Leukemia inhibitory factor (LIF) receptor amplifies pathogenic activation of fibroblasts in lung fibrosis.

Fibrosis drives end-organ damage in many diseases. However, clinical trials targeting individual upstream activators of fibroblasts, such as TGFß, have largely failed. Here, we target the leukemia inhibitory factor receptor (LIFR) as a "master amplifier" of multiple upstream activators of lung fibroblasts. In idiopathic pulmonary fibrosis (IPF), the most common fibrotic lung disease, we found that lung myofibroblasts had high LIF expression. Further, TGFß1, one of the key drivers of fibrosis, upregulated LIF expression in IPF fibroblasts. In vitro anti-LIFR antibody blocking on human IPF lung fibroblasts reduced induction of profibrotic genes downstream of TGFß1, IL-4 and IL-13. Further, siRNA silencing of LIFR in IPF precision cut lung slices reduced expression of fibrotic proteins. Together, we find that LIFR drives an autocrine positive feedback loop that amplifies and sustains pathogenic activation of IPF fibroblasts downstream of multiple external stimuli, implicating LIFR as a therapeutic target in fibrosis. Significance Statement: Fibroblasts have a central role in the pathogenesis of fibrotic diseases. However, due to in part to multiple profibrotic stimuli, targeting a single activator of fibroblasts, like TGFß, has not yielded successful clinical treatments. We hypothesized that a more effective therapeutic strategy is identifying a downstream "master amplifier" of a range of upstream profibrotic stimuli. This study identifies the leukemia inhibitory factor receptor (LIFR) on fibrotic lung fibroblasts amplifies multiple profibrotic stimuli, such as IL-13 and TGFß. Blocking LIFR reduced fibrosis in ex vivo lung tissue from patients with idiopathic pulmonary fibrosis (IPF). LIFR, acting as a master amplifier downstream of fibroblast activation, offers an alternative therapeutic strategy for fibrotic diseases.

Influence of ZIF-9 and ZIF-12 structure on the formation of a series of new Co/N-doped porous carbon composites as anode electrodes for high-performance lithium-ion batteries.

A series of new Co/N-doped porous carbon composites, denoted as Co/CZIF-9 and Co/CZIF-12, containing Co nanoparticles encapsulated in nitrogen-doped carbon matrices were prepared by annealing Co-based zeolite imidazolate framework materials, ZIF-9 and ZIF-12, as the efficient precursors at different temperatures. The structural features of the as-synthesized composites at 900 °C were determined by analytical methods with high reliability. Consequently, Co/CZIF-12_900 exhibits a high first specific discharge capacity of 971.0 mA h g-1 at a current density of 0.1 A g-1. Notably, the specific discharge/charge capacity of Co/CZIF-12_900 reaches about 508.8 mA h g-1 at 0.1 A g-1 after 100 cycles. The outstanding behaviors can be accounted for by the efficient incorporation of hetero-nitrogen doping and the Co nanoparticles within the layered structure of porous carbon, enhancing electrical conductivity and structural stability and limiting volume change during the intercalation/deintercalation of Li+ ions. These findings suggest that the Co/CZIF-12_900 material could be employed as a promising anode electrode for energy storage products.

Engineering of appropriate pore size combined with sulfonic functionalization in a Zr-MOF with reo topology for the ultra-high removal of cationic malachite green dye from an aqueous medium.

