Evaluation of the Laguerre-Gaussian mode purity produced by three-dimensional-printed microwave spiral phase plates.

Computer-aided design software and additive manufacturing provide flexibility for the direct fabrication of multi-material devices. This design and fabrication versatility has been investigated for the manufacture of dielectric spiral phase plates (SPP) that generate electromagnetic waves with helical wavefronts. Three types of SPPs designed to produce an orbital angular momentum (OAM) mode number l = |1| were additively manufactured using material extrusion and polyjet fabrication methods. The OAM mode characteristics of the transformed helical microwaves as a function of the SPP geometrical features were investigated experimentally in the 12-18 GHz frequency range. The SPPs were further combined with an additively manufactured dielectric lens that provided a marked improvement in OAM mode purity. Finally, multiplexing and de-multiplexing of two OAM modes were demonstrated successfully using an optimum SPP geometry and arrangement.

Positive Energy Functional for Massless Scalars in Rotating Black Hole Backgrounds of Maximal Ungauged Supergravity.

We outline a proof of the stability of a massless neutral scalar field ψ in the background of a wide class of four dimensional asymptotically flat rotating and "electrically charged" solutions of supergravity, and the low energy limit of string theory, known as STU metrics. Despite their complexity, we find it possible to circumvent the difficulties presented by the existence of ergo regions and the related phenomenon of superradiance in the original metrics by following a strategy due to Whiting, and passing to an auxiliary metric admitting an everywhere lightlike Killing field and constructing a scalar field ψ (related to a possible unstable mode ψ by a nonlocal transformation) which satisfies the massless wave equation with respect to the auxiliary metric. By contrast with the case for ψ, the associated energy density of ψ is not only conserved but is also non-negative.

Helical phase of chiral nematic liquid crystals as the Bianchi VII0 group manifold.

We show that the optical structure of the helical phase of a chiral nematic is naturally associated with the Bianchi VII(0) group manifold, of which we give a full account. The Joets-Ribotta metric governing propagation of the extraordinary rays is invariant under the simply transitive action of the universal cover E(2) of the three-dimensional Euclidean group of two dimensions. Thus extraordinary light rays are geodesics of a left-invariant metric on this Bianchi type VII(0) group. We are able to solve, by separation of variables, both the wave equation and the Hamilton-Jacobi equation for this metric. The former reduces to Mathieu's equation, and the latter to the quadrantal pendulum equation. We discuss Maxwell's equations for uniaxial optical materials where the configuration is invariant under a group action and develop a formalism to take advantage of these symmetries. The material is not assumed to be impedance matched, thus going beyond the usual scope of transformation optics. We show that for a chiral nematic in its helical phase Maxwell's equations reduce to a generalized Mathieu equation. Our results may also be relevant to helical phases of some magnetic materials and to light propagation in certain cosmological models.

Universal area product formulas for rotating and charged black holes in four and higher dimensions.

We present explicit results for the product of all horizon areas for general rotating multicharge black holes, both in asymptotically flat and asymptotically anti-de Sitter spacetimes in four and higher dimensions. The expressions are universal, and depend only on the quantized charges, quantized angular momenta and the cosmological constant. If the latter is also quantized these universal results may provide a "looking glass" for probing the microscopics of general black holes.

Peroxisome proliferator-activated receptor alpha deficiency modifies glucose handling by isolated mouse adipocytes.

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a transcription factor that regulates enzymes involved in fatty acid (FA) utilisation. PPARalpha null mice have recently been demonstrated to have increased whole-body glucose turnover in vivo. This has been attributed to increased glucose uptake by adipose tissue, but the impact of PPARalpha deficiency on the characteristics of glucose handling by isolated adipocytes ex vivo is unknown. To determine directly the impact of PPARalpha deficiency on adipocyte glucose handling, thereby excluding any influence of humoral/neuronal factors, we examined total glucose metabolism as well as glucose disposition towards alternative fates in epididymal adipocytes isolated from wild-type and PPARalphanull mice. Total glucose metabolism (oxidation, incorporation into FA and glycerol moieties of triglyceride (TAG) and conversion to lactate) was measured under basal conditions (low glucose) and 'stimulated lipogenic' conditions (high glucose + insulin). Adipocytes from PPARalpha null mice had higher rates of glucose metabolism under both basal and stimulated lipogenic conditions, with increased glucose utilisation both for oxidation and entry into the synthesis of the FA and glycerol components of lipid. In particular, the capacity of adipocytes from PPARalpha-deficient mice to utilise glucose for synthesis of the glycerol backbone of TAG was greatly enhanced under stimulated (high glucose + insulin) conditions. The increased use of glucose for the glycerol moiety of adipocyte TAG may therefore contribute to, and provide explanation for, enhanced glucose turnover in PPARalpha null mice.

