Estimation of the Thermophysical Properties of Pentaalkylguanidinium-Based Magnetic Ionic Liquids with Unusual Thermal Expansion Coefficient.

The thermal expansion coefficient (αexp. ), the molecular volume (Vm ), the entropy of surface formation (Sa ), and the Gibbs energy of surface formation (Ea ) of four pentaalkylguanidinium-based MILs [Cn TMG][FeCl3 Br] (n=2, 4, 6, 8) were calculated based on the density and surface tension data determined from 278.15 to 323.15 K. In terms of classical semiempirical methods, the standard molar entropy (S0 ), the lattice energy (UPOT ), the molar enthalpy of evaporation ( Δ l g H m 0 ( T b ) ${{\rm{\Delta }}_{\rm{l}}^{\rm{g}} H_{\rm{m}}^0 (T_{\rm{b}} )}$ , Δ l g H m 0 ${{\rm{\Delta }}_{\rm{l}}^{\rm{g}} H_{\rm{m}}^0 }$ (298 K)), and the thermal expansion coefficient (αest. ) of the MILs were further estimated. The estimation results indicate that the classical semiempirical methods are suitable for estimating the thermophysical properties of the MILs, except the unusual αexp. , which were extremely larger than those of representative non-magnetic ionic liquids (ILs). We further optimized the estimation methods and discussed the potential reasons for the unusual thermal expansion coefficient of the MILs.

Acylhydrazones as sensitive fluorescent sensors for discriminative detection of thorium (IV) from uranyl and lanthanide ions.

Thorium, as a radioactive element, is always associated with rare earth in nature. So it is an exacting challenge to recognize thorium ion (Th4+) in the presence of lanthanide ions because of their overlapping ionic radii. Here three simple acylhydrazones (AF, AH and ABr, with the functional group fluorine, hydrogen and bromine, respectively) are explored for Th4+ detection. They all exhibit excellent "turn-on" fluorescence selectivity toward Th4+ among f-block ions in aqueous medium with outstanding anti-interference abilities, where the coexistence of lanthanide and uranyl ions in addition with other ordinary metal ions have negligible effects during Th4+ detection. Interestingly, pH variation from 2 to 11 has no significant influence on the detection. Among the three sensors, AF displays the highest sensitivity to Th4+ and ABr the lowest with the emission wavelengths in the order of λAF-Th < λAH-Th < λABr-Th. The detection limit of AF to Th4+ can reach 29 nM (pH = 2) with a binding constant of 6.64 × 109 M-2. Response mechanism for AF toward Th4+ is proposed based on the results of HR-MS, 1H NMR and FT-IR spectroscopies together with DFT calculations. This work provides important implications on the development of related series of ligands in nuclide ions detection and future separation from lanthanide ions.

Size-Controlled Formation of Polymer Janus Discs.

A straightforward method is presented for the preparation of nano- to micrometer-sized Janus discs with controlled shape, size, and aspect ratio. The method relies on cross-linkable ABC triblock terpolymers and involves first the preparation of prolate ellipsoidal microparticles by combining Shirasu porous glass (SPG) membrane emulsification with evaporation-induced confinement assembly (EICA). By varying the pore diameter of the SPG membrane, we produce Janus discs with controlled size distributions centered around hundreds of nanometers to several microns. We further transferred the discs to water by mild sulfonation of PS to polystyrene sulfonic acid (PSS) and verified the Janus character by subsequent labelling with cationic nanoparticles. Finally, we show that the sulfonated Janus discs are amphiphilic and can be used as efficient colloidal stabilizers for oil-in-water (O/W) emulsions.

Magnetic Microemulsions Stabilized by Alkyltrimethylammonium-Based Magnetic Ionic Liquids Surfactants (MILSs).