A Zr-based metal-organic framework with reo topology, denoted as Reo-MOF-1, was fabricated through a solvothermal method capable of efficiently removing the cationic MG dye from an aqueous medium. The effect of pH solution, adsorbent content, adsorption isotherm, and kinetics on the MG capture was observed to determine the optimal conditions. Accordingly, the maximum adsorption capacity of MG over H+⊂Reo-MOF-1 reaches the value of 2532.1 mg g-1 at neutral pH, which is much greater than the published materials. Moreover, the results of the MG process on H+⊂Reo-MOF-1 fit with the Langmuir isotherm and pseudo second order kinetic model. Hence, MG removal is a chemical adsorption process. Remarkably, H+⊂Reo-MOF-1 can maintain the uptake for MG at about 94% over eight cycles. The MG adsorption mechanism is interpreted via the incorporated analyses and experiments. In detail, Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, powder X-ray diffraction (PXRD), and thermogravimetric analysis (TGA-DSC) of MG⊂Reo-MOF-1 in comparison with H+⊂Reo-MOF-1 indicate that the electrostatic attraction and π-π stacking interaction are found via the interaction between the cationic MG ions and SO3 - moieties within MOF as well as the π electron clouds in the benzene ring of the adsorbent and adsorbate, resulting in significant improvement the MG adsorption uptake. These data prove that acidified Reo-MOF-1 possesses promising application as an effective absorbent of toxic dye in practical conditions.

Population-Based Pharmacokinetics and Dose Optimization of Imipenem in Vietnamese Critically-Ill Patients.

Purpose: The purpose of this study was to characterize the population-based pharmacokinetic (POP-PK) profile of imipenem in Vietnamese adult patients and to assess the probability of target attainment (PTA) of the pharmacokinetic/pharmacodynamic (PK/PD) parameter to determine the optimal dose. Patients and Methods: A POP-PK model of imipenem was developed in patients with severe infection from a 1500-bed general hospital in Vietnam, using MONOLIX 2019. After the initial dose infusion, 6 blood samples per patient were collected to measure plasma imipenem levels. Eight covariates (eg, age, weight) were investigated to ascertain their influence on imipenem's PK. Monte Carlo simulations were performed to determine the PTA for the time in which the total steady-state imipenem concentrations remained above the MIC (T>MIC) for 40% and 100% of the dosing interval. Results: The best fit to the PK data was a two-compartment model with inter-individual variability (IIV) in clearance (CL), central volume of distribution (Vc), intercompartmental clearance (Q), and peripheral volume of distribution (Vp). Only creatinine clearance was retained as a covariate on CL in the final model. The typical value of CL and Vc were estimated to be 4.79 L/h and 11.1 L, respectively. The between-subject variability in this population was noted to be high (>38%, especially for IIV on Q at 110%). Prolonged or continuous infusion demonstrated efficacy (40% T>MIC) against bacteria with a MIC of 4mg/L. To achieve 100% T>MIC or bacteria with MIC>4 mg/L, however, the number of doses must be increased while maintaining the same daily dose for the 3-hour prolonged infusion regimen. Conclusion: A population pharmacokinetic model of imipenem was developed for Vietnamese adult patients with severe illness. By using Monte Carlo simulation, the appropriate dose has been suggested based on the bacterial MIC value and the targeted PK/PD goal.

Enhancing the remarkable adsorption of Pb2+ in a series of sulfonic-functionalized Zr-based MOFs: a combined theoretical and experimental study for elucidating the adsorption mechanism.

A series of Zr-based metal-organic frameworks was prepared via the solvothermal route using sulfonic-rich linkers for the efficient capture of Pb2+ ions from aqueous medium. The factors affecting adsorption such as the solution pH, adsorbent dosage, contact time, adsorption isotherms, and mechanism were studied. Consequently, the maximum adsorption capacity of Pb2+ on the acidified VNU-23 was determined to be 617.3 mg g-1, which is much higher than that of previously reported adsorbents and MOF materials. Furthermore, the adsorption isotherms and kinetics of the Pb2+ ion are in good accordance with the Langmuir and pseudo-second-order kinetic model, suggesting that the uptake of Pb2+ is a chemisorption process. The reusability experiments demonstrated the facile recovery of the H+⊂VNU-23 material through immersion in an HNO3 solution (pH = 3), where its Pb2+ adsorption efficiency still remained at about 90% of the initial uptake over seven cycles. Remarkably, the adsorption mechanism was elucidated through a combined theoretical and experimental investigation. Accordingly, the Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, scanning electron microscopy connected to energy-dispersive X-ray mapping (SEM-EDX-mapping), and X-ray photoelectron spectroscopy (XPS) analysis of the Pb⊂VNU-23 sample and comparison with H+⊂VNU-23 confirmed that the electrostatic interaction occurs via the interaction between the SO3- moieties in the framework and the Pb2+ ion, leading to the formation of a Pb-O bond. In addition, the density functional theory (DFT) calculations showed the effective affinity of the MOF adsorbent toward the Pb2+ ion via the strong driving force mentioned in the experimental studies. Thus, these findings illustrate that H+⊂VNU-23 can be employed as a potential adsorbent to eliminate Pb2+ ions from wastewater.

