Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation.

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1ß production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.

Integration of longitudinal deep-radiomics and clinical data improves the prediction of durable benefits to anti-PD-1/PD-L1 immunotherapy in advanced NSCLC patients.

BACKGROUND: Identifying predictive non-invasive biomarkers of immunotherapy response is crucial to avoid premature treatment interruptions or ineffective prolongation. Our aim was to develop a non-invasive biomarker for predicting immunotherapy clinical durable benefit, based on the integration of radiomics and clinical data monitored through early anti-PD-1/PD-L1 monoclonal antibodies treatment in patients with advanced non-small cell lung cancer (NSCLC). METHODS: In this study, 264 patients with pathologically confirmed stage IV NSCLC treated with immunotherapy were retrospectively collected from two institutions. The cohort was randomly divided into a training (n = 221) and an independent test set (n = 43), ensuring the balanced availability of baseline and follow-up data for each patient. Clinical data corresponding to the start of treatment was retrieved from electronic patient records, and blood test variables after the first and third cycles of immunotherapy were also collected. Additionally, traditional radiomics and deep-radiomics features were extracted from the primary tumors of the computed tomography (CT) scans before treatment and during patient follow-up. Random Forest was used to implementing baseline and longitudinal models using clinical and radiomics data separately, and then an ensemble model was built integrating both sources of information. RESULTS: The integration of longitudinal clinical and deep-radiomics data significantly improved clinical durable benefit prediction at 6 and 9 months after treatment in the independent test set, achieving an area under the receiver operating characteristic curve of 0.824 (95% CI: [0.658,0.953]) and 0.753 (95% CI: [0.549,0.931]). The Kaplan-Meier survival analysis showed that, for both endpoints, the signatures significantly stratified high- and low-risk patients (p-value< 0.05) and were significantly correlated with progression-free survival (PFS6 model: C-index 0.723, p-value = 0.004; PFS9 model: C-index 0.685, p-value = 0.030) and overall survival (PFS6 models: C-index 0.768, p-value = 0.002; PFS9 model: C-index 0.736, p-value = 0.023). CONCLUSIONS: Integrating multidimensional and longitudinal data improved clinical durable benefit prediction to immunotherapy treatment of advanced non-small cell lung cancer patients. The selection of effective treatment and the appropriate evaluation of clinical benefit are important for better managing cancer patients with prolonged survival and preserving quality of life.

Proinflammatory polarization of monocytes by particulate air pollutants is mediated by induction of trained immunity in pediatric asthma.

BACKGROUND: The impact of exposure to air pollutants, such as fine particulate matter (PM), on the immune system and its consequences on pediatric asthma, are not well understood. We investigated whether ambient levels of fine PM with aerodynamic diameter ≤2.5 microns (PM2.5 ) are associated with alterations in circulating monocytes in children with or without asthma. METHODS: Monocyte phenotyping was performed by cytometry time-of-flight (CyTOF). Cytokines were measured using cytometric bead array and Luminex assay. ChIP-Seq was utilized to address histone modifications in monocytes. RESULTS: Increased exposure to ambient PM2.5 was linked to specific monocyte subtypes, particularly in children with asthma. Mechanistically, we hypothesized that innate trained immunity is evoked by a primary exposure to fine PM and accounts for an enhanced inflammatory response after secondary stimulation in vitro. We determined that the trained immunity was induced in circulating monocytes by fine particulate pollutants, and it was characterized by the upregulation of proinflammatory mediators, such as TNF, IL-6, and IL-8, upon stimulation with house dust mite or lipopolysaccharide. This phenotype was epigenetically controlled by enhanced H3K27ac marks in circulating monocytes. CONCLUSION: The specific alterations of monocytes after ambient pollution exposure suggest a possible prognostic immune signature for pediatric asthma, and pollution-induced trained immunity may provide a potential therapeutic target for asthmatic children living in areas with increased air pollution.

The Pathway from Anatomy and Physiology to Diagnosis: A Developmental Perspective on Swallowing and Dysphagia.

