Regulation of TFEB and V-ATPases by mTORC1TORC1 is a key regulator of cell growth in response to nutrients and acts at the surface of the late endosome. This study identifies V-ATPase genes as transcriptional targets of TORC1 and implicates the transcription factor TFEB as an important mediator of TORC1-dependent gene expression and TORC1-regulated endocytosis.

Background Our objectives were to: (1) determine the pharmacokinetic [PK] indices of vancomycin in pediatric patients; and (2) compare attainment of two target exposures: AUC/MIC ≥ 400 and trough concentration ≥ 15 mcg/mL. Methods The population-based PK modeling was performed using NONMEM 7.2 for children ≥ 3 months old who received vancomycin for ≥ 48 hr from 2003 to 2011. A one-compartment model with first-order kinetics was used to estimate clearance (CL), volume of distribution (Vd) and area-under-curve (AUC). Empiric Bayesian post-hoc individual parameters and Monte Carlo simulations (N=11,000) were performed. Results Analysis included 702 patients with 1660 vancomycin serum concentrations. Median age was 6.6 (interquartile range [IQR] 2.2–13.4) yr, weight 22.7 (12.6–46) kg, and baseline serum creatinine (SCr) 0.40 (0.30–0.60) mg/dL. Final model PK indices were: CL(L/h) = 0.248*Wt0.75*(0.48/SCr)0.361*(ln(age)/7.8)0.995; and Vd(L) = 0.636*Wt. Using these parameters and the observed MIC distribution, Monte Carlo simulation indicated that the initial median dose of 44 (39–52) mg/kg/day was inadequate in most subjects. Regimens of 60 mg/kg/day for subjects ≥ 12 years old and 70 mg/kg/day for those < 12 years old achieved target AUC/MIC in ~ 75% and trough concentrations ≥ 15 in ~ 45% of virtual subjects. An AUC/MIC ~ 400 corresponded to trough concentration ~ 8 to 9 mcg/mL. Conclusions Targeted exposure using vancomycin AUC/MIC, compared with trough concentrations, is a more realistic target in children. Depending on age, serum creatinine, and MIC distribution, vancomycin in a dosage of 60 to 70 mg/kg/day was necessary to achieve AUC/MIC ≥ 400 in 75% of patients.

Type IIB supergravity can be consistently truncated to the metric and the self-dual 5-form. We obtain the complete non-linear Kaluza-Klein S 5 reduction Ansatz for this theory, giving rise to gravity coupled to the fifteen Yang-Mills gauge fields of SO(6) and the twenty scalars of the coset SL(6, IR)/SO(6). This provides a consistent embedding of this subsector of N = 8, D = 5 gauged supergravity in type IIB in D = 10. We demonstrate that the self-duality of the 5-form plays a crucial role in the consistency of the reduction. We also discuss certain necessary conditions for a theory of gravity and an antisymmetric tensor in an arbitrary dimension D to admit a consistent sphere reduction, keeping all the massless fields. We find that it is only possible for D = 11, with a 4-form field, and D = 10, with a 5-form. Furthermore, in D = 11 the full bosonic structure of eleven-dimensional supergravity is required, while in D = 10 the 5-form must be self-dual. It is remarkable that just from the consistency requirement alone one would discover D = 11 and type IIB supergravities, and that D = 11 is an upper bound on the dimension.

