Efficient B cell responses to Borrelia hermsii infection depend on BAFF and BAFFR but not TACI.

T cell-independent antibody responses develop rapidly, within 3 to 4 days, and are critical for preventing blood-borne pathogens from evolving into life-threatening infections. The interaction of BAFF, also known as BLyS, with its receptors BAFFR and TACI on B cells is critical for B cell homeostasis and function. Using a synthetic polysaccharide antigen, it has previously been shown that TACI is critical for T cell-independent antibody responses. To examine the role of BAFFR and TACI in T cell-independent antibody responses to an active infection, we utilized the Borrelia hermsii infection system. In this infection system, T cell-independent responses mediated by the B1b cell subset are critical for controlling bacteremia. We found that B1b cells express BAFFR and TACI and that the surface expression of both receptors is upregulated on B1b cells following exposure to whole B. hermsii cells. Surprisingly, we found that TACI(-/-) mice are not impaired either in specific antibody responses to B. hermsii or in controlling B. hermsii bacteremia. In contrast, TACI-deficient mice immunized with heat-killed type 3 serotype pneumococcus cells are impaired in generating pneumococcal polysaccharide-specific responses and succumb to challenge with live type 3 serotype pneumococcus, indicating that TACI is required for T cell-independent antibody responses to bacterial-associated polysaccharides. Although we have found that TACI is dispensable for controlling B. hermsii infection, mice deficient in BAFFR or BAFF exhibit impairment in B. hermsii-specific IgM responses and clearance of bacteremia. Collectively, these data indicate a disparity in the roles for TACI and BAFFR in primary T cell-independent antibody responses to bacterial pathogens

The UKIRT Infrared Deep Sky Survey and the search for the most distant quasars

The UKIRT Infrared Deep Sky Survey (UKIDSS) Large Area Survey (LAS) has the necessary combination of filters (Y, J, H and K), depth (Y <~ 20.2) and area coverage (~4000 deg^2) to detect several redshift z >~ 6.4 quasars. The Third Data Release (DR3) included ~1000 deg^2 of LAS observations which have so far yielded two previously known z ~= 6 quasars and two new discoveries: ULAS J0203+0012, at z = 5.72; and ULAS J1319+0950, at z = 6.13.Comment: to appear in Proceedings of the XXth Moriond Meeting: Cosmology, J. Tran Thanh Van et al., eds.; 4 pages, 2 figure

Recombinant cell bioassays for the detection of (gluco)corticosteroids and endocrine-disrupting potencies of several environmental PCB contaminants

Sensitive and robust bioassays for glucocorticoids are very useful for the pharmaceutical industry, environmental scientists and veterinary control. Here, a recombinant yeast cell was constructed that expresses the human glucocorticoid receptor alpha and a green fluorescent reporter protein in response to glucocorticoids. Both the receptor construct and the reporter construct were stably integrated into the yeast genome. The correct and specific functioning of this yeast glucocorticoid bioassay was studied by exposures to cortisol and other related compounds and critically compared to a GR-CALUX bioassay based on a human bone cell. Although less sensitive, the new yeast glucocorticoid bioassay showed sensitivity towards all (gluco)corticoids tested, with the following order in relative potencies: budesonide >> corticosterone > dexamethasone > cortisol = betamethasone > prednisolone > aldosterone. Hormone representatives for other hormone nuclear receptors, like 17β-estradiol for the oestrogen receptor, 5α-dihydrotestosterone for the androgen receptor and progesterone for the progesterone receptor, showed no clear agonistic responses, whilst some polychlorinated biphenyls were clearly able to interfere with the GR activity

An Interstellar Conduction Front Within a Wolf-Rayet Ring Nebula Observed with the GHRS

With the High Resolution Spectrograph aboard the Hubble Space Telescope we obtained high signal-to-noise (S/N > 200 - 600 per 17 km/s resolution element) spectra of narrow absorption lines toward the Wolf-Rayet star HD 50896. The ring nebula S308 that surrounds this star is thought to be caused by a pressure-driven bubble bounded by circumstellar gas (most likely from a red supergiant or luminous blue variable progenitor) pushed aside by a strong stellar wind. Our observation has shown for the first time that blueshifted (approximately 70 km/s relative to the star) absorption components of C IV and N V arise in a conduction front between the hot interior of the bubble and the cold shell of swept-up material. These lines set limits on models of the conduction front. Nitrogen in the shell appears to be overabundant by a factor ~10. The P Cygni profiles of N V and C IV are variable, possibly due to a suspected binary companion to HD 50896.Comment: 32 pages, Latex, to appear in the Astrophysical Journal, April, 199