While traditional microemulsions are versatile media for nanoscience and nanotechnology, stimulus-responsive microemulsions are more challenging to realize, and only a handful of cases have been reported. We here introduce magnetic microemulsions (MMEs) stabilized by alkyltrimethylammonium-based magnetic ionic liquids surfactants (MILSs), paired with water as the polar phase, aliphatic oils as the nonpolar phase, and aliphatic alcohols as the cosurfactant. n-Hexane coupled with n(MILSs/1-butanol) = 1:4 showed the most excellent ability to form MMEs, and the range of the monophasic region was expanded with increasing alkyl chain length of MILSs cation. Classical oil-in-water (O/W), bicontinuous (BC) sponge structure, and inverse water-in-oil (W/O) subregions were clarified by conductivity method. Dynamic light scattering showed that the diameter of W/O microemulsions droplets were about 2-6 nm. Magnetic susceptibility and rheological measurements revealed that these MMEs are with high magnetic susceptibility and low viscosity, which show interesting potential applications based on a manipulation via external magnetic field. Moreover, these MMEs showed Newtonian-like flow behavior within respective subregions, and their magnetic susceptibility was not affected by the subregion structure but MILSs mass fraction.

Frustrated Microparticle Morphologies of a Semicrystalline Triblock Terpolymer in 3D Soft Confinement.

Self-assembly of block copolymers (BCPs) in three-dimensional (3D) confinement of emulsion droplets has emerged as a versatile route for the formation of functional micro- and nanoparticles. While the self-assembly of amorphous coil-coil BCPs is fairly well documented, less is known about the behavior of crystalline-coil BCPs. Here, we demonstrate that confining a linear ABC triblock terpolymer with a crystallizable middle block in oil-in-water (O/W) emulsions results in a range of microparticles with frustrated inner structure originating from the conflict between crystallization and curved interfaces. Polystyrene-block-polyethylene-block-poly(methyl methacrylate) (PS-b-PE-b-PMMA, S32E36M3293) in toluene droplets was subjected to different preparation protocols. If evaporation was performed well above the bulk crystallization temperature of the PE block (Tevap > Tc), S32E36M3293 first microphase-separated into microparticles with lamella morphology followed by crystallization into a variety of frustrated morphologies (e.g., bud-like, double staircase, spherocone). By evaporating at significantly lower temperatures that allow the PE block to crystallize from solution (Tevap < Tc), S32E36M3293 underwent crystallization-driven self-assembly into patchy crystalline-core micelles, followed by confinement assembly into lenticular microparticles with compartmentalized hexagonal cylinder lattices. The frequency of these frustrated morphologies depends on polymer concentration and the evaporation protocol. These results provide a preliminary understanding of the morphological behavior of semicrystalline block copolymers in 3D soft confinement and may provide alternative routes to structure multicompartment microparticles from a broader range of polymer properties.

Phosphatase PTPN22 Regulates Dendritic Cell Homeostasis and cDC2 Dependent T Cell Responses.

Dendritic cells (DCs) are specialized antigen presenting cells that instruct T cell responses through sensing environmental and inflammatory danger signals. Maintaining the homeostasis of the multiple functionally distinct conventional dendritic cells (cDC) subsets that exist in vivo is crucial for regulating immune responses, with changes in numbers sufficient to break immune tolerance. Using Ptpn22-/- mice we demonstrate that the phosphatase PTPN22 is a highly selective, negative regulator of cDC2 homeostasis, preventing excessive population expansion from as early as 3 weeks of age. Mechanistically, PTPN22 mediates cDC2 homeostasis in a cell intrinsic manner by restricting cDC2 proliferation. A single nucleotide polymorphism, PTPN22R620W, is one of the strongest genetic risk factors for multiple autoantibody associated human autoimmune diseases. We demonstrate that cDC2 are also expanded in mice carrying the orthologous PTPN22619W mutation. As a consequence, cDC2 dependent CD4+ T cell proliferation and T follicular helper cell responses are increased. Collectively, our data demonstrate that PTPN22 controls cDC2 homeostasis, which in turn ensures appropriate cDC2-dependent T cell responses under antigenic challenge. Our findings provide a link between perturbations in DC development and susceptibility to a broad spectrum of PTPN22R620W associated human autoimmune diseases.