SLAMF7 engagement superactivates macrophages in acute and chronic inflammation.

Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a superactivated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression and engaging SLAMF7 drove a strong wave of inflammatory cytokine expression. Induction of TNF-α after SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients but also in gut macrophages from patients with active Crohn's disease and in lung macrophages from patients with severe COVID-19. This suggests a central role for SLAMF7 in macrophage superactivation with broad implications in human disease pathology.

Fibroblast pathology in inflammatory diseases.

Fibroblasts are important cells for the support of homeostatic tissue function. In inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, fibroblasts take on different roles (a) as inflammatory cells themselves and (b) in recruiting leukocytes, driving angiogenesis, and enabling chronic inflammation in tissues. Recent advances in single-cell profiling techniques have transformed the ability to examine fibroblast states and populations in inflamed tissues, providing evidence of previously underappreciated heterogeneity and disease-associated fibroblast populations. These studies challenge the preconceived notion that fibroblasts are homogeneous and provide new insights into the role of fibroblasts in inflammatory pathology. In addition, new molecular insights into the mechanisms of fibroblast activation reveal powerful cell-intrinsic amplification loops that synergize with primary fibroblast stimuli to result in striking responses. In this Review, we focus on recent developments in our understanding of fibroblast heterogeneity and fibroblast pathology across tissues and diseases in rheumatoid arthritis and inflammatory bowel diseases. We highlight new approaches to, and applications of, single-cell profiling techniques and what they teach us about fibroblast biology. Finally, we address how these insights could lead to the development of novel therapeutic approaches to targeting fibroblasts in disease.

The genomic basis of evolutionary differentiation among honey bees.

In contrast to the western honey bee, Apis mellifera, other honey bee species have been largely neglected despite their importance and diversity. The genetic basis of the evolutionary diversification of honey bees remains largely unknown. Here, we provide a genome-wide comparison of three honey bee species, each representing one of the three subgenera of honey bees, namely the dwarf (Apis florea), giant (A. dorsata), and cavity-nesting (A. mellifera) honey bees with bumblebees as an outgroup. Our analyses resolve the phylogeny of honey bees with the dwarf honey bees diverging first. We find that evolution of increased eusocial complexity in Apis proceeds via increases in the complexity of gene regulation, which is in agreement with previous studies. However, this process seems to be related to pathways other than transcriptional control. Positive selection patterns across Apis reveal a trade-off between maintaining genome stability and generating genetic diversity, with a rapidly evolving piRNA pathway leading to genomes depleted of transposable elements, and a rapidly evolving DNA repair pathway associated with high recombination rates in all Apis species. Diversification within Apis is accompanied by positive selection in several genes whose putative functions present candidate mechanisms for lineage-specific adaptations, such as migration, immunity, and nesting behavior.

A confinement of N-heterocyclic molecules in a metal-organic framework for enhancing significant proton conductivity.

