, we studied the relationship between the HNDVI and NTL at the grid and county levels, respectively. Our results show that the mean adjusted DN values of the NTL data (NTLI) continuously increase (+0.2938) across our study area from 1998 to 2018, whereas the HNDVI values fluctuate with a general upward trend (+0.0018). Most grids (91.2%) with increased HNDVI were found in rural areas, particularly in the Northeast forest shelterbelt and the Loess Plateau. By contrast, the HNDVI values in rapidly urbanized areas in Chinese major urban agglomerations mainly show a downward trend, especially in the Yangtze River Delta (YRD) urban agglomeration. The relationships between the NTLI and HNDVI are inconsistent over time and across space, which could be attributed to land use conditions, afforestation projects in rural areas, and greening activities in urban areas over different periods and regions.

Carbon Dioxide Chemically Responsive Switchable Gas Valves with Protonation-Induced Liquid Gating Self-Adaptive Systems.

Carbon dioxide (CO2 ) capture and storage technologies are promising to limit CO2 emission from anthropogenic activities, to achieve carbon neutrality goals. CO2 capture requires one to separate CO2 from other gases, and therefore a gas flow system that exhibits discernible gating behaviors for CO2 would be very useful. Here we propose a self-adaptive CO2 gas valve composed of chemically responsive liquid gating systems. The transmembrane critical pressures of the liquid gate vary upon the presence of CO2 , due to the superamphiphiles assembled by poly(propylene glycol) bis(2-aminopropyl ether) and oleic acid in gating liquids that are protonated specifically by CO2 . It is shown that the valve can perform self-adaptive regulation for specific gases and different concentrations of CO2 . This protonation-induced liquid gating mechanism opens a potential platform for applications of CO2 separators, detectors, sensors and beyond.

Mucosal-Associated Invariant T Cells Augment Immunopathology and Gastritis in Chronic Helicobacter pylori Infection.

Mucosal-associated invariant T (MAIT) cells produce inflammatory cytokines and cytotoxic granzymes in response to by-products of microbial riboflavin synthesis. Although MAIT cells are protective against some pathogens, we reasoned that they might contribute to pathology in chronic bacterial infection. We observed MAIT cells in proximity to Helicobacter pylori bacteria in human gastric tissue, and so, using MR1-tetramers, we examined whether MAIT cells contribute to chronic gastritis in a mouse H. pylori SS1 infection model. Following infection, MAIT cells accumulated to high numbers in the gastric mucosa of wild-type C57BL/6 mice, and this was even more pronounced in MAIT TCR transgenic mice or in C57BL/6 mice where MAIT cells were preprimed by Ag exposure or prior infection. Gastric MAIT cells possessed an effector memory Tc1/Tc17 phenotype, and were associated with accelerated gastritis characterized by augmented recruitment of neutrophils, macrophages, dendritic cells, eosinophils, and non-MAIT T cells and by marked gastric atrophy. Similarly treated MR1-/- mice, which lack MAIT cells, showed significantly less gastric pathology. Thus, we demonstrate the pathogenic potential of MAIT cells in Helicobacter-associated immunopathology, with implications for other chronic bacterial infections.

The mechanisms of glycemic variability accelerate diabetic central neuropathy and diabetic peripheral neuropathy in diabetic rats.

The effect of glycemic variability (GV) on diabetic neuropathy, including diabetic central neuropathy and diabetic peripheral neuropathy (DPN), and the involved mechanism are not fully understood. In this study, a fluctuant hyperglycemia rat model was induced by alternate intraperitoneal injections of glucose and insulin. To assess diabetic central neuropathy, step-down type passive avoidance tests were conducted, and the expression levels of p-Tau, T-Tau, p-GSK3ß, GSK3ß, p-Akt, and Akt in the hippocampus were measured. To assess DPN, the motor nerve conduction velocity (MNCV) was measured, and the microstructure of the sciatic nerve was observed. Additionally, the expression levels of oxidative stress and inflammation indicators were detected in the sciatic nerve. We observed that both learning and memory abilities were disrupted by GV. GV promoted Tau phosphorylation and inhibited the Akt/GSK3ß pathway in the hippocampus. Additionally, GV weakened the MNCV of the sciatic nerve, and the structures of both the myelin sheath and the axons in the sciatic nerve were disrupted. GV also significantly reduced the expression of superoxide dismutase (SOD) and increased the expression levels of malondialdehyde (MDA), of proinflammatory cytokines (TNF-α and IL-6) and of NF-κB. In conclusion, the present study highlighted that GV might induce diabetic central neuropathy through the hyperphosphorylation of Tau in the hippocampus by inhibiting the Akt/GSK3ß pathway and that it may cause DPN through oxidative stress and inflammatory responses by activating the NF-κB pathway.