Loss of PTPN22 abrogates the beneficial effect of cohousing-mediated fecal microbiota transfer in murine colitis.

Fecal microbiota transfer (FMT) is a very efficient approach for the treatment of severe and recurring C. difficile infections. However, the beneficial effect of FMT in other disorders such as ulcerative colitis (UC) or Crohn's disease remains unclear. Furthermore, it is currently unknown how disease-associated genetic variants in donors or recipients influence the effect of FMT. We found that bacteria-transfer from wild-type (WT) donors via cohousing was efficient in inducing recovery from colitis in WT mice, but not in mice deficient in protein-tyrosine phosphatase non-receptor type 22 (PTPN22), a known risk gene for several chronic inflammatory diseases. Also cohousing of PTPN22-deficient mice with diseased WT mice failed to induce faster recovery. Our data indicate that the genetic background of the donor and the recipient influences the outcome of microbiota transfer, and offers a potential explanation why transfer of fecal microbes from some, but not all donors is efficient in UC patients.

Protein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent manner.

The gut microbiota is crucial for our health, and well-balanced interactions between the host's immune system and the microbiota are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). A variant in protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with reduced risk of developing IBD, but promotes the onset of autoimmune disorders. While the role of PTPN22 in modulating molecular pathways involved in IBD pathogenesis is well studied, its impact on shaping the intestinal microbiota has not been addressed in depth. Here, we demonstrate that mice carrying the PTPN22 variant (619W mice) were protected from acute dextran sulfate sodium (DSS) colitis, but suffered from pronounced inflammation upon chronic DSS treatment. The basal microbiota composition was distinct between genotypes, and DSS-induced dysbiosis was milder in 619W mice than in WT littermates. Transfer of microbiota from 619W mice after the first DSS cycle into treatment-naive 619W mice promoted colitis, indicating that changes in microbial composition enhanced chronic colitis in those animals. This indicates that presence of the PTPN22 variant affects intestinal inflammation by modulating the host's response to the intestinal microbiota.

Multicompartment Microparticles with Patchy Topography through Solvent-Adsorption Annealing.

We report on the evaporation-induced confinement assembly (EICA) of polystyrene-b-polybutadiene-b-poly(methyl methacrylate) (PS-b-PB-b-PMMA, SBM) triblock terpolymers into multicompartment microparticles and follow their morphological evolution during solvent-adsorption annealing. We initially obtain elliptic microparticles with axially stacked PS/PB/PMMA morphology using cetyltrimethylammonium bromide (CTAB) as surfactant. Exchanging the surfactant to poly(vinyl alcohol) (PVA) during solvent vapor annealing with chloroform (CHCl3), PMMA preferentially interacts with the interface, and microparticles change their shape into spheres with concentric morphology. Surprisingly, this transformation initiates at both poles of the microparticles simultaneously and then proceeds toward the equator, resulting in particles with inner morphology and patchy topography. We observed this evolution for different PB fractions, suggesting the mechanism to be more general and the EICA process to be a suitable method to generate patchy particle surfaces.

Protein tyrosine phosphatase PTPN22 regulates LFA-1 dependent Th1 responses.