A series of N-heterocyclic⊂VNU-23 materials have been prepared via the impregnation procedure of N-heterocyclic molecules into VNU-23. Their structural characterizations, PXRD, FT-IR, Raman, TGA, 1H-NMR, SEM-EDX, and EA, confirmed that N-heterocyclic molecules presented within the pores of parent VNU-23, leading to a remarkable enhancement in proton conductivity. Accordingly, the composite with the highest loading of imidazole, Im13.5⊂VNU-23, displays a maximum proton conductivity value of 1.58 × 10-2 S cm-1 (85% RH and 70 °C), which is ∼4476-fold higher than H+⊂VNU-23 under the same conditions. Remarkably, the proton conductivity of Im13.5⊂VNU-23 exceeds the values at 85% RH for several of the reported high-performing MOF materials. Furthermore, Im13.5⊂VNU-23 can retain a stable proton conductivity for more than 96 h, as evidenced by FT-IR and PXRD analyses. These results prove that this hybrid material possesses potential applications as a commercial proton exchange membrane fuel cell.

A new approach for ultra-high adsorption of cationic methylene blue in a Zr-sulfonic-based metal-organic framework.

A series of Zr-sulfonic-based metal-organic frameworks have been synthesized by the solvothermal method, namely VNU-17 and VNU-23. Particularly, VNU-17 and VNU-23 adopt the sulfonate group (SO3 -) moieties densely packed within their structure, which can efficiently uptake MB+ from wastewater. The maximum adsorption capacity for MB+ onto VNU-23 is up to 1992 mg g-1 at pH = 7, which is more than five times that of activated carbon and possesses the highest value among all the reported MOF materials. In addition, VNU-23 retains the adsorption uptake of MB for at least five cycles. The adsorption isotherms and kinetic studies reveal that MB+ dye adsorption onto VNU-23 fits a Langmuir isotherm and the pseudo second order kinetic model. Furthermore, the ultra-high adsorption capacity of VNU-23 for MB dye can be accounted for by the suitable pore/channel size together with electrostatic attraction and π-π interactions. These results indicate that VNU-23 can be utilized as a promising candidate for removing MB+ from an aqueous medium.

MaizeMine: A Data Mining Warehouse for the Maize Genetics and Genomics Database.

MaizeMine is the data mining resource of the Maize Genetics and Genome Database (MaizeGDB; http://maizemine.maizegdb.org). It enables researchers to create and export customized annotation datasets that can be merged with their own research data for use in downstream analyses. MaizeMine uses the InterMine data warehousing system to integrate genomic sequences and gene annotations from the Zea mays B73 RefGen_v3 and B73 RefGen_v4 genome assemblies, Gene Ontology annotations, single nucleotide polymorphisms, protein annotations, homologs, pathways, and precomputed gene expression levels based on RNA-seq data from the Z. mays B73 Gene Expression Atlas. MaizeMine also provides database cross references between genes of alternative gene sets from Gramene and NCBI RefSeq. MaizeMine includes several search tools, including a keyword search, built-in template queries with intuitive search menus, and a QueryBuilder tool for creating custom queries. The Genomic Regions search tool executes queries based on lists of genome coordinates, and supports both the B73 RefGen_v3 and B73 RefGen_v4 assemblies. The List tool allows you to upload identifiers to create custom lists, perform set operations such as unions and intersections, and execute template queries with lists. When used with gene identifiers, the List tool automatically provides gene set enrichment for Gene Ontology (GO) and pathways, with a choice of statistical parameters and background gene sets. With the ability to save query outputs as lists that can be input to new queries, MaizeMine provides limitless possibilities for data integration and meta-analysis.

CUX1 and IκBζ (NFKBIZ) mediate the synergistic inflammatory response to TNF and IL-17A in stromal fibroblasts.