Fasting-induced increases in aquaporin 7 and adipose triglyceride lipase mRNA expression in adipose tissue are attenuated by peroxisome proliferator-activated receptor alpha deficiency.

OBJECTIVE: To investigate the impact of peroxisome proliferator-activated receptor alpha deficiency on gene expression of adipose triglyceride lipase and the glycerol transporter aquaglyceroporin 7 in white adipose tissue in the fed and fasted states in relation to glycerol release by isolated adipocytes. MEASUREMENTS: Studies using wild-type and peroxisome proliferator-activated receptor alpha null mice. Hormone and metabolite concentrations, real-time polymerase chain reaction (PCR), basal and stimulated adipocyte lipolysis, estimated by glycerol release. RESULTS: Peroxisome proliferator-activated receptor alpha deficiency blocked the increase in aquaglyceroporin 7 transcript level and attenuated the increase in adipose triglyceride lipase transcript level in white adipose tissue elicited by fasting. Fasting glycerol levels were lower in peroxisome proliferator-activated receptor alpha null than wild-type mice, despite increased mobilization of adipocyte fat reserves in vivo as indicated by reduced adipose tissue masses (three distinct depots) and a significantly lower epididymal adipocyte diameter. Basal net glycerol release was unchanged but beta-adrenergic-stimulated net glycerol release was higher with isolated adipocytes from fasted peroxisome proliferator-activated receptor alpha null mice compared with those of fasted wild-type mice. CONCLUSION: Peroxisome proliferator-activated receptor alpha deficiency prevents effects of fasting to increase adipocyte aquaglyceroporin 7 gene expression, and influences the regulation of inter-tissue glycerol flux after fasting via lowered adipocyte aquaglyceroporin 7 expression. Lowered gene expression of adipose triglyceride lipase and aquaglyceroporin 7 in peroxisome proliferator-activated receptor alpha null mice is not limiting for adipose triglyceride breakdown in vivo during fasting.

Anti-de Sitter-space/conformal-field-theory Casimir energy for rotating black holes.

We show that, if one chooses the Einstein static universe as the metric on the conformal boundary of Kerr-anti-de Sitter spacetime, then the Casimir energy of the boundary conformal field theory can easily be determined. The result is independent of the rotation parameters, and the total boundary energy then straightforwardly obeys the first law of thermodynamics. Other choices for the metric on the conformal boundary will give different, more complicated, results. As an application, we calculate the Casimir energy for free self-dual tensor multiplets in six dimensions and compare it with that of the seven-dimensional supergravity dual. They differ by a factor of 5/4.

Deficiency of PPARalpha disturbs the response of lipogenic flux and of lipogenic and cholesterogenic gene expression to dietary cholesterol in mouse white adipose tissue.

PPARalpha-deficiency in mice fed a high-carbohydrate, low-cholesterol diet was associated with a decreased weight of epididymal adipose tissue and an increased concentration of adipose tissue cholesterol. Consumption of a high (2% w/w) cholesterol diet resulted in a further increase in the concentration of cholesterol and a further decrease in epididymal fat pad weight in PPARalpha-null mice, but had no effect in the wild-type. These reductions in fat pad weight were associated with an increase in hepatic triacylglycerol content, indicating that both PPARalpha-deficiency and cholesterol altered the distribution of triacylglycerol in the body. Adipose tissue de novo lipogenesis was increased in PPARalpha-null mice and was further enhanced when they were fed a cholesterol-rich diet; no such effect was observed in the wild-type mice. The increased lipogenesis in the chow-fed PPARalpha-null mice was accompanied paradoxically by lower mRNA expression of SREBP-1c and its target genes, acetyl-CoA carboxylase and fatty acid synthase. Consumption of a high-cholesterol diet increased the mRNA expression of these genes in the PPARalpha-deficient mice but not in the wild-type. De novo cholesterol synthesis was not detectable in the adipose tissue of either genotype despite a relatively high expression of the mRNA's encoding SREBP-2 and 3-hydroxy-3-methylglutaryl Coenzyme A reductase. The mRNA expression of these genes and of the LDL-receptor in adipose tissue of the PPARalpha-deficient mice was lower than that of the wild-type and was not downregulated by cholesterol feeding. The results suggest that PPARalpha plays a role in adipose tissue cholesterol and triacylglycerol homeostasis and prevents cholesterol-mediated changes in de novo lipogenesis.

