Hydrogen Storage in Partially Exfoliated Magnesium Diboride Multilayers.

Metal boride nanostructures have shown significant promise for hydrogen storage applications. However, the synthesis of nanoscale metal boride particles is challenging because of their high surface energy, strong inter- and intraplanar bonding, and difficult-to-control surface termination. Here, it is demonstrated that mechanochemical exfoliation of magnesium diboride in zirconia produces 3-4 nm ultrathin MgB2 nanosheets (multilayers) in high yield. High-pressure hydrogenation of these multilayers at 70 MPa and 330 °C followed by dehydrogenation at 390 °C reveals a hydrogen capacity of 5.1 wt%, which is ≈50 times larger than the capacity of bulk MgB2 under the same conditions. This enhancement is attributed to the creation of defective sites by ball-milling and incomplete Mg surface coverage in MgB2 multilayers, which disrupts the stable boron-boron ring structure. The density functional theory calculations indicate that the balance of Mg on the MgB2 nanosheet surface changes as the material hydrogenates, as it is energetically favorable to trade a small number of Mg vacancies in Mg(BH4 )2 for greater Mg coverage on the MgB2 surface. The exfoliation and creation of ultrathin layers is a promising new direction for 2D metal boride/borohydride research with the potential to achieve high-capacity reversible hydrogen storage at more moderate pressures and temperatures.

Oral delivery of the anti-tumor necrosis factor α domain antibody, V565, results in high intestinal and fecal concentrations with minimal systemic exposure in cynomolgus monkeys.

OBJECTIVE: V565 is a novel oral anti-tumor necrosis factor (TNF)-α domain antibody being developed for topical treatment of inflammatory bowel disease (IBD) patients. Protein engineering rendered the molecule resistant to intestinal proteases. Here we investigate the formulation of V565 required to provide gastro-protection and enable optimal delivery to the lower intestinal tract in monkeys. METHODS: Enteric-coated V565 mini-tablets were prepared and dissolution characteristics tested in vitro. Oral dosing of monkeys with enteric-coated mini-tablets containing V565 and methylene blue dye enabled in vivo localization of mini-tablet dissolution. V565 distribution in luminal contents and feces was measured by enzyme-linked immunosorbent assay (ELISA). To mimic transit across the damaged intestinal epithelium seen in IBD patients an intravenous (i.v.) bolus of V565 was given to monkeys and pharmacokinetic parameters of V565 measured in serum and urine by ELISA. RESULTS: Enteric-coated mini-tablets resisted dissolution in 0.1 M HCl, before dissolving in a sustained release fashion at neutral pH. In orally dosed monkeys methylene blue intestinal staining indicated the jejunum and ileum as sites for mini-tablet dissolution. Measurements of V565 in monkey feces confirmed V565 survival through the intestinal tract. Systemic exposure after oral dosing was very low consistent with limited V565 mucosal penetration in healthy monkeys. The rapid clearance of V565 after i.v. dosing was consistent with renal excretion as the primary route for elimination of any V565 reaching the circulation. CONCLUSIONS: These results suggest that mini-tablets with a 24% Eudragit enteric coating are suitable for targeted release of orally delivered V565 in the intestine for topical treatment of IBD.

Interleukins and their signaling pathways in the Reactome biological pathway database.