The role of stromal fibroblasts in chronic inflammation is unfolding. In rheumatoid arthritis, leukocyte-derived cytokines TNF and IL-17A work together, activating fibroblasts to become a dominant source of the hallmark cytokine IL-6. However, IL-17A alone has minimal effect on fibroblasts. To identify key mediators of the synergistic response to TNF and IL-17A in human synovial fibroblasts, we performed time series, dose-response, and gene-silencing transcriptomics experiments. Here we show that in combination with TNF, IL-17A selectively induces a specific set of genes mediated by factors including cut-like homeobox 1 (CUX1) and IκBζ (NFKBIZ). In the promoters of CXCL1, CXCL2, and CXCL3, we found a putative CUX1-NF-κB binding motif not found elsewhere in the genome. CUX1 and NF-κB p65 mediate transcription of these genes independent of LIFR, STAT3, STAT4, and ELF3. Transcription of NFKBIZ, encoding the atypical IκB factor IκBζ, is IL-17A dose-dependent, and IκBζ only mediates the transcriptional response to TNF and IL-17A, but not to TNF alone. In fibroblasts, IL-17A response depends on CUX1 and IκBζ to engage the NF-κB complex to produce chemoattractants for neutrophil and monocyte recruitment.

Author Correction: γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis.

In the version of this article initially published, three authors (Hui-Fern Kuoy, Adam P. Uldrich and Dale. I. Godfrey) and their affiliations, acknowledgments and contributions were not included. The correct information is as follows:Ayano C. Kohlgruber1,2, Shani T. Gal-Oz3, Nelson M. LaMarche1,2, Moto Shimazaki1, Danielle Duquette4, Hui-Fern Koay5,6, Hung N. Nguyen1, Amir I. Mina4, Tyler Paras1, Ali Tavakkoli7, Ulrich von Andrian2,8, Adam P. Uldrich5,6, Dale I. Godfrey5,6, Alexander S. Banks4, Tal Shay3, Michael B. Brenner1,10* and Lydia Lynch1,4,9,10*1Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA. 2Division of Medical Sciences, Harvard Medical School, Boston, MA, USA. 3Department of Life Sciences, Ben-Gurion University of the Negev, Beersheba, Israel. 4Division of Endocrinology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. 5Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia. 6ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Australia. 7Department of General and Gastrointestinal Surgery, Brigham and Women's Hospital, Boston, MA, USA. 8Department of Microbiology and Immunology, Harvard Medical School, Boston, MA, USA. 9School of Biochemistry and Immunology, Trinity College, Dublin, Ireland. 10These authors jointly supervised this work: Michael B. Brenner, Lydia Lynch. *e-mail: mbrenner@research.bwh.harvard.edu; llynch@bwh.harvard.eduAcknowledgementsWe thank A.T. Chicoine, flow cytometry core manager at the Human Immunology Center at BWH, for flow cytometry sorting. We thank D. Sant'Angelo (Rutgers Cancer Institute) for providing Zbtb16-/- mice and R. O'Brien (National Jewish Health) for providing Vg4/6-/- mice. Supported by NIH grant R01 AI11304603 (to M.B.B.), ERC Starting Grant 679173 (to L.L.), the National Health and Medical Research Council of Australia (1013667), an Australian Research Council Future Fellowship (FT140100278 for A.P.U.) and a National Health and Medical Research Council of Australia Senior Principal Research Fellowship (1117766 for D.I.G.).Author contributionsA.C.K., L.L., and M.B.B. conceived and designed the experiments, and wrote the manuscript. A.C.K., N.M.L., L.L., H.N.N., M.S., T.P., and D.D. performed the experiments. S.T.G.-O. and T.S. performed the RNA-seq analysis. A.S.B. and A.I.M. provided advice and performed the CLAMS experiments. A.T. provided human bariatric patient samples. Parabiosis experiments were performed in the laboratory of U.v.A. H.-F.K., A.P.U. and D.I.G provided critical insight into the TCR chain usage of PLZF+ γδ T cells. M.B.B., N.M.L., and L.L. critically reviewed the manuscript.The errors have been corrected in the HTML and PDF version of the article.Correction to: Nature Immunology doi:10.1038/s41590-018-0094-2 (2018), published online 18 April 2018.

Historical demography of four gecko species specializing in boulder cave habitat: Implications in the evolutionary dead end hypothesis and conservation.