Brane worlds in collision.

We obtain an exact solution of the supergravity equations of motion in which the four-dimensional observed Universe is one of a number of colliding D3 branes in a Calabi-Yau background. The collision results in the ten-dimensional spacetime splitting into disconnected regions, bounded by curvature singularities. However, near the D3 branes the metric remains static during and after the collision. We also obtain a general class of solutions representing p-brane collisions in arbitrary dimensions, including one in which the universe ends with the mutual annihilation of a positive-tension and a negative-tension 3 brane.

A dominant negative human peroxisome proliferator-activated receptor (PPAR){alpha} is a constitutive transcriptional corepressor and inhibits signaling through all PPAR isoforms.

Several missense mutations in the ligand-binding domain of human peroxisome proliferator-activated receptor (PPAR)gamma have been described in subjects with dominantly inherited severe insulin resistance associated with partial lipodystrophy, hypertension, and dyslipidemia. These mutant receptors behave as dominant-negative inhibitors of PPARgamma signaling when studied in transfected cells. The extent to which such dominant-negative effects extend to signaling through other coexpressed PPAR isoforms has not been evaluated. To examine these issues further, we have created a PPARalpha mutant harboring twin substitutions, Leu459Ala and Glu462Ala, within the ligand binding domain (PPARalpha(mut)), examined its signaling properties, and compared the effects of dominant-negative PPARalpha and PPARgamma mutants on basal and ligand-induced gene transcription in adipocytes and hepatocytes. PPARalpha(mut) was transcriptionally inactive, repressed basal activity from a PPAR response element-containing promoter, inhibited the coactivator function of cotransfected PPAR-gamma coactivator 1alpha, and strongly inhibited the transcriptional response to cotransfected wild-type receptor. In contrast to PPARgamma, wild-type PPARalpha failed to recruit the transcriptional corepressors NCoR and SMRT. However, PPARalpha(mut) avidly recruited these corepressors in a ligand-dissociable manner. In hepatocytes and adipocytes, both PPARalpha(mut) and the corresponding PPARgamma mutant were capable of inhibiting the expression of genes primarily regulated by PPARalpha, -gamma, or -delta ligands, albeit with some differences in potency. Thus, dominant-negative forms of PPARalpha and PPARgamma are capable of interfering with PPAR signaling in a manner that is not wholly restricted to their cognate target genes. These findings may have implications for the pathogenesis of human syndromes resulting from mutations in this family of transcription factors.

Rotating black holes in higher dimensions with a cosmological constant.

We present the metric for a rotating black hole with a cosmological constant and with arbitrary angular momenta in all higher dimensions. The metric is given in both Kerr-Schild and the Boyer-Lindquist form. In the Euclidean-signature case, we also obtain smooth compact Einstein spaces on associated S(D-2) bundles over S2, infinitely many for each odd D>/=5. Applications to string theory and M-theory are indicated.

Synthesis and function of hepatic very-low-density lipoprotein.

Most of the triacylglycerol (TAG) utilized for the assembly of very-low-density lipoprotein (VLDL) in the secretory apparatus of the hepatocyte is mobilized by lipolysis of the cytosolic TAG pool, followed by re-esterification. The lipases involved include arylacetamide deacetylase and/or triacylglycerol hydrolase. Some of the re-esterified products of lipolysis gain access to an apolipoprotein-B-rich VLDL precursor to form mature VLDL. Some, however, are returned to the cytosolic pool in a process that is stimulated by insulin and inhibited by microsomal triacylglycerol transfer protein (MTP). Phospholipids also contribute to VLDL TAG in a process which involves ADP-ribosylation factor-1 (ARF-1)-mediated activation of phospholipase D. The temporary storage of TAG in the liver, followed by its mobilization and secretion as VLDL, form part of a process by which the liver protects vulnerable body tissues from excess lipotoxic non-esterified ('free') fatty acids in the plasma.

Apolipoprotein E-deficient mice created by systemic administration of antisense oligodeoxynucleotides: a new model for lipoprotein metabolism studies.