Dysphagia results from diverse and distinct etiologies. The pathway from anatomy and physiology to clinical diagnosis is complex and hierarchical. Our approach in this paper is to show the linkages from the underlying anatomy and physiology to the clinical presentation. In particular, the terms performance, function, behavior, and physiology are often used interchangeably, which we argue is an obstacle to clear discussion of mechanism of pathophysiology. We use examples from pediatric populations to highlight the importance of understanding anatomy and physiology to inform clinical practice. We first discuss the importance of understanding anatomy in the context of physiology and performance. We then use preterm infants and swallow-breathe coordination as examples to explicate the hierarchical nature of physiology and its impact on performance. We also highlight where the holes in our knowledge lie, with the ultimate endpoint of providing a framework that could enhance our ability to design interventions to help patients. Clarifying these terms, and the roles they play in the biology of dysphagia will help both the researchers studying the problems as well as the clinicians applying the results of those studies.

The Impact of Varying Nipple Properties on Infant Feeding Physiology and Performance Throughout Ontogeny in a Validated Animal Model.

Infant feeding requires successful interactions between infant physiology and the maternal (or bottle) nipple. Within artificial nipples, there is variation in both nipple stiffness and flow rates, as well as variation in infant physiology as they grow and mature. However, we have little understanding into how infants interact with variable nipple properties to generate suction and successfully feed. We designed nipples with two different stiffnesses and hole sizes and measured infant feeding performance through ontogeny using a pig model. We evaluated their response to nipple properties using high-speed X-Ray videofluoroscopy. Nipple properties substantially impacted sucking physiology and performance. Hole size had the most profound impact on the number of sucks infants took per swallow. Pressure generation generally increased with age, especially in nipples where milk acquisition was more difficult. However, most strikingly, in nipples with lower flow rates the relationship between suction generation and milk acquisition was disrupted. In order to design effective interventions for infants with feeding difficulties, we must consider how variation in nipple properties impacts infant physiology in a targeted manner. While reducing flow rate may reduce the frequency an infant aspirates, it may impair systems involved in sensorimotor integration.

Multiple molecular mechanisms are involved in the activation of the kidney sodium-chloride cotransporter by hypokalemia.

Low potassium intake activates the kidney sodium-chloride cotransporter (NCC) whose phosphorylation and activity depend on the With-No-Lysine kinase 4 (WNK4) that is inhibited by chloride binding to its kinase domain. Low extracellular potassium activates NCC by decreasing intracellular chloride thereby promoting chloride dissociation from WNK4 where residue L319 of WNK4 participates in chloride coordination. Since the WNK4-L319F mutant is constitutively active and chloride-insensitive in vitro, we generated mice harboring this mutation that displayed slightly increased phosphorylated NCC and mild hyperkalemia when on a 129/sv genetic background. On a low potassium diet, upregulation of phosphorylated NCC was observed, suggesting that in addition to chloride sensing by WNK4, other mechanisms participate which may include modulation of WNK4 activity and degradation by phosphorylation of the RRxS motif in regulatory domains present in WNK4 and KLHL3, respectively. Increased levels of WNK4 and kidney-specific WNK1 and phospho-WNK4-RRxS were observed in wild-type and WNK4L319F/L319F mice on a low potassium diet. Decreased extracellular potassium promoted WNK4-RRxS phosphorylation in vitro and ex vivo as well. These effects might be secondary to intracellular chloride depletion, as reduction of intracellular chloride in HEK293 cells increased phospho-WNK4-RRxS. Phospho-WNK4-RRxS levels were increased in mice lacking the Kir5.1 potassium channel, which presumably have decreased distal convoluted tubule intracellular chloride. Similarly, phospho-KLHL3 was modulated by changes in intracellular chloride in HEK293 cells. Thus, our data suggest that multiple chloride-regulated mechanisms are responsible for NCC upregulation by low extracellular potassium.

Photoactivated Nanoscale Temperature Gradient Detection Using X-ray Absorption Spectroscopy as a Direct Nanothermometry Method.

Nanoparticle-mediated thermal treatments have demonstrated high efficacy and versatility as a local anticancer strategy beyond traditional global hyperthermia. Nanoparticles act as heating generators that can trigger therapeutic responses at both the cell and tissue level. In some cases, treatment happens in the absence of a global temperature rise, damaging the tumor cells even more selectively than other nanotherapeutic strategies. The precise determination of the local temperature in the vicinity of such nanoheaters then stands at the heart of thermal approaches to better adjust the therapeutic thermal onset and reduce potential toxicity-related aspects. Herein, we describe an experimental procedure by X-ray absorption spectroscopy, which directly and accurately infers the local temperature of gold-based nanoparticles, single and hybrid nanocrystals, upon laser photoexcitation, revealing significant nanothermal gradients. Such nanothermometric methodology based on the temperature-dependency of atomic parameters of nanoparticles can be extended to any nanosystem upon remote hyperthermal conditions.