BACKGROUND: There is a wealth of biological pathway information available in the scientific literature, but it is spread across many thousands of publications. Alongside publications that contain definitive experimental discoveries are many others that have been dismissed as spurious, found to be irreproducible, or are contradicted by later results and consequently now considered controversial. Many descriptions and images of pathways are incomplete stylized representations that assume the reader is an expert and familiar with the established details of the process, which are consequently not fully explained. Pathway representations in publications frequently do not represent a complete, detailed, and unambiguous description of the molecules involved; their precise posttranslational state; or a full account of the molecular events they undergo while participating in a process. Although this might be sufficient to be interpreted by an expert reader, the lack of detail makes such pathways less useful and difficult to understand for anyone unfamiliar with the area and of limited use as the basis for computational models. OBJECTIVE: Reactome was established as a freely accessible knowledge base of human biological pathways. It is manually populated with interconnected molecular events that fully detail the molecular participants linked to published experimental data and background material by using a formal and open data structure that facilitates computational reuse. These data are accessible on a Web site in the form of pathway diagrams that have descriptive summaries and annotations and as downloadable data sets in several formats that can be reused with other computational tools. The entire database and all supporting software can be downloaded and reused under a Creative Commons license. METHODS: Pathways are authored by expert biologists who work with Reactome curators and editorial staff to represent the consensus in the field. Pathways are represented as interactive diagrams that include as much molecular detail as possible and are linked to literature citations that contain supporting experimental details. All newly created events undergo a peer-review process before they are added to the database and made available on the associated Web site. New content is added quarterly. RESULTS: The 63rd release of Reactome in December 2017 contains 10,996 human proteins participating in 11,426 events in 2,179 pathways. In addition, analytic tools allow data set submission for the identification and visualization of pathway enrichment and representation of expression profiles as an overlay on Reactome pathways. Protein-protein and compound-protein interactions from several sources, including custom user data sets, can be added to extend pathways. Pathway diagrams and analytic result displays can be downloaded as editable images, human-readable reports, and files in several standard formats that are suitable for computational reuse. Reactome content is available programmatically through a REpresentational State Transfer (REST)-based content service and as a Neo4J graph database. Signaling pathways for IL-1 to IL-38 are hierarchically classified within the pathway "signaling by interleukins." The classification used is largely derived from Akdis et al. CONCLUSION: The addition to Reactome of a complete set of the known human interleukins, their receptors, and established signaling pathways linked to annotations of relevant aspects of immune function provides a significant computationally accessible resource of information about this important family. This information can be extended easily as new discoveries become accepted as the consensus in the field. A key aim for the future is to increase coverage of gene expression changes induced by interleukin signaling.

Elucidating the mechanism of MgB2 initial hydrogenation via a combined experimental-theoretical study.

Mg(BH4)2 is a promising solid-state hydrogen storage material, releasing 14.9 wt% hydrogen upon conversion to MgB2. Although several dehydrogenation pathways have been proposed, the hydrogenation process is less well understood. Here, we present a joint experimental-theoretical study that elucidates the key atomistic mechanisms associated with the initial stages of hydrogen uptake within MgB2. Fourier transform infrared, X-ray absorption, and X-ray emission spectroscopies are integrated with spectroscopic simulations to show that hydrogenation can initially proceed via direct conversion of MgB2 to Mg(BH4)2 complexes. The associated energy landscape is mapped by combining ab initio calculations with barriers extracted from the experimental uptake curves, from which a kinetic model is constructed. The results from the kinetic model suggest that initial hydrogenation takes place via a multi-step process: molecular H2 dissociation, likely at Mg-terminated MgB2 surfaces, is followed by migration of atomic hydrogen to defective boron sites, where the formation of stable B-H bonds ultimately leads to the direct creation of Mg(BH4)2 complexes without persistent BxHy intermediates. Implications for understanding the chemical, structural, and electronic changes upon hydrogenation of MgB2 are discussed.

Dangling Bonds as Possible Contributors to Charge Noise in Silicon and Silicon-Germanium Quantum Dot Qubits.

Spin qubits based on Si and Si1-xGex quantum dot architectures exhibit among the best coherence times of competing quantum computing technologies, yet they still suffer from charge noise that limit their qubit gate fidelities. Identifying the origins of these charge fluctuations is therefore a critical step toward improving Si quantum-dot-based qubits. Here, we use hybrid functional calculations to investigate possible atomistic sources of charge noise, focusing on charge trapping at Si and Ge dangling bonds (DBs). We evaluate the role of global and local environment in the defect levels associated with DBs in Si, Ge, and Si1-xGex alloys, and consider their trapping and excitation energies within the framework of configuration coordinate diagrams. We additionally consider the influence of strain and oxidation in charge-trapping energetics by analyzing Si and GeSi DBs in SiO2 and strained Si layers in typical Si1-xGex quantum dot heterostructures. Our results identify that Ge dangling bonds are more problematic charge-trapping centers both in typical Si1-xGex alloys and associated oxidation layers, and they may be exacerbated by compositional inhomogeneities. These results suggest the importance of alloy homogeneity and possible passivation schemes for DBs in Si-based quantum dot qubits and are of general relevance to mitigating possible trap levels in other Si, Ge, and Si1-xGex-based metal-oxide-semiconductor stacks and related devices.

Selective sorption of oxygen and nitrous oxide by an electron donor-incorporated flexible coordination network.