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We study the Euclidean-signature supergravities that arise by compactifying D = 11 supergravity or type IIB supergravity on a torus that includes the time direction. We show that the usual T-duality relation between type IIA and type IIB supergravities compactified on a spatial circle no longer holds if the reduction is performed on the time direction. Thus there are two inequivalent Euclidean-signature nine-dimensional maximal supergravities.They become equivalent upon further spatial compactification to D = 8. We also show that duality symmetries of Euclidean-signature supergravities allow the harmonic functions of any single-charge or multi-charge instanton to be rescaled and shifted by constant factors.Combined with the usual diagonal dimensional reduction and oxidation procedures, this allows us to use the duality symmetries to map any single-charge or multi-charge p-brane soliton, or any intersection, into its near-horizon regime. Similar transformations can also be made on non-extremal p-branes. We also study the structures of duality multiplets of instanton and (D − 3)-brane solutions.theories are distinct, and cannot be related to one another by any valid field redefinition.It is only after a further reduction of the two Euclidean-signature theories to D = 8 that an equivalence emerges.One of the motivations for investigating Euclidean-signature supergravities is to study the instanton states, which necessarily live in Euclidean-signature space. Unlike p-branes with p ≥ 0, which are supported by higher-degree field strengths, and which form linear representations under the U-duality group, the instantons are supported by axionic scalars, which transform non-linearly under U-duality. The orbits of the higher p-branes in M-theory are much better understood, and were obtained in [3,4]. In this paper, we shall study the U-duality transformations of instanton solutions, and also the orbits of their charges, which are the Noether charges of the global symmetry group.Another of our results is concerned with the properties of the instanton solutions that are the natural end-points of a sequence of diagonal reductions of p-branes, when the reduction has encompassed the entire world-volume including the time direction. We show that all instanton solutions, including multi-charge ones and even non-extremal ones, have the property that they can be transformed, using SL(2, IR) global duality symmetries of the lower-dimensional theories, into solutions where the harmonic functions characterising the solutions are shifted and scaled by constants. In particular, the shifts can be chosen so as to remove the constant terms in the harmonic functions altogether, with the result that for extremal p-branes the entire solution is of the form that was previously approached only asymptotically in the near-horizon limit. The solutions can then be oxidised back to higher dimensions, by retracing the sequence of reduction steps. They then describe p-branes again, but now with similarly shifted harmonic functions. Thus the asymptoti...

Objective. Ankylosing spondylitis and related spondylarthritides are associated with HLA-B27, and also with intestinal inflammation, by unknown mechanisms. The folded HLA-B27 molecule is a trimer of heavy chain, ␤ 2 -microglobulin (␤ 2 m), and short peptide. However, B27 heavy chain has an unusual propensity to misfold and trigger the unfolded protein response (UPR). This study was initiated to test the hypothesis that B27 misfolding plays a role in the pathogenesis of spondylarthritis.Methods. Rats with high transgene copy numbers of HLA-B27 heavy chain together with human ␤ 2 m (Hu␤ 2 m) spontaneously develop colitis, peripheral arthritis, and occasional spondylitis, and those with lower transgene copy numbers remain healthy. We crossed disease-prone and healthy HLA-B27/Hu␤ 2 mtransgenic rat lines with a healthy line, 283-2, carrying only the Hu␤ 2 m transgene. HLA-B27 assembly was assessed by pulse-chase analysis of B27 molecules, and UPR triggering was assessed by measuring BiP/Grp78 messenger RNA (mRNA) in splenic concanavalin A blasts. Surface expression of B27 and Hu␤ 2 m was determined by flow cytometry. Disease manifestations were identified by clinical observation, histology, and measurement of cytokine mRNA.Results. The extra Hu␤ 2 m from the 283-2 line significantly reduced B27 misfolding and UPR triggering. Unexpectedly, however, F 1 male offspring of the healthy 21-3 line crossed with the 283-2 line showed a high prevalence, severity, and duration of arthritis and spondylitis, in the absence of colitis. The arthropathy showed many features characteristic of human spondylarthritis.Conclusion. These results suggest that B27 misfolding is associated with intestinal inflammation, but that neither B27 misfolding nor intestinal inflammation is critical to the development of B27-associated arthropathy.The spondylarthritides are a group of inflammatory rheumatic diseases characterized by axial and peripheral arthropathy and a variety of extraarticular lesions (1). In the prototype of these disorders, ankylosing spondylitis (AS), there is inflammation in the spinal and sacroiliac joints and in ligamentous attachments that, in severe cases, leads to bony fusion. The pathogenesis of spondylarthritis is poorly understood. Two factors strongly associated with these conditions are intestinal inflammation and the major histocompatibility complex (MHC) class I gene HLA-B27.With regard to the association with intestinal inflammation, the prevalence of inflammatory bowel disease (IBD) (both Crohn's disease and ulcerative colitis) is increased in individuals with AS. An even higher prevalence of IBD is found in individuals with other forms of spondylarthritis (2), and endoscopic studies with biopsy have shown a prevalence of microscopic inflammatory bowel lesions in 60-70% of patients