The contractile patterns, anatomy and physiology of the hyoid musculature change longitudinally through infancy.

All mammalian infants suckle, a fundamentally different process than drinking in adults. Infant mammal oropharyngeal anatomy is also anteroposteriorly compressed and becomes more elongate postnatally. While suckling and drinking require different patterns of muscle use and kinematics, little insight exists into how the neuromotor and anatomical systems change through the time that infants suckle. We measured the orientation, activity and contractile patterns of five muscles active during infant feeding from early infancy until weaning using a pig model. Muscles not aligned with the long axis of the body became less mediolaterally orientated with age. However, the timing of activation and the contractile patterns of those muscles exhibited little change, although variation was larger in younger infants than older infants. At both ages, there were differences in contractile patterns within muscles active during both sucking and swallowing, as well as variation among muscles during swallowing. The changes in anatomy, coupled with less variation closer to weaning and little change in muscle firing and shortening patterns suggest that the neuromotor system may be optimized to transition to solid foods. The lesser consequences of aspiration during feeding on an all-liquid diet may not necessitate the evolution of variation in neuromotor function through infancy.

In operando evidence of deoxygenation in ionic liquid gating of YBa2Cu3O7-X.

Field-effect experiments on cuprates using ionic liquids have enabled the exploration of their rich phase diagrams [Leng X, et al. (2011) Phys Rev Lett 107(2):027001]. Conventional understanding of the electrostatic doping is in terms of modifications of the charge density to screen the electric field generated at the double layer. However, it has been recently reported that the suppression of the metal to insulator transition induced in VO2 by ionic liquid gating is due to oxygen vacancy formation rather than to electrostatic doping [Jeong J, et al. (2013) Science 339(6126):1402-1405]. These results underscore the debate on the true nature, electrostatic vs. electrochemical, of the doping of cuprates with ionic liquids. Here, we address the doping mechanism of the high-temperature superconductor YBa2Cu3O7-X (YBCO) by simultaneous ionic liquid gating and X-ray absorption experiments. Pronounced spectral changes are observed at the Cu K-edge concomitant with the superconductor-to-insulator transition, evidencing modification of the Cu coordination resulting from the deoxygenation of the CuO chains, as confirmed by first-principles density functional theory (DFT) simulations. Beyond providing evidence of the importance of chemical doping in electric double-layer (EDL) gating experiments with superconducting cuprates, our work shows that interfacing correlated oxides with ionic liquids enables a delicate control of oxygen content, paving the way to novel electrochemical concepts in future oxide electronics.

Clinical relevance of pulmonary vasculature involvement in sickle cell disease.

Pulmonary complications are frequent in patients with sickle cell disease (SCD), but few studies have described lung pathology in SCD. We studied the lung tissue of 30 deceased SCD patients (1994-2012). Demographics, genotype, clinical characteristics, cause of death and associated conditions are presented. We quantified the presence of pulmonary arterial changes, thrombosis and venous thickening. Alveolar capillary abnormalities were demonstrated using CD34 expression and confocal microscopy. Autopsy and echocardiography reports were reviewed to classify heart abnormalities. Tissue expression of markers of endothelial activation (vascular cell adhesion molecule 1, intercellular adhesion molecule 1 and vascular endothelial growth factor) was quantified in pulmonary vessels. Median age was 33 years; genotype was SS in 19, SC in 7 and Sß in 4, and there were 18 males. Hypertensive arterial changes were present in 76% of the patients, recent thrombosis in 80% and old thrombosis in 43%. Venous thickening was present in 23% and pulmonary capillary haemangiomatosis foci in 87%. Ten percent of the patients presented right ventricular hypertrophy. There was no increased expression of endothelial activation markers when compared to controls. SCD affects the whole pulmonary vascular tree and reflects the multiple burden on lung vasculature imposed by the disease upon time.

Peptoid microsphere coatings: The effects of helicity, temperature, pH, and ionic strength.