Adequate symptom relief justifies hepatic resection for benign disease

BACKGROUND: The purpose of this study was to evaluate the long-term results of partial liver resection for benign liver lesions. METHODS: All patients operated on for benign liver lesions from 1991 to 2002 were included. Information was retrieved from medical records, the hospital registration system and by a telephonic questionnaire. RESULTS: Twenty-eight patients with a median age of 41 years (17–71) were operated on (M/F ratio 5/23). The diagnosis was haemangioma in 8 patients, FNH in 6, HCA in 13 and angiomyolipoma in 1. Eight patients were known to have relevant co-morbidity. Median operating time was 207 minutes (45–360). The morbidity rate was 25% and no postoperative mortality was observed. Twenty-two patients (79%) had symptoms (mainly abdominal pain) prior to surgery. Twenty-five patients were reached for a questionnaire. The median follow up was 55 months (4–150). In 89% of patients preoperative symptoms had decreased or disappeared after surgery. Four patients developed late complications. CONCLUSION: Long-term follow up after liver surgery for benign liver lesions shows considerable symptom relief and patient satisfaction. In addition to a correct indication these results justify major surgery with associated morbidity and mortality

Models of X-ray Photoionization in LMC X-4: Slices of a Stellar Wind

We show that the orbital variation in the UV P Cygni lines of the X-ray binary LMC X-4 results when X-rays photoionize nearly the entire region outside of the X-ray shadow of the normal star. We fit models to HST GHRS observations of N V and C IV P Cygni line profiles. Analytic methods assuming a spherically symmetric wind show that the wind velocity law is well-fit by v~(1-1/r)^beta, where beta is likely 1.4-1.6 and definitely <2.5. Escape probability models can fit the observed P Cygni profiles, and provide measurements of the stellar wind parameters. The fits determine Lx/Mdot=2.6+/-0.1 x10^43 erg/s/Msun yr, where Lx is the X-ray luminosity and Mdot is the mass-loss rate of the star. Allowing an inhomogeneous wind improves the fits. IUE spectra show greater P Cygni absorption during the second half of the orbit than during the first. We discuss possible causes of this effect.Comment: 56 pages, 12 figures, to be published in the Astrophysical Journa

BCMA Is Essential for the Survival of Long-lived Bone Marrow Plasma Cells

Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and APRIL as factors that can support the survival of B lineage lymphocytes. We show that BLyS can sustain PC survival in vitro, and this survival can be further enhanced by interleukin 6. Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this α-apoptotic gene product may play an important role in PC survival. Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor–immunoglobulin treatment, inhibited PC survival in vitro and in vivo. Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival. Affirmation of the importance of BCMA in PC survival was provided by studies in BCMA−/− mice in which the survival of long-lived bone marrow PCs was impaired compared with wild-type controls. These findings offer new insights into the molecular basis for the long-term survival of PCs

TACI and BAFF-R mediate isotype switching in B cells

The tumor necrosis factor family members BAFF and APRIL induce Ig isotype switching in human B cells. We analyzed the ability of BAFF and APRIL to induce isotype switching in murine B cells to IgG1, IgA, and IgE. APRIL and BAFF each engage two receptors, transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI) and B cell maturation antigen (BCMA), on B cells. In addition, BAFF engages a third receptor on B cells, BAFF-R. To determine the role of these receptors in isotype switching, we examined B cells from mice deficient in TACI, BCMA, and BAFF-R. The results obtained indicate that both TACI and BAFF-R are able to transduce signals that result in isotype switching

Cyclophilins A and B oppositely regulate renal tubular epithelial cell phenotype

Altres ajuts: E.S. and M.D. were supported by the generous contribution of Asdent Patients Association. This work was supported in part by grants from Ministerio de Ciencia e Innovación, the Fundación Senefro (SEN2019 to A.M.), and Red de Investigación Renal REDinREN (12/0021/0013). K.A.N. is supported by National Institutes of Health (NIH) DK 47060. A.M. group holds the Quality Mention from the Generalitat de Catalunya.Restoration of kidney tubular epithelium following sublethal injury sequentially involves partial epithelial-mesenchymal transition (pEMT), proliferation, and further redifferentiation into specialized tubule epithelial cells (TECs). Because the immunosuppressant cyclosporine-A produces pEMT in TECs and inhibits the peptidyl-prolyl isomerase (PPIase) activity of cyclophilin (Cyp) proteins, we hypothesized that cyclophilins could regulate TEC phenotype. Here we demonstrate that in cultured TECs, CypA silencing triggers loss of epithelial features and enhances transforming growth factor β (TGF β)-induced EMT in association with upregulation of epithelial repressors Slug and Snail. This pro-epithelial action of CypA relies on its PPIase activity. By contrast, CypB emerges as an epithelial repressor, because CypB silencing promotes epithelial differentiation, prevents TGF β -induced EMT, and induces tubular structures in 3D cultures. In addition, in the kidneys of CypB knockout mice subjected to unilateral ureteral obstruction, inflammatory and pro-fibrotic events were attenuated. CypB silencing/knockout leads to Slug, but not Snail, downregulation. CypB support of Slug expression depends on its endoplasmic reticulum location, where it interacts with calreticulin, a calcium-buffering chaperone related to Slug expression. As CypB silencing reduces ionomycin-induced calcium release and Slug upregulation, we suggest that Slug expression may rely on CypB modulation of calreticulin-dependent calcium signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating TEC plasticity and identifies CypB as a druggable target potentially relevant in promoting kidney repair