A missense C1858T single nucleotide polymorphism within PTPN22 is a strong genetic risk factor for the development of multiple autoimmune diseases. PTPN22 encodes a protein tyrosine phosphatase that negatively regulates immuno-receptor proximal Src and Syk family kinases. Notably, PTPN22 negatively regulates kinases downstream of T-cell receptor (TCR) and LFA-1, thereby setting thresholds for T-cell activation. Alterations to the quality of TCR and LFA-1 engagement at the immune synapse and the regulation of downstream signals can have profound effects on the type of effector T-cell response induced. Here we describe how IFNγ+ Th1 responses are potentiated in Ptpn22-/- T-cells and in T-cells from mice expressing Ptpn22R619W (the mouse orthologue of the human genetic variant) as they age, or following repeated immune challenge, and explore the mechanisms contributing to the expansion of Th1 cells. Specifically, we uncover two LFA-1-ICAM dependent mechanisms; one T-cell intrinsic, and one T-cell extrinsic. Firstly, we found that in vitro anti-CD3/LFA-1 induced Th1 responses were enhanced in Ptpn22-/- T-cells compared to WT, whereas anti-CD3/anti-CD28 induced IFNy responses were similar. These data were associated with an enhanced ability of Ptpn22-/- T-cells to engage ICAM-1 at the immune synapse when incubated on planar lipid bilayers, and to form conjugates with dendritic cells. Secondly, we observed a T-cell extrinsic mechanism whereby repeated stimulation of WT OT-II T-cells with LPS and OVA323-339 pulsed Ptpn22-/- bone marrow derived dendritic cells (BMDCs) was sufficient to enhance Th1 cell development compared to WT BMDCs. Furthermore, this response could be reversed by LFA-1 blockade. Our data point to two related but distinct mechanisms by which PTPN22 regulates LFA-1 dependent signals to enhance Th1 development, highlighting how perturbations to PTPN22 function over time to regulate the balance of the immune response.

Protein tyrosine phosphatase PTPN22 regulates IL-1ß dependent Th17 responses by modulating dectin-1 signaling in mice.

A single nucleotide polymorphism within the PTPN22 gene is a strong genetic risk factor predisposing to the development of multiple autoimmune diseases. PTPN22 regulates Syk and Src family kinases downstream of immuno-receptors. Fungal ß-glucan receptor dectin-1 signals via Syk, and dectin-1 stimulation induces arthritis in mouse models. We investigated whether PTPN22 regulates dectin-1 dependent immune responses. Bone marrow derived dendritic cells (BMDCs) generated from C57BL/6 wild type (WT) and Ptpn22-/- mutant mice, were pulsed with OVA323-339 and the dectin-1 agonist curdlan and co-cultured in vitro with OT-II T-cells or adoptively transferred into OT-II mice, and T-cell responses were determined by immunoassay. Dectin-1 activated Ptpn22-/- BMDCs enhanced T-cell secretion of IL-17 in vitro and in vivo in an IL-1ß dependent manner. Immunoblotting revealed that compared to WT, dectin-1 activated Ptpn22-/- BMDCs displayed enhanced Syk and Erk phosphorylation. Dectin-1 activation of BMDCs expressing Ptpn22R619W (the mouse orthologue of human PTPN22R620W ) also resulted in increased IL-1ß secretion and T-cell dependent IL-17 responses, indicating that in the context of dectin-1 Ptpn22R619W operates as a loss-of-function variant. These findings highlight PTPN22 as a novel regulator of dectin-1 signals, providing a link between genetically conferred perturbations of innate receptor signaling and the risk of autoimmune disease.

Protein tyrosine phosphatase PTPN22 is dispensable for dendritic cell antigen processing and promotion of T-cell activation by dendritic cells.

The PTPN22R620W single nucleotide polymorphism increases the risk of developing multiple autoimmune diseases including type 1 diabetes, rheumatoid arthritis and lupus. PTPN22 is highly expressed in antigen presenting cells (APCs) where the expression of the murine disease associated variant orthologue (Ptpn22R619W) is reported to dysregulate pattern recognition receptor signalling in dendritic cells (DCs) and promote T-cell proliferation. Because T-cell activation is dependent on DC antigen uptake, degradation and presentation, we analysed the efficiency of these functions in splenic and GM-CSF bone marrow derived DC from wild type (WT), Ptpn22-/- or Ptpn22R619W mutant mice. Results indicated no differential ability of DCs to uptake antigen via macropinocytosis or receptor-mediated endocytosis. Antigen degradation and presentation was also equal as was WT T-cell conjugate formation and subsequent T-cell proliferation. Despite the likely presence of multiple phosphatase-regulated pathways in the antigen uptake, processing and presentation pathways that we investigated, we observed that Ptpn22 and the R619W autoimmune associated variant were dispensable. These important findings indicate that under non-inflammatory conditions there is no requirement for Ptpn22 in DC dependent antigen uptake and T-cell activation. Our findings reveal that perturbations in antigen uptake and processing, a fundamental pathway determining adaptive immune responses, are unlikely to provide a mechanism for the risk associated with the Ptpn22 autoimmune associated polymorphism.