Peptoids are peptidomimetic oligomers that predominantly harness similarities to peptides for biomimetic functionality. They have potential for use in biomedical applications and biosensors due to resistance to proteolytic degradation and low immunogenicity. The incorporation of chiral, aromatic side chains in the peptoid sequence allows for the formation of distinct secondary structures and self-assembly into supramolecular assemblies, including microspheres. Peptoid microspheres can be coated onto substrates for potential use in biosensor technologies, tissue engineering platforms, and drug-delivery systems. In order to be useful for these applications, the peptoid coatings must be robust under physiological conditions. In this study, we report the effects of various conditions on the peptoid microsphere coatings, including (i) helicity, (ii) temperature, (iii) pH, and (iv) ionic strength. These studies show that microsphere size decreases with increasing peptoid helicity and the positively charged side chains are positioned on the outside of the microspheres. The peptoid microsphere coatings are robust under physiological conditions but degrade in acidic conditions (pH < 7) and at low ionic strengths (<150 µM).

Activated plasmacytoid dendritic cells regulate type 2 innate lymphoid cell-mediated airway hyperreactivity.

BACKGROUND: Allergic asthma is a prevalent inflammatory disease of the airways caused by dysregulated immune balance in the lungs with incompletely understood pathogenesis. The recently identified type 2 innate lymphoid cells (ILC2s) play significant roles in the pathogenesis of asthma. Although ILC2-activating factors have been identified, the mechanisms that suppress ILC2s remain largely unknown. Plasmacytoid dendritic cells (pDCs) are important in antiviral immunity and in maintaining tolerance to inert antigens. OBJECTIVE: We sought to address the role of pDCs in regulating ILC2 function and ILC2-mediated airway hyperreactivity (AHR) and lung inflammation. METHODS: We used several murine models, including BDCA-2-diphtheria toxin receptor (DTR) transgenic and IFN-α receptor 1-deficient mice, as well as purified primary ILC2s, to reach our objective. We extended and validated our findings to human ILC2s. RESULTS: We show that activation of pDCs through Toll-like receptor 7/8 suppresses ILC2-mediated AHR and airway inflammation and that depletion of pDCs reverses this suppression. We further show that pDCs suppress cytokine production and the proliferation rate while increasing the apoptosis rate of ILC2s through IFN-α production. Transcriptomic analysis of both human and murine ILC2s confirms the activation of regulatory pathways in ILC2s by IFN-α. CONCLUSION: Activation of pDCs alleviates AHR and airway inflammation by suppressing ILC2 function and survival. Our findings reveal a novel regulatory pathway in ILC2-mediated pulmonary inflammation with important clinical implications.

WNT10B mutations associated with isolated dental anomalies.

Isolated hypodontia is the most common human malformation. It is caused by heterozygous variants in various genes, with heterozygous WNT10A variants being the most common cause. WNT10A and WNT10B are paralogs that likely evolved from a common ancestral gene after its duplication. Recently, an association of WNT10B variants with oligodontia (severe tooth agenesis) has been reported. We performed mutational analysis in our cohort of 256 unrelated Thai families with various kinds of isolated dental anomalies. In 7 families afflicted with dental anomalies we detected 4 heterozygous missense variants in WNT10B. We performed whole exome sequencing in the patients who had WNT10B mutations and found no mutations in other known hypodontia-associated genes, including WNT10A, MSX1, PAX9, EDA, AXIN2, EDAR, EDARADD, LPR6, TFAP2B, LPR6, NEMO, KRT17, and GREM2. Our findings indicate that the variants c.475G>C [p.(Ala159Pro)], found in 4 families, and c.1052G>A [p.(Arg351His)], found in 1 family, are most probably causative. They also show that WNT10B variants are associated not only with oligodontia and isolated tooth agenesis, but also with microdontia, short tooth roots, dental pulp stones, and taurodontism.

Making Graphene Nanoribbons Photoluminescent.