Visual Biosensing with Specific Liquid-Based Interface Behaviors.

Liquid-based interface behaviors at micro/nano or even smaller scales induced by biomolecules take us into a fascinating realm, fostering a deeper understanding and innovation in visual biosensing. This biosensing technology, grounded in specific liquid-based interface behaviors, redefines how diseases can be detected, monitored, and diagnosed in resource-limited settings, providing rapid, cost-effective, and self-testing solutions to the current healthcare landscape. To date, the technology has witnessed significant advancements in visual sensing, driven by diverse liquid-based materials, advanced nanomanufacturing techniques, and a profound understanding of interface-material interactions. In this Perspective, we discuss and elucidate the interface biosensing mechanisms arising from three types, including liquid-solid, liquid-liquid, and liquid-gas interfaces, and we provide insights into the challenges and future development of visual biosensing applications.

RIPK3 controls MAIT cell accumulation during development but not during infection.

Cell death mechanisms in T lymphocytes vary according to their developmental stage, cell subset and activation status. The cell death control mechanisms of mucosal-associated invariant T (MAIT) cells, a specialized T cell population, are largely unknown. Here we report that MAIT cells express key necroptotic machinery; receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) protein, in abundance. Despite this, we discovered that the loss of RIPK3, but not necroptotic effector MLKL or apoptotic caspase-8, specifically increased MAIT cell abundance at steady-state in the thymus, spleen, liver and lungs, in a cell-intrinsic manner. In contrast, over the course of infection with Francisella tularensis, RIPK3 deficiency did not impact the magnitude of the expansion nor contraction of MAIT cell pools. These findings suggest that, distinct from conventional T cells, the accumulation of MAIT cells is restrained by RIPK3 signalling, likely prior to thymic egress, in a manner independent of canonical apoptotic and necroptotic cell death pathways.

Synthetic 5-amino-6-D-ribitylaminouracil paired with inflammatory stimuli facilitates MAIT cell expansion in vivo.

Introduction: Mucosal-associated invariant T (MAIT) cells are a population of innate-like T cells, which mediate host immunity to microbial infection by recognizing metabolite antigens derived from microbial riboflavin synthesis presented by the MHC-I-related protein 1 (MR1). Namely, the potent MAIT cell antigens, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) and 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil (5-OE-RU), form via the condensation of the riboflavin precursor 5-amino-6-D-ribitylaminouracil (5-A-RU) with the reactive carbonyl species (RCS) methylglyoxal (MG) and glyoxal (G), respectively. Although MAIT cells are abundant in humans, they are rare in mice, and increasing their abundance using expansion protocols with antigen and adjuvant has been shown to facilitate their study in mouse models of infection and disease. Methods: Here, we outline three methods to increase the abundance of MAIT cells in C57BL/6 mice using a combination of inflammatory stimuli, 5-A-RU and MG. Results: Our data demonstrate that the administration of synthetic 5-A-RU in combination with one of three different inflammatory stimuli is sufficient to increase the frequency and absolute numbers of MAIT cells in C57BL/6 mice. The resultant boosted MAIT cells are functional and can provide protection against a lethal infection of Legionella longbeachae. Conclusion: These results provide alternative methods for expanding MAIT cells with high doses of commercially available 5-A-RU (± MG) in the presence of various danger signals.