PTPN22 regulates NLRP3-mediated IL1B secretion in an autophagy-dependent manner.

A variant within the gene locus encoding PTPN22 (protein tyrosine phosphatase, non-receptor type 22) emerged as an important risk factor for auto-inflammatory disorders, including rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes, but at the same time protects from Crohn disease, one of the 2 main forms of inflammatory bowel diseases. We have previously shown that loss of PTPN22 results in decreased NLRP3 (NLR family pyrin domain containing 3) activation and that this effect is mediated via enhanced NLRP3 phosphorylation. However, it is unclear how phosphorylation of NLRP3 mediates its inhibition. Here, we demonstrate that loss of macroautophagy/autophagy abrogates the inhibitory effect on NLRP3 activation observed upon loss of PTPN22. Phosphorylated, but not nonphosphorylated NLRP3 is found in autophagosomes, indicating that NLRP3 phosphorylation mediates its inactivation via promoting sequestration into phagophores, the precursors to autophagosomes. This finding shows that autophagy and NLRP3 inflammasome activation are connected, and that PTPN22 plays a key role in the regulation of those 2 pathways. Given its role in inflammatory disorders, PTPN22 might be an attractive therapeutic target, and understanding the cellular mechanisms modulated by PTPN22 is of crucial importance.

The Autoimmune Risk Variant PTPN22 C1858T Alters B Cell Tolerance at Discrete Checkpoints and Differentially Shapes the Naive Repertoire.

A common genetic variant in the gene encoding the protein tyrosine phosphatase nonreceptor type 22 (PTPN22 C1858T) has been linked to a wide range of autoimmune disorders. Although a B cell-intrinsic role in promoting disease has been reported, the mechanism(s) through which this variant functions to alter the preimmune B cell repertoire remains unknown. Using a series of polyclonal and transgenic self-reactive models harboring the analogous mutation in murine Ptpn22, we show evidence for enhanced BCR, B cell-activating factor receptor, and CD40 coreceptor programs, leading to broadly enhanced positive selection of B cells at two discrete checkpoints in the bone marrow and spleen. We further identified a bias for selection of B cells into the follicular mature versus marginal zone B cell compartment. Using a biomarker to track a self-reactive H chain in peripheral blood, we found evidence of similarly enhanced positive selection in human carriers of the PTPN22 C1858T variant. Our combined data support a model whereby the risk variant augments the BCR and coreceptor programs throughout B cell development, promoting enrichment of self-reactive specificities into the follicular mature compartment and thereby likely increasing the risk for seeding of autoimmune B cell responses.

The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity.

The single-nucleotide polymorphism rs1990760 in the gene encoding the cytosolic viral sensor IFIH1 results in an amino-acid change (A946T; IFIH1T946) that is associated with multiple autoimmune diseases. The effect of this polymorphism on both viral sensing and autoimmune pathogenesis remains poorly understood. Here we found that human peripheral blood mononuclear cells (PBMCs) and cell lines expressing the risk variant IFIH1T946 exhibited heightened basal and ligand-triggered production of type I interferons. Consistent with those findings, mice with a knock-in mutation encoding IFIH1T946 displayed enhanced basal expression of type I interferons, survived a lethal viral challenge and exhibited increased penetrance in autoimmune models, including a combinatorial effect with other risk variants. Furthermore, IFIH1T946 mice manifested an embryonic survival defect consistent with enhanced responsiveness to RNA self ligands. Together our data support a model wherein the production of type I interferons driven by an autoimmune risk variant and triggered by ligand functions to protect against viral challenge, which probably accounts for its selection within human populations but provides this advantage at the cost of modestly promoting the risk of autoimmunity.

NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22.

Inflammasomes form as the result of the intracellular presence of danger-associated molecular patterns and mediate the release of active IL-1ß, which influences a variety of inflammatory responses. Excessive inflammasome activation results in severe inflammatory conditions, but physiological IL-1ß secretion is necessary for intestinal homeostasis. Here, we have described a mechanism of NLRP3 inflammasome regulation by tyrosine phosphorylation of NLRP3 at Tyr861. We demonstrated that protein tyrosine phosphatase non-receptor 22 (PTPN22), variants in which are associated with chronic inflammatory disorders, dephosphorylates NLRP3 upon inflammasome induction, allowing efficient NLRP3 activation and subsequent IL-1ß release. In murine models, PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1ß. Conversely, patients with inflammatory bowel disease (IBD) that carried an autoimmunity-associated PTPN22 variant had increased IL-1ß levels. Together, our results identify tyrosine phosphorylation as an important regulatory mechanism for NLRP3 that prevents aberrant inflammasome activation.

Analysis of the origin of peak aerosol optical depth in springtime over the Gulf of Tonkin.

By aggregating MODIS (moderate-resolution imaging spectroradiometer) AOD (aerosol optical depth) and OMI (ozone monitoring instrument) UVAI (ultra violet aerosol index) datasets over 2010-2014, it was found that peak aerosol loading in seasonal variation occurred annually in spring over the Gulf of Tonkin (17-23 °N, 105-110 °E). The vertical structure of the aerosol extinction coefficient retrieved from the spaceborne lidar CALIOP (cloud-aerosol lidar with orthogonal polarization) showed that the springtime peak AOD could be attributed to an abrupt increase in aerosol loading between altitudes of 2 and 5 km. In contrast, aerosol loading in the low atmosphere (below 1 km) was only half of that in winter. Wind fields in the low and high atmosphere exhibited opposite transportation patterns in spring over the Gulf of Tonkin, implying different sources for each level. By comparing the emission inventory of anthropogenic sources with biomass burning, and analyzing the seasonal variation of the vertical structure of aerosols over the Northern Indo-China Peninsula (NIC), it was concluded that biomass burning emissions contributed to high aerosol loading in spring. The relatively high topography and the high surface temperature in spring made planetary boundary layer height greater than 3 km over NIC. In addition, small-scale cumulus convection frequently occurred, facilitating pollutant rising to over 3 km, which was a height favoring long-range transport. Thus, pollutants emitted from biomass burning over NIC in spring were raised to the high atmosphere, then experienced long-range transport, leading to the increase in aerosol loading at high altitudes over the Gulf of Tonkin during spring.

The role of PTPN22 risk variant in the development of autoimmunity: finding common ground between mouse and human.

The PTPN22 1858T variant was among the first single nucleotide polymorphisms to be associated with multiple autoimmune diseases. Lymphocyte tyrosine phosphatase, a coding variant within the tyrosine phosphatases, is known to participate in AgR signaling; the impact of this variant on the immune response and its role in the development of autoimmunity have been a focus of study. These studies used a series of approaches, including transfected cell lines, animal models, and primary human lymphocytes, and identified multiple alterations in cell signaling and function linked to the PTPN22 variant. Conflicting findings led to questions of how best to study the role of this variant in human autoimmunity. In this review, we discuss these differences and the factors that may account for them, as well as show how an integrated approach can lead to a more complete understanding of the mechanisms that promote autoimmunity in the context of the PTPN22 1858T risk variant.