Incorporating strong electron donor functionality into flexible coordination networks is intriguing for sorption applications due to a built-in mechanism for electron-withdrawing guests. Here we report a 2D flexible porous coordination network, [Ni2(4,4'-bipyridine)(VTTF)2]n(1) (where H2VTTF = 2,2'-[1,2-bis(4-benzoic acid)-1,2ethanediylidene]bis-1,3-benzodithiole), which exhibits large structural deformation from the as-synthesized or open phase (1α) into the closed phase (1ß) after guest removal, as demonstrated by X-ray and electron diffraction. Interestingly, upon exposure to electron-withdrawing species, 1ß reversibly undergoes guest accommodation transitions; 1α⊃O2 (90 K) and 1α⊃N2O (185 K). Moreover, the 1ß phase showed exclusive O2 sorption over other gases (N2, Ar, and CO) at 120 K. The phase transformations between the 1α and 1ß phases under these gases were carefully investigated by in-situ X-ray diffraction, in-situ spectroscopic studies, and DFT calculations, validating that the unusual sorption was attributed to the combination of flexible frameworks and VTTF (electron-donor) that induces strong interactions with electron-withdrawing species.

Nonsteroidal anti-inflammatory drugs increase TNF production in rheumatoid synovial membrane cultures and whole blood.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase activity and hence PG production. However, the ability of NSAIDs to ameliorate pain and tenderness does not prevent disease progression in rheumatoid arthritis, a disease whose pathogenesis is linked to the presence of proinflammatory cytokines, such as TNF-alpha. To understand this observation, we have examined the effect of NSAIDs on the production of clinically validated proinflammatory cytokines. We show that a variety of NSAIDs superinduce production of TNF from human peripheral blood monocytes and rheumatoid synovial membrane cultures. A randomized, double-blinded, crossover, placebo-controlled trial in healthy human volunteers also revealed that the NSAID drug celecoxib increased LPS-induced TNF production in whole blood. NSAID-mediated increases in TNF are reversed by either the addition of exogenous PGE(2) or by a PGE(2) EP2 receptor agonist, revealing that PGE(2) signaling via its EP2 receptor provides a valuable mechanism for controlling excess TNF production. Thus, by reducing the level of PGE(2), NSAIDs can increase TNF production and may exacerbate the proinflammatory environment both within the rheumatoid arthritis joint and the systemic environment.

Understanding Hydrogenation Chemistry at MgB2 Reactive Edges from Ab Initio Molecular Dynamics.

Solid-state hydrogen storage materials often operate via transient, multistep chemical reactions at complex interfaces that are difficult to capture. Here, we use direct ab initio molecular dynamics simulations at accelerated temperatures and hydrogen pressures to probe the hydrogenation chemistry of the candidate material MgB2 without a priori assumption of reaction pathways. Focusing on highly reactive (101̅0) edge planes where initial hydrogen attack is likely to occur, we track mechanistic steps toward the formation of hydrogen-saturated BH4- units and key chemical intermediates, involving H2 dissociation, generation of functionalities and molecular complexes containing BH2 and BH3 motifs, and B-B bond breaking. The genesis of higher-order boron clustering is also observed. Different charge states and chemical environments at the B-rich and Mg-rich edge planes are found to produce different chemical pathways and preferred speciation, with implications for overall hydrogenation kinetics. The reaction processes rely on B-H bond polarization and fluctuations between ionic and covalent character, which are critically enabled by the presence of Mg2+ cations in the nearby interphase region. Our results provide guidance for devising kinetic improvement strategies for MgB2-based hydrogen storage materials, while also providing a template for exploring chemical pathways in other solid-state energy storage reactions.

Inhibitors of p38 suppress cytokine production in rheumatoid arthritis synovial membranes: does variable inhibition of interleukin-6 production limit effectiveness in vivo?

