Hyperkahler Metrics from Periodic Monopoles

Relative moduli spaces of periodic monopoles provide novel examples of Asymptotically Locally Flat hyperkahler manifolds. By considering the interactions between well-separated periodic monopoles, we infer the asymptotic behavior of their metrics. When the monopole moduli space is four-dimensional, this construction yields interesting examples of metrics with self-dual curvature (gravitational instantons). We discuss their topology and complex geometry. An alternative construction of these gravitational instantons using moduli spaces of Hitchin equations is also described.Comment: 23 pages, latex. v2: an erroneous formula is corrected, and its derivation is given. v3 (published version): references adde

Twistors and Black Holes

Motivated by black hole physics in N=2, D=4 supergravity, we study the geometry of quaternionic-Kahler manifolds M obtained by the c-map construction from projective special Kahler manifolds M_s. Improving on earlier treatments, we compute the Kahler potentials on the twistor space Z and Swann space S in the complex coordinates adapted to the Heisenberg symmetries. The results bear a simple relation to the Hesse potential \Sigma of the special Kahler manifold M_s, and hence to the Bekenstein-Hawking entropy for BPS black holes. We explicitly construct the ``covariant c-map'' and the ``twistor map'', which relate real coordinates on M x CP^1 (resp. M x R^4/Z_2) to complex coordinates on Z (resp. S). As applications, we solve for the general BPS geodesic motion on M, and provide explicit integral formulae for the quaternionic Penrose transform relating elements of H^1(Z,O(-k)) to massless fields on M annihilated by first or second order differential operators. Finally, we compute the exact radial wave function (in the supergravity approximation) for BPS black holes with fixed electric and magnetic charges.Comment: 47 pages, v2: typos corrected, reference added, v3: minor change

Transcription networks responsible for early regulation of Salmonella_induced inflammation in the jejunum of pigs

Background The aim of this study was to identify transcription factors/regulators that play a crucial role in steering the (innate) immune response shortly (within a few hours) after the first contact of the intestinal mucosa with an inflammatory mediator, and to test whether the processes regulated by these factors/regulators can be modulated by chemical substances of natural origin. Methods We experimentally induced inflammation by perfusion of surgically applied jejunal loops with Salmonella enterica subspecies enterica serovar Typhimurium DT104 in three pigs. Segments of mock and Salmonella treated loops were dissected after 2, 4 and 8¿hours of perfusion. IL8 and IL1-beta mRNA expression levels were measured in mucosal scrapings of all segments. Furthermore, intra-animal microarray comparisons (isogenic) between Salmonella and mock treated segments after 8¿hours, and inter-animal comparisons between similar Salmonella-treated loops of each pig at 2 and 4¿hours, were performed. Results IL-1beta and IL8 mRNA levels, and intra-animal microarray comparisons at 8¿hours between Salmonella and mock treated segments showed that the response-time and type of response to Salmonella was different in all three pigs. This plasticity allowed us to extract a comprehensive set of differentially expressed genes from inter-animal comparisons at 2 and 4¿hours. Pathway analysis indicated that many of these genes play a role in induction and/or tempering the inflammatory response in the intestine. Among them a set of transcription factors/regulators known to be involved in regulation of inflammation, but also factors/regulators for which involvement was not expected. Nine out of twenty compounds of natural origin, which according to literature had the potential to modulate the activity of these factors/regulators, were able to stimulate or inhibit a Salmonella-induced mRNA response of inflammatory-reporter genes IL8 and/or nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha in cultured intestinal porcine epithelial cells. Conclusions We describe a set of transcription factors/regulators possibly involved in regulation of “very early” immune mechanism which determines the inflammatory status of the intestine later on. In addition, we show that these mechanisms may be modulated by chemical substances of natural origin. Keywords: Transcription regulation; Salmonella-induced inflammation; Pig intestin

A novel method for adult height prediction in children with idiopathic short stature derived from a German-Dutch cohort