Specialization in narrow ecological niches may not only help species to survive in competitive or unique environments but also contribute to their extermination over evolutionary time. Although the "evolutionary dead end" hypothesis has long been debated, empirical evidence from species with detailed information on niche specialization and evolutionary history remains rare. Here we use a group of four closely related Cnemaspis gecko species that depend highly on granite boulder caves in the Mekong Delta to investigate the potential impact of ecological specialization on their evolution and population dynamics. Isolated by unsuitable floodplain habitats, these boulder-dwelling geckos are among the most narrowly distributed Squamata in the world. We applied several coalescence-based approaches combined with the RAD-seq technique to estimate their divergence times, gene flow and demographic fluctuations during the speciation and population differentiation processes. Our results reveal long-term population shrinkage in the four geckos and limited gene flow during their divergence. The results suggest that the erosion and fragmentation of the granite boulder hills have greatly impacted population divergence and declines. The habitat specialization of these geckos has led to fine-scaled speciation in these granite rocky hills; in contrast, specialization might also have pushed these species toward the edge of extinction. Our study also emphasizes the conservation urgency of these vulnerable, cave-dependent geckos.

A Series of Metal-Organic Frameworks for Selective CO2 Capture and Catalytic Oxidative Carboxylation of Olefins.

Three new lanthanide-based metal-organic frameworks (Ln-MOFs), namely MOF-590, -591, and -592 constructed from a tetratopic linker, benzoimidephenanthroline tetracarboxylic acid (H4BIPA-TC), were synthesized under solvothermal conditions and fully characterized. All of the new MOFs exhibit three-dimensional frameworks, which adopt unprecedented topologies in MOF field. Gas adsorption measurements of MOF-591 and -592 revealed good adsorption of CO2 (low pressure, at room temperature) and moderate CO2 selectivity over N2 and CH4. Consequently, breakthrough experiments illustrated the separation of CO2 from binary mixture of CO2 and N2 with the use of MOF-592. Accordingly, MOF-592 revealed the selective CO2 capture effectively without any loss in performance after three cycles. Moreover, MOF-590, -591, and -592 showed to be catalytically active in the oxidative carboxylation of styrene and CO2 for a one-pot synthesis of styrene carbonate under mild conditions (1 atm CO2, 80 °C, and without solvent). Among the new materials, MOF-590 revealed a remarkable efficiency with exceptional conversion (96%), selectivity (95%), and yield (91%).

High-throughput identification of noncoding functional SNPs via type IIS enzyme restriction.

Genome-wide association studies (GWAS) have identified many disease-associated noncoding variants, but cannot distinguish functional single-nucleotide polymorphisms (fSNPs) from others that reside incidentally within risk loci. To address this challenge, we developed an unbiased high-throughput screen that employs type IIS enzymatic restriction to identify fSNPs that allelically modulate the binding of regulatory proteins. We coupled this approach, termed SNP-seq, with flanking restriction enhanced pulldown (FREP) to identify regulation of CD40 by three disease-associated fSNPs via four regulatory proteins, RBPJ, RSRC2 and FUBP-1/TRAP150. Applying this approach across 27 loci associated with juvenile idiopathic arthritis, we identified 148 candidate fSNPs, including two that regulate STAT4 via the regulatory proteins SATB2 and H1.2. Together, these findings establish the utility of tandem SNP-seq/FREP to bridge the gap between GWAS and disease mechanism.

γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis.

γδ T cells are situated at barrier sites and guard the body from infection and damage. However, little is known about their roles outside of host defense in nonbarrier tissues. Here, we characterize a highly enriched tissue-resident population of γδ T cells in adipose tissue that regulate age-dependent regulatory T cell (Treg) expansion and control core body temperature in response to environmental fluctuations. Mechanistically, innate PLZF+ γδ T cells produced tumor necrosis factor and interleukin (IL) 17 A and determined PDGFRα+ and Pdpn+ stromal-cell production of IL-33 in adipose tissue. Mice lacking γδ T cells or IL-17A exhibited decreases in both ST2+ Treg cells and IL-33 abundance in visceral adipose tissue. Remarkably, these mice also lacked the ability to regulate core body temperature at thermoneutrality and after cold challenge. Together, these findings uncover important physiological roles for resident γδ T cells in adipose tissue immune homeostasis and body-temperature control.

Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis.

Fibroblasts regulate tissue homeostasis, coordinate inflammatory responses, and mediate tissue damage. In rheumatoid arthritis (RA), synovial fibroblasts maintain chronic inflammation which leads to joint destruction. Little is known about fibroblast heterogeneity or if aberrations in fibroblast subsets relate to pathology. Here, we show functional and transcriptional differences between fibroblast subsets from human synovial tissues using bulk transcriptomics of targeted subpopulations and single-cell transcriptomics. We identify seven fibroblast subsets with distinct surface protein phenotypes, and collapse them into three subsets by integrating transcriptomic data. One fibroblast subset, characterized by the expression of proteins podoplanin, THY1 membrane glycoprotein and cadherin-11, but lacking CD34, is threefold expanded in patients with RA relative to patients with osteoarthritis. These fibroblasts localize to the perivascular zone in inflamed synovium, secrete proinflammatory cytokines, are proliferative, and have an in vitro phenotype characteristic of invasive cells. Our strategy may be used as a template to identify pathogenic stromal cellular subsets in other complex diseases.

New Metal-Organic Frameworks for Chemical Fixation of CO2.

A novel series of two zirconium- and one indium-based metal-organic frameworks (MOFs), namely, MOF-892, MOF-893, and MOF-894, constructed from the hexatopic linker, 1',2',3',4',5',6'-hexakis(4-carboxyphenyl)benzene, were synthesized and fully characterized. MOF-892 and MOF-893 are two new exemplars of materials with topologies previously unseen in the important family of zirconium MOFs. MOF-892, MOF-893, and MOF-894 exhibit efficient heterogeneous catalytic activity for the cycloaddition of CO2, resulting in a cyclic organic carbonate formation with high conversion, selectivity, and yield under mild conditions (1 atm CO2, 80 °C, and solvent-free). Because of the structural features provided by their building units, MOF-892 and MOF-893 are replete with accessible Lewis and Brønsted acid sites located at the metal clusters and the non-coordinating carboxylic groups of the linkers, respectively, which is found to promote the catalytic CO2 cycloaddition reaction. As a proof-of-concept, MOF-892 exhibits high catalytic activity in the one-pot synthesis of styrene carbonate from styrene and CO2 without preliminary synthesis and isolation of styrene oxide.

CD177 modulates human neutrophil migration through activation-mediated integrin and chemoreceptor regulation.

CD177 is a glycosylphosphatidylinositol (GPI)-anchored protein expressed by a variable proportion of human neutrophils that mediates surface expression of the antineutrophil cytoplasmic antibody antigen proteinase 3. CD177 associates with ß2 integrins and recognizes platelet endothelial cell adhesion molecule 1 (PECAM-1), suggesting a role in neutrophil migration. However, CD177pos neutrophils exhibit no clear migratory advantage in vivo, despite interruption of in vitro transendothelial migration by CD177 ligation. We sought to understand this paradox. Using a PECAM-1-independent transwell system, we found that CD177pos and CD177neg neutrophils migrated comparably. CD177 ligation selectively impaired migration of CD177pos neutrophils, an effect mediated through immobilization and cellular spreading on the transwell membrane. Correspondingly, CD177 ligation enhanced its interaction with ß2 integrins, as revealed by fluorescence lifetime imaging microscopy, leading to integrin-mediated phosphorylation of Src and extracellular signal-regulated kinase (ERK). CD177-driven cell activation enhanced surface ß2 integrin expression and affinity, impaired internalization of integrin attachments, and resulted in ERK-mediated attenuation of chemokine signaling. We conclude that CD177 signals in a ß2 integrin-dependent manner to orchestrate a set of activation-mediated mechanisms that impair human neutrophil migration.