OBJECTIVE: The activity of p38 MAPK regulates lipopolysaccharide (LPS)-stimulated production of key proinflammatory cytokines such as tumor necrosis factor α (TNFα). Consequently, p38 MAPK inhibitors have attracted considerable interest as potential treatments of rheumatoid arthritis (RA), and studies in murine models of arthritis have yielded promising results. However, the performance of several compounds in human clinical trials has been disappointing. At present, the reason for this poor performance is unclear. The aim of this study was to examine the effects of p38 inhibitors on both diseased and normal human tissue and cells, in order to test whether this kinase still plays a critical role in cytokine production under conditions of chronic inflammation. METHODS: Proinflammatory and antiinflammatory cytokine production was monitored after treatment of primary human monocytes, macrophages, and RA synovial membrane cultures with p38 MAPK inhibitor compounds. The following 3 inhibitors were used in these studies: SB-203580 (inhibits the α and ß isoforms), BIRB-796 (inhibits the α, ß, γ, and δ isoforms), and a novel, structurally distinct p38 MAPK inhibitor, SB-731445 (inhibits the α and ß isoforms). RESULTS: SB-731445 and SB-203580 produced profound inhibition of spontaneous production of proinflammatory cytokines (TNFα and interleukin-1 [IL-1]) in both RA membrane cultures and LPS-stimulated primary human monocytes. However, this and other p38 MAPK inhibitors produced a significant increase in IL-6 production by LPS-stimulated primary human macrophages and a decrease in IL-10 production by all cell types examined. CONCLUSION: The potentially proinflammatory consequences of these activities (decreased IL-10 production and increased IL-6 production) may offer some explanation for the inability of p38 MAPK inhibitors to provide the therapeutic benefit that had been hoped for in RA.

Simulation training for embryo transfer: findings from the American Society for Reproductive Medicine Embryo Transfer Certificate Course.

OBJECTIVE: To assess the value of the American Society for Reproductive Medicine Embryo Transfer Certificate Course in confidence and skill building for performing a live embryo transfer (ET). DESIGN: Prospective cohort study. SETTING: Two-day simulation workshops of reproductive endocrine and infertility (REI) fellows from American Board of Obstetrics and Gynecology-approved training programs, using four different uterine models (A-D). PATIENT(S): None. INTERVENTION(S): Didactic and hands-on simulation training program. MAIN OUTCOME MEASURE(S): Primary outcomes included ET simulation scores of all exercises analyzed at various points of the training and self-assessed confidence before and after the completion of the Embryo Transfer Certificate Course based on a 6-point Likert scale and association of both with extent of prior live ET experience and year of fellowship. RESULT(S): Data were collected for 78 REI fellows who completed the Embryo Transfer Certificate Course and demonstrated significant improvements in both skill and confidence. The data for a subset of 58 fellows who performed five direct transfers on both Embryo Transfer Certificate Course uterine models A and B demonstrated significant overall improvement in ET simulation scores between the first and fifth direct transfers. A separate data subset of 57 fellows who performed five afterload transfers for each exercise on all four uterine models demonstrated differences in difficulty among them. Embryo transfer simulation using the uterine A model was consistently the easiest. The ET simulation scores for fellows using the uterine B and C models showed a progressive and significant increase across the five afterload ETs. When using the uterine D model, ET simulation scores increased significantly between the first and second transfers but remained at the same level for the remaining three transfers. Except for uterus A, a significant increase in ET simulation scores between the first and last transfers was observed for fellows overall in all afterload transfers and for those fellows with <50 prior live transfers. Data for all 78 fellows demonstrate a significant gain of self-confidence for all parameters, with the highest overall increase (78%) observed for first-year fellows as well as for fellows of any year with no prior live transfer experience (109%). Fellows with the largest number of prior live ET experience started with higher confidence, which also increased significantly, although they had a lower gain in confidence compared with fellows with less experience. CONCLUSION(S): The American Society for Reproductive Medicine Embryo Transfer Certificate Course data analysis demonstrates the effectiveness of simulator-based ET training for REI fellows across the 3 years of training, regardless of prior experience with live ET.

Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease.

Anti-TNFα and anti-IL-23 antibodies are highly effective therapies for Crohn's disease or ulcerative colitis in a proportion of patients. V56B2 is a novel bispecific domain antibody in which a llama-derived IL-23p19-specific domain antibody, humanised and engineered for intestinal protease resistance, V900, was combined with a previously-described TNFα-specific domain antibody, V565. V56B2 contains a central protease-labile linker to create a single molecule for oral administration. Incubation of V56B2 with trypsin or human faecal supernatant resulted in a complete separation of the V565 and V900 monomers without loss of neutralising potency. Following oral administration of V900 and V565 in mice, high levels of each domain antibody were detected in the faeces, demonstrating stability in the intestinal milieu. In ex vivo cultures of colonic biopsies from IBD patients, treatment with V565 or V900 inhibited tissue phosphoprotein levels and with a combination of the two, inhibition was even greater. These results support further development of V56B2 as an oral therapy for IBD with improved safety and efficacy in a greater proportion of patients as well as greater convenience for patients compared with traditional monoclonal antibody therapies.