Context: Prediction of adult height (AH) is important in clinical management of short children. The conventional methods of Bayley-Pinneau (BP) or Roche-Wainer-Thissen (RWT) have limitations. Objective: We aimed to develop a set of algorithms for AH prediction in patients with idiopathic short stature (ISS) which are specific for combinations of predicting variables. Methods: Demographic and auxologic data were collected in childhood (1980s) and at AH (1990s). Data were collected by Dutch and German referral centers for pediatric endocrinology. A total of 292 subjects with ISS (219 male, 73 female) were enrolled. The population was randomly split into modeling (n = 235) and validation (n = 57) cohorts. Linear multi-regression analysis was performed with predicted AH (PAH) as response variable and combinations of chronological age (CA), baseline height, parental heights, relative bone age (BA/CA), birth weight, and sex as exploratory variables. Results: Ten models including different exploratory variables were selected with adjusted R-2 ranging from 0.84 to 0.78 and prediction errors from 3.16 to 3.68 cm. Applied to the validation cohort, mean residuals (PAH minus observed AH) ranged from -0.29 to -0.82 cm, while the conventional methods showed some overprediction (BP: +0.53 cm; RWT: +1.33 cm; projected AH: +3.81 cm). There was no significant trend of residuals with PAH or any exploratory variables, in contrast to BP and projected AH. Conclusion: This set of 10 multi-regression algorithms, developed specifically for children with ISS, provides a flexible tool for AH prediction with better accuracy than the conventional methods.Developmen

Destabilising Divergences in the NMSSM

The problem of destabilising divergences is discussed for singlet extensions of the MSSM. It is shown that models which possess either gauged-$R$ symmetry or target space duality at the Planck scale are able to circumvent this problem whilst avoiding cosmological domain walls.Comment: 19 pages, 5 figures requiring axodraw.sty, plain LaTeX, to appear in Nucl.Phys.

Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection

Recent thymic emigrants can be identified by T cell receptor excision circles (TRECs) formed during T-cell receptor rearrangement. Decreasing numbers of TRECs have been observed with aging and in human immunodeficiency virus (HIV)-1 infected individuals, suggesting for thymic impairment. Here, we show that in healthy individuals, declining thymic output will affect the TREC content only when accompanied by naive T-cell division. The rapid decline in TRECs observed during HIV-1 infection and the increase following HAART are better explained not by thymic impairment, but by changes in peripheral T-cell division rates. Our data indicate that TREC content in healthy individuals is only indirectly related to thymic output, and in HIV-1 infection is mainly affected by immune activation

SUSY Breaking and Moduli Stabilization from Fluxes in Gauged 6D Supergravity

We construct the 4D N=1 supergravity which describes the low-energy limit of 6D supergravity compactified on a sphere with a monopole background a la Salam and Sezgin. This provides a simple setting sharing the main properties of realistic string compactifications such as flat 4D spacetime, chiral fermions and N=1 supersymmetry as well as Fayet-Iliopoulos terms induced by the Green-Schwarz mechanism. The matter content of the resulting theory is a supersymmetric SO(3)xU(1) gauge model with two chiral multiplets, S and T. The expectation value of T is fixed by the classical potential, and S describes a flat direction to all orders in perturbation theory. We consider possible perturbative corrections to the Kahler potential in inverse powers of $Re S$ and $Re T$, and find that under certain circumstances, and when taken together with low-energy gaugino condensation, these can lift the degeneracy of the flat direction for $Re S$. The resulting vacuum breaks supersymmetry at moderately low energies in comparison with the compactification scale, with positive cosmological constant. It is argued that the 6D model might itself be obtained from string compactifications, giving rise to realistic string compactifications on non Ricci flat manifolds. Possible phenomenological and cosmological applications are briefly discussed.Comment: 32 pages, 2 figures. Uses JHEP3.cls. References fixed and updated, some minor typos fixed. Corrected minor error concerning Kaluza-Klein scales. Results remain unchange

Solar Wind Turbulence and the Role of Ion Instabilities

International audienc

Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia

Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10−5 and c.2702T > G [p.V901G], MAF 2.51 × 10−3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05–13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10−8), viability (P = 8.9 × 10−7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T (P = 0.006) and CSPG4V901G (P = 3.4 × 10−4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10−5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia

Predictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial

The RANGE study (NCT02426125) evaluated ramucirumab (an anti-VEGFR2 monoclonal antibody) in patients with platinum-refractory advanced urothelial carcinoma (UC). Here, we use programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) and transcriptome analysis to evaluate the association of immune and angiogenesis pathways, and molecular subtypes, with overall survival (OS) in UC. Higher PD-L1 IHC and immune pathway scores, but not angiogenesis scores, are associated with greater ramucirumab OS benefit. Additionally, Basal subtypes, which have higher PD-L1 IHC and immune/angiogenesis pathway scores, show greater ramucirumab OS benefit compared to Luminal subtypes, which have relatively lower scores. Multivariable analysis suggests patients from East Asia as having lower immune/angiogenesis signature scores, which correlates with decreased ramucirumab OS benefit. Our data highlight the utility of multiple biomarkers including PD-L1, molecular subtype, and immune phenotype in identifying patients with UC who might derive the greatest benefit from treatment with ramucirumab