Divergent molecular networks program functionally distinct CD8+ skin-resident memory T cells.

Skin-resident CD8+ T cells include distinct interferon-γ-producing [tissue-resident memory T type 1 (TRM1)] and interleukin-17 (IL-17)-producing (TRM17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that TRM1 and TRM17 cells navigate divergent trajectories to acquire tissue residency in the skin. TRM1 cells depend on a T-bet-Hobit-IL-15 axis, whereas TRM17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in TRM17 cells parallel to that induced by Hobit in TRM1 cells, with an ICOS-c-Maf-IL-7 axis pivotal to TRM17 cell commitment. Accordingly, by targeting this pathway, skin TRM17 cells can be ablated without compromising their TRM1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity.

Energy saving thermal adaptive liquid gating system.

Thermal transfer systems involving temperature control through heating, ventilation, and air conditioning applications have emerged as one of the largest energy issues in buildings. Traditional approaches mainly comprise closed and open systems, both of which have certain advantages and disadvantages in a single heating or cooling process. Here we report a thermal adaptive system with beneficial energy-saving properties, which uses functional liquid to exhibit high metastability, providing durability in a temperature-responsive liquid gating system. With an efficient use of energy, this system achieves smart "breathing" during both heating and cooling processes to dynamically tune the indoor temperature. Theoretical modeling and experiments demonstrate that the adaptive, sandwich-structured, membrane-based system can achieve temperature control, producing obvious advantages of energy saving compared with both closed and open systems through the bistable interfacial design of the liquid gating membrane. Further energy saving evaluation of the system on the basis of simulation with current global greenhouse plantation data shows a reduction of energy consumption of 7.9 × 1013 kJ/year, a percentage change of ∼11.6%. Because the adaptive system can be applied to a variety of thermal transfer processes, we expect it to prove useful in a wide range of real-world applications.

Host-guest liquid gating mechanism with specific recognition interface behavior for universal quantitative chemical detection.

Universal visual quantitative chemical detection technology has emerged as an increasingly crucial tool for convenient testing with immediate results in the fields of environmental assessment, homeland security, clinical drug testing and health care, particularly in resource-limited settings. Here, we show a host-guest liquid gating mechanism to translate molecular interface recognition behavior into visually quantifiable detection signals. Quantitative chemical detection is achieved, which has obvious advantages for constructing a portable, affordable, on-site sensing platform to enable the visual quantitative testing of target molecules without optical/electrical equipment. Experiments and theoretical calculations confirm the specificity and scalability of the system. This mechanism can also be tailored by the rational design of host-guest complexes to quantitatively and visually detect various molecules. With the advantages of versatility and freedom from additional equipment, this detection mechanism has the potential to revolutionize environmental monitoring, food safety analysis, clinical drug testing, and more.

Liquid Gating Meniscus-Shaped Deformable Magnetoelastic Membranes with Self-Driven Regulation of Gas/Liquid Release.

Liquid gating membranes have been demonstrated to show unprecedented properties of dynamicity, stability, adaptivity, and stimulus-responsiveness. Most recently, smart liquid gating membranes have attracted increasing attention to bring some brand-new properties for real-world applications, and various environment-driven systems have been created. Here, a self-driven system of a smart liquid gating membrane is further developed by designing a new sytem based on a liquid gating magnetoelastic porous membrane with reversible meniscus-shaped deformations, and it is not subject to the complex gating liquid restriction of magnetorheological fluids. Compared with other systems, this magnetic-responsive self-driven system has the advantage that it provides a universal and convenient way to realize active regulation of gas/liquid release. Experiments and theoretical calculations demonstrate the stability, the nonfouling behavior, and the tunability of the system. In addition, this system can be used to perfectly open and close gas transport, and the gating pressure threshold for the liquid release can be reduced under the same conditions. Based on the above capabilities, combined with the fast and 3D contactless operation, it will be of benefit in fields ranging from visible gas/liquid mixture content monitoring and energy-saving multiphase separation, remote fluid release, and beyond.