Spontaneous dynamical disordering of borophenes in MgB2 and related metal borides.

Layered boron compounds have attracted significant interest in applications from energy storage to electronic materials to device applications, owing in part to a diversity of surface properties tied to specific arrangements of boron atoms. Here we report the energy landscape for surface atomic configurations of MgB2 by combining first-principles calculations, global optimization, material synthesis and characterization. We demonstrate that contrary to previous assumptions, multiple disordered reconstructions are thermodynamically preferred and kinetically accessible within exposed B surfaces in MgB2 and other layered metal diborides at low boron chemical potentials. Such a dynamic environment and intrinsic disordering of the B surface atoms present new opportunities to realize a diverse set of 2D boron structures. We validated the predicted surface disorder by characterizing exfoliated boron-terminated MgB2 nanosheets. We further discuss application-relevant implications, with a particular view towards understanding the impact of boron surface heterogeneity on hydrogen storage performance.

Recombinant expression, purification, and characterization of ThmD, the oxidoreductase component of tetrahydrofuran monooxygenase.

Tetrahydrofuran monooxygenase (Thm) catalyzes the NADH-and oxygen-dependent hydroxylation of tetrahydrofuran to 2-hydroxytetrahydrofuran. Thm is composed of a hydroxylase enzyme, a regulatory subunit, and an oxidoreductase named ThmD. ThmD was expressed in Escherichia coli as a fusion to maltose-binding protein (MBP) and isolated to homogeneity after removal of the MBP. Purified ThmD contains covalently bound FAD, [2Fe-2S] center, and was shown to use ferricyanide, cytochrome c, 2,6-dichloroindophenol, and to a lesser extent, oxygen as surrogate electron acceptors. ThmD displays 160-fold preference for NADH over NADPH and functions as a monomer. The flavin-binding domain of ThmD (ThmD-FD) was purified and characterized. ThmD-FD displayed similar activity as the full-length ThmD and showed a unique flavin spectrum with a major peak at 463nm and a small peak at 396 nm. Computational modeling and mutagenesis analyses suggest a novel three-dimensional fold or covalent flavin attachment in ThmD.

Targeting IKKß for the treatment of rheumatoid arthritis.

Activation of the nuclear factor-κB (NF-κB) family of transcription factors results in the expression of numerous genes involved in the regulation of the innate and adaptive immune responses, and has been implicated as a key mechanism in chronic inflammatory diseases including rheumatoid arthritis (RA). The IκB kinases (IKKs) are key components in the signaling pathway by which proinflammatory stimuli, such as lipopolysaccharide and tumor necrosis factor-α lead to the activation of NF-κB. The most widely studied of the IKKs is IKKß. Inhibitors of the kinase activity of IKKß offer opportunities for intervention in RA, as well as other inflammatory disorders. Some examples for which the most extensive data are available will here be reviewed.

The discovery and initial optimisation of pyrrole-2-carboxamides as inhibitors of p38alpha MAP kinase.

A novel pyrrole-2-carboxamide series of p38alpha inhibitors, discovered through the application of virtual screening, is presented. Following evaluation of activity, selectivity and developability properties of commercially available analogues, a synthesis program enabled rapid assessment of the series' suitability for further lead optimisation studies.

A Mechanistic Analysis of Phase Evolution and Hydrogen Storage Behavior in Nanocrystalline Mg(BH4)2 within Reduced Graphene Oxide.

Magnesium borohydride (Mg(BH4)2, abbreviated here MBH) has received tremendous attention as a promising onboard hydrogen storage medium due to its excellent gravimetric and volumetric hydrogen storage capacities. While the polymorphs of MBH-alpha (α), beta (ß), and gamma (γ)-have distinct properties, their synthetic homogeneity can be difficult to control, mainly due to their structural complexity and similar thermodynamic properties. Here, we describe an effective approach for obtaining pure polymorphic phases of MBH nanomaterials within a reduced graphene oxide support (abbreviated MBHg) under mild conditions (60-190 °C under mild vacuum, 2 Torr), starting from two distinct samples initially dried under Ar and vacuum. Specifically, we selectively synthesize the thermodynamically stable α phase and metastable ß phase from the γ-phase within the temperature range of 150-180 °C. The relevant underlying phase evolution mechanism is elucidated by theoretical thermodynamics and kinetic nucleation modeling. The resulting MBHg composites exhibit structural stability, resistance to oxidation, and partially reversible formation of diverse [BH4]- species during de- and rehydrogenation processes, rendering them intriguing candidates for further optimization toward hydrogen storage applications.