We demonstrate the alignment-preserving transfer of parallel graphene nanoribbons (GNRs) onto insulating substrates. The photophysics of such samples is characterized by polarized Raman and photoluminescence (PL) spectroscopies. The Raman scattered light and the PL are polarized along the GNR axis. The Raman cross section as a function of excitation energy has distinct excitonic peaks associated with transitions between the one-dimensional parabolic subbands. We find that the PL of GNRs is intrinsically low but can be strongly enhanced by blue laser irradiation in ambient conditions or hydrogenation in ultrahigh vacuum. These functionalization routes cause the formation of sp3 defects in GNRs. We demonstrate the laser writing of luminescent patterns in GNR films for maskless lithography by the controlled generation of defects. Our findings set the stage for further exploration of the optical properties of GNRs on insulating substrates and in device geometries.

TßRIII is induced by TCR signaling and downregulated in FoxP3+ regulatory T cells.

TGF-ß type III receptor (TßRIII) is a co-receptor for TGFß family members required for high-affinity binding of these ligands to their receptors, potentiating their cellular functions. TGF-ßs, Bone Morphogenetic Proteins (BMP2/4) and Inhibins/Activins regulate different checkpoints during T cell differentiation. We have previously reported that TßRIII modulates T cell development by protecting developing thymocytes from apoptosis, however the role of this co-receptor in peripheral lymphocytes still remains elusive. Here we describe a detailed characterization of TßRIII expression in murine and human lymphocyte subpopulations demonstrating that this co-receptor is significantly expressed in T but not B lymphocytes and among them, preferentially expressed on naïve and central memory T cells. TßRIII was upregulated after TCR stimulation, in parallel to other early activation markers. In contrast, natural and induced Tregs downregulated TßRIII in association with FoxP3 upregulation. Finally, anti-TßRIII blocking experiments demonstrated that TßRIII promotes TGFß-dependent iTreg conversion in vitro, and suggest that this co-receptor may be involved in modulating peripheral T cell tolerance and could be considered as a potential target to boost T cell immune responses.

Singlet Orbital Ordering in Bilayer Sr_{3}Cr_{2}O_{7}.

We perform an extensive study of Sr_{3}Cr_{2}O_{7}, the n=2 member of the Ruddlesden-Popper Sr_{n+1}Cr_{n}O_{3n+1} system. An antiferromagnetic ordering is clearly visible in the magnetization and the specific heat, which yields a huge transition entropy, Rln(6). By neutron diffraction as a function of temperature we have determined the antiferromagnetic structure that coincides with the one obtained from density functional theory calculations. It is accompanied by anomalous asymmetric distortions of the CrO_{6} octahedra. Strong coupling and Lanczos calculations on a derived Kugel-Khomskii Hamiltonian yield a simultaneous orbital and moment ordering. Our results favor an exotic ordered phase of orbital singlets not originated by frustration.

Pre-pharyngeal Swallow Effects of Recurrent Laryngeal Nerve Lesion on Bolus Shape and Airway Protection in an Infant Pig Model.

Recurrent laryngeal nerve (RLN) damage in infants leads to increased dysphagia and aspiration pneumonia. Recent work has shown that intraoral transport and swallow kinematics change following RLN lesion, suggesting potential changes in bolus formation prior to the swallow. In this study, we used geometric morphometrics to understand the effect of bolus shape on penetration and aspiration in infants with and without RLN lesion. We hypothesized (1) that geometric bolus properties are related to airway protection outcomes and (2) that in infants with RLN lesion, the relationship between geometric bolus properties and dysphagia is changed. In five infant pigs, dysphagia in 188 swallows was assessed using the Infant Mammalian Penetration-Aspiration Scale (IMPAS). Using images from high-speed VFSS, bolus shape, bolus area, and tongue outline were quantified digitally. Bolus shape was analyzed using elliptical Fourier analysis, and tongue outline using polynomial curve fitting. Despite large inter-individual differences, significant within individual effects of bolus shape and bolus area on airway protection exist. The relationship between penetration-aspiration score and both bolus area and shape changed post lesion. Tongue shape differed between pre- and post-lesion swallows, and between swallows with different IMPAS scores. Bolus shape and area affect airway protection outcomes. RLN lesion changes that relationship, indicating that proper bolus formation and control by the tongue require intact laryngeal sensation. The impact of RLN lesion on dysphagia is pervasive.

Melanin granules melanophages and a fully-melanized epidermis are common traits of odontocete and mysticete cetaceans.