Correlation coefficient-directed label-free characterization of native proteins by surface-enhanced Raman spectroscopy.

Investigation of proteins in their native state is the core of proteomics towards better understanding of their structures and functions. Surface-enhanced Raman spectroscopy (SERS) has shown its unique advantages in protein characterization with fingerprint information and high sensitivity, which makes it a promising tool for proteomics. It is still challenging to obtain SERS spectra of proteins in the native state and evaluate the native degree. Here, we constructed 3D physiological hotspots for a label-free dynamic SERS characterization of a native protein with iodide-modified 140 nm Au nanoparticles. We further introduced the correlation coefficient to quantitatively evaluate the variation of the native degree, whose quantitative nature allows us to explicitly investigate the Hofmeister effect on the protein structure. We realized the classification of a protein of SARS-CoV-2 variants in 15 min, which has not been achieved before. This study offers an effective tool for tracking the dynamic structure of proteins and biomedical research.

CD8 coreceptor engagement of MR1 enhances antigen responsiveness by human MAIT and other MR1-reactive T cells.

Mucosal-associated invariant T (MAIT) cells detect microbial infection via recognition of riboflavin-based antigens presented by the major histocompatibility complex class I (MHC-I)-related protein 1 (MR1). Most MAIT cells in human peripheral blood express CD8αα or CD8αß coreceptors, and the binding site for CD8 on MHC-I molecules is relatively conserved in MR1. Yet, there is no direct evidence of CD8 interacting with MR1 or the functional consequences thereof. Similarly, the role of CD8αα in lymphocyte function remains ill-defined. Here, using newly developed MR1 tetramers, mutated at the CD8 binding site, and by determining the crystal structure of MR1-CD8αα, we show that CD8 engaged MR1, analogous to how it engages MHC-I molecules. CD8αα and CD8αß enhanced MR1 binding and cytokine production by MAIT cells. Moreover, the CD8-MR1 interaction was critical for the recognition of folate-derived antigens by other MR1-reactive T cells. Together, our findings suggest that both CD8αα and CD8αß act as functional coreceptors for MAIT and other MR1-reactive T cells.

Mouse models illuminate MAIT cell biology.

The field of mucosal-associated invariant T cell (MAIT) biology has grown rapidly since the identification of the vitamin-B-based antigens recognised by these specialised T cells. Over the past few years, our understanding of the complexities of MAIT cell function has developed, as they find their place among the other better known cells of the immune system. Key questions relate to understanding when MAIT cells help, when they hinder or cause harm, and when they do not matter. Exploiting mouse strains that differ in MAIT cell numbers, leveraged by specific detection of MAIT cells using MR1-tetramers, it has now been shown that MAIT cells play important immune roles in settings that include bacterial and viral infections, autoimmune diseases and cancer. We have also learnt much about their development, modes of activation and response to commensal microbiota, and begun to try ways to manipulate MAIT cells to improve disease outcomes. Here we review recent studies that have assessed MAIT cells in models of disease.

Repurposing ICG enables MR/PA imaging signal amplification and iron depletion for iron-overload disorders.

Precise and noninvasive theranostic methods to quantify and deplete focal iron are of crucial importance for iron-overload disorders. Here, we developed an indocyanine green (ICG)­based imaging platform to reveal Fe3+ in vitro and in vivo. The high sensitivity and specificity of ICG-Fe interaction facilitated MR images with a marked correlation between T1 signal intensity ratio (T1SIR) changes and Fe3+ concentration in rodent models and humans. On the basis of these findings, a rational design for coordination-driven self-assembly ICG-Lecithin (ICG/Leci) was proposed to determine Fe3+. The enhancement of photoacoustic signal at 890 nm with increasing Fe3+ concentration showed an over 600% higher linear slope than that of T1SIR changes in animal models. ICG/Leci also promoted a 100% increase in iron depletion in the liver compared with deferoxamine. The high MR sensitivity and superior photoacoustic contrast, combined with enhanced iron depletion, demonstrate that ICG/Leci is a promising theranostic agent for simultaneous detection and treatment of iron-overload disorders.