Oral Anti-Tumour Necrosis Factor Domain Antibody V565 Provides High Intestinal Concentrations, and Reduces Markers of Inflammation in Ulcerative Colitis Patients.

V565 is an engineered TNFα-neutralising single domain antibody formulated into enteric coated mini-tablets to enable release in the intestine after oral administration as a possible oral treatment for inflammatory bowel disease (IBD). Following oral administration, ileal recovery of V565 was investigated in four patients with terminal ileostomy. Intestinal and systemic pharmacokinetics were measured in six patients with Crohn's disease and evidence of target engagement assessed in five patients with ulcerative colitis. Following oral administration, V565 was detected at micromolar concentrations in ileal fluid from the ileostomy patients and in stools of the Crohn's patients. In four of the five ulcerative colitis patients, biopsies taken after 7d dosing demonstrated V565 in the lamina propria with co-immunostaining on CD3+ T-lymphocytes and CD14+ macrophages. Phosphorylation of signalling proteins in biopsies taken after 7d oral dosing was decreased by approximately 50%. In conclusion, enteric coating of V565 mini-tablets provided protection in the stomach with gradual release in intestinal regions affected by IBD. Immunostaining revealed V565 tissue penetration and association with inflammatory cells, while decreased phosphoproteins after 7d oral dosing was consistent with V565-TNFα engagement and neutralising activity. Overall these results are encouraging for the clinical utility of V565 in the treatment of IBD.

Preclinical Development of a Novel, Orally-Administered Anti-Tumour Necrosis Factor Domain Antibody for the Treatment of Inflammatory Bowel Disease.

TNFα is an important cytokine in inflammatory bowel disease. V565 is a novel anti-TNFα domain antibody developed for oral administration in IBD patients, derived from a llama domain antibody and engineered to enhance intestinal protease resistance. V565 activity was evaluated in TNFα-TNFα receptor-binding ELISAs as well as TNFα responsive cellular assays and demonstrated neutralisation of both soluble and membrane TNFα with potencies similar to those of adalimumab. Although sensitive to pepsin, V565 retained activity after lengthy incubations with trypsin, chymotrypsin, and pancreatin, as well as mouse small intestinal and human ileal and faecal supernatants. In orally dosed naïve and DSS colitis mice, high V565 concentrations were observed in intestinal contents and faeces and immunostaining revealed V565 localisation in mouse colon tissue. V565 was detected by ELISA in post-dose serum of colitis mice, but not naïve mice, demonstrating penetration of disrupted epithelium. In an ex vivo human IBD tissue culture model, V565 inhibition of tissue phosphoprotein levels and production of inflammatory cytokine biomarkers was similar to infliximab, demonstrating efficacy when present at the disease site. Taken together, results of these studies provide confidence that oral V565 dosing will be therapeutic in IBD patients where the mucosal epithelial barrier is compromised.

Effects of dexamethasone on TNF-alpha-induced release of cytokines from purified human blood eosinophils.

BACKGROUND: TNF-alpha is an important mediator in allergy also for its effects on eosinophils. METHODS: The effect of dexamethasone on TNF-alpha induced eosinophils survival, degranulation (ECP), cytokines release (IL-8, GM-CSF) and adhesion to VCAM-1, ICAM-1 and IgG coated wells (EPO release) were evaluated. RESULTS: The drug inhibited IL-8 and GM-CSF production, but not viability, degranulation or adhesion in human peripheral blood eosinophils. CONCLUSION: These results indicate that part of the activity of glucocorticosteroids on eosinophils may be mediated by their ability to inhibit cytokine secretion that in turn is important for the perpetuation of the allergic inflammation.

Regulation of B lymphocytes in health and disease. Meeting review.

Signal transduction by the B cell receptor (BCR) is an absolute requirement for the selection and development of B lymphocytes at multiple checkpoints. Binding to antigen via the BCR is complemented by a co-stimulus delivered through accessory and co-stimulatory cell surface molecules that regulate the signalling threshold. In addition, identification of genes associated with immunodeficiency syndromes has highlighted the importance of genetic regulation, particularly in immunoglobulin class-switching and somatic hypermutation. A 1-day symposium organised by the Biochemical Society considered some of the recent advances in our understanding of the molecules and regulatory pathways involved in B lymphocyte activation, differentiation and survival and the health consequences when threshold settings malfunction.