BACKGROUND: The cellular mechanisms used to counteract or limit damage caused by exposure of marine vertebrates to solar ultraviolet (UV) radiation are poorly understood. Cetaceans are vulnerable because they lack protective skin appendages and are obliged to surface continuously to breathe, thus being exposed repeatedly to UV light. Although molecular mechanisms of photoprotection of cetaceans have been studied, there is limited knowledge about their epidermal structure and photoprotective effectors. OBJECTIVE: To describe and compare the epidermis of mysticete and odontocete cetaceans and identify potentially photoprotective traits. ANIMALS: Twenty eight free-living individuals belonging to six cetacean species were sampled in the Mexican Central Pacific and Gulf of California. Species sampled were the bottlenose dolphin, pantropical spotted dolphin, spinner dolphin, Bryde's whale, fin whale and humpback whale. METHODS: Histological and cytological evaluation of skin biopsy tissue collected in the field between 2014 and 2016. RESULTS: All cetaceans had only three epidermal layers, lacking both the stratum granulosum and stratum lucidum. A relatively thick stratum corneum with a parakeratosis-like morphology was noted. Melanin was observed within keratinocytes in all epidermal layers, including the stratum corneum and apical melanin granules obscured the keratinocyte nucleus. Keratinocytes had a perinuclear halo. Keratinocyte diameter differed between cetacean suborders and amongst species. Melanophage clusters were common in most cetacean species. CONCLUSIONS: The widespread presence of melanin and the unexpectedly high number of melanophages may constitute a unique photoprotective trait of cetaceans and could reflect primitive adaptations to their environment and to their obligate marine-bound life.

TGFß responsive tyrosine phosphatase promotes rheumatoid synovial fibroblast invasiveness.

OBJECTIVE: In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) that line joint synovial membranes aggressively invade the extracellular matrix, destroying cartilage and bone. As signal transduction in FLS is mediated through multiple pathways involving protein tyrosine phosphorylation, we sought to identify protein tyrosine phosphatases (PTPs) regulating the invasiveness of RA FLS. We describe that the transmembrane receptor PTPκ (RPTPκ), encoded by the transforming growth factor (TGF) ß-target gene, PTPRK, promotes RA FLS invasiveness. METHODS: Gene expression was quantified by quantitative PCR. PTP knockdown was achieved using antisense oligonucleotides. FLS invasion and migration were assessed in transwell or spot assays. FLS spreading was assessed by immunofluorescence microscopy. Activation of signalling pathways was analysed by Western blotting of FLS lysates using phosphospecific antibodies. In vivo FLS invasiveness was assessed by intradermal implantation of FLS into nude mice. The RPTPκ substrate was identified by pull-down assays. RESULTS: PTPRK expression was higher in FLS from patients with RA versus patients with osteoarthritis, resulting from increased TGFB1 expression in RA FLS. RPTPκ knockdown impaired RA FLS spreading, migration, invasiveness and responsiveness to platelet-derived growth factor, tumour necrosis factor and interleukin 1 stimulation. Furthermore, RPTPκ deficiency impaired the in vivo invasiveness of RA FLS. Molecular analysis revealed that RPTPκ promoted RA FLS migration by dephosphorylation of the inhibitory residue Y527 of SRC. CONCLUSIONS: By regulating phosphorylation of SRC, RPTPκ promotes the pathogenic action of RA FLS, mediating cross-activation of growth factor and inflammatory cytokine signalling by TGFß in RA FLS.

Design and development of a controlled pressure/temperature set-up for in situ studies of solid-gas processes and reactions in a synchrotron X-ray powder diffraction station.

A novel set-up has been designed and used for synchrotron radiation X-ray high-resolution powder diffraction (SR-HRPD) in transmission geometry (spinning capillary) for in situ solid-gas reactions and processes in an isobaric and isothermal environment. The pressure and temperature of the sample are controlled from 10(-3) to 1000 mbar and from 80 to 1000 K, respectively. To test the capacities of this novel experimental set-up, structure deformation in the porous material zeolitic imidazole framework (ZIF-8) by gas adsorption at cryogenic temperature has been studied under isothermal and isobaric conditions. Direct structure deformations by the adsorption of Ar and N2 gases have been observed in situ, demonstrating that this set-up is perfectly suitable for direct structural analysis under in operando conditions. The presented results prove the feasibility of this novel experimental station for the characterization in real time of solid-gas reactions and other solid-gas processes by SR-HRPD.