Atherosclerotic cardiovascular disease results from complex interactions among multiple genetic and environmental factors. Thus, it is important to elucidate the influence of each factor on cholesterol metabolism. For this purpose, transgenic/gene-targeting technology is a powerful tool for studying gene functions. However, this technology has several disadvantages such as being time consuming and expensive. Accordingly, we established new animal models using in vivo gene transfer technology. In this study, we examined the feasibility of the creation of a new animal model for the study of atherosclerosis. We hypothesized that apolipoprotein (apo) E-deficient mice can be created by systemic administration of antisense apo E oligodeoxynucleotides (ODN) coupled to the HVJ-liposome complex. Initially, we examined the localization and cellular fate of FITC-labeled antisense ODN administered intravenously. FITC-labeled ODN transfection by the HVJ-liposome method resulted in fluorescence in the liver, spleen and kidney, but not in other organs such as brain. Moreover, fluorescence with the HVJ-liposome method was sustained for up to 2 weeks after transfection, which resulted in a striking difference from transfection of ODN alone or ODN in liposomes without HVJ, which showed rapid disappearance of fluorescence (within 1 day). Given these unique characteristics of the HVJ-liposome method, we next examined transfection of antisense apo E ODN by intravenous administration. Transfection of antisense apo E ODN resulted in a marked reduction of apo E mRNA levels in the liver, but no change in apo B and beta-actin mRNA levels. In mice fed a normal diet, a transient increase in cholesterol and triglyceride levels was observed in the antisense apo E-treated group, but they returned to normal levels by 6 days after transfection. Similar findings were also found in mice fed a high cholesterol diet. Neither scrambled nor mismatched ODN resulted in any increase in cholesterol. To make chronic hypercholesterolemic mice, we therefore performed repeated injections of apo E antisense ODN. Whenever antisense apo E ODN were injected, mice showed a transient increase in cholesterol and triglyceride. Cumulative administration of antisense apo E ODN resulted in a sustained increase in cholesterol for up to 3 weeks after the last transfection. Finally, mice treated with repeated injections of antisense apo E every week developed sustained hypercholesterolemia and hypertriglyceridemia until withdrawal of injections. Apolipoprotein-deficient mice created by intravenous administration of antisense ODN are a promising new animal model to help understand the role of apolipoprotein in vivo and develop a new drug therapy targeting apolipoprotein.

M-theory conifolds.

Seven manifolds of G2 holonomy provide a bridge between M-theory and string theory, via Kaluza-Klein reduction to Calabi-Yau six manifolds. We find first-order equations for a new family of G2 metrics D7, with S3 x S3 principal orbits. These are related at weak string coupling to the resolved conifold, paralleling earlier examples B7 that are related to the deformed conifold, allowing a deeper study of topology change and mirror symmetry in M-theory. The D7 metrics' nontrivial parameter characterizes the squashing of an S3 bolt, which limits to S2 at weak coupling. In general the D7 metrics are asymptotically locally conical, with a nowhere-singular circle action.

Role of peroxisome proliferator-activated receptor-alpha in the mechanism underlying changes in renal pyruvate dehydrogenase kinase isoform 4 protein expression in starvation and after refeeding.

The pyruvate dehydrogenase complex (PDC) occupies a strategic role in renal intermediary metabolism, via partitioning of pyruvate flux between oxidation and entry into the gluconeogenic pathway. Inactivation of PDC via activation of pyruvate dehydrogenase kinases (PDKs), which catalyze PDC phosphorylation, occurs secondary to increased fatty acid oxidation (FAO). In kidney, inactivation of PDC after prolonged starvation is mediated by up-regulation of the protein expression of two PDK isoforms, PDK2 and PDK4. The lipid-activated transcription factor, peroxisome proliferator-activated receptor-alpha (PPAR alpha), plays a pivotal role in the cellular metabolic response to fatty acids and is abundant in kidney. In the present study we used PPAR alpha null mice to examine the potential role of PPAR alpha in regulating renal PDK protein expression. In wild-type mice, fasting (24 h) induced marked up-regulation of the protein expression of PDK4, together with modest up-regulation of PDK2 protein expression. In striking contrast, renal protein expression of PDK4 was only marginally induced by fasting in PPAR alpha null mice. The present results define a critical role for PPAR alpha in renal adaptation to fasting, and identify PDK4 as a downstream target of PPAR alpha activation in the kidney. We propose that specific up-regulation of renal PDK4 protein expression in starvation, by maintaining PDC activity relatively low, facilitates pyruvate carboxylation to oxaloacetate and therefore entry of acetyl-CoA derived from FA beta-oxidation into the TCA cycle, allowing adequate ATP production for brisk rates of gluconeogenesis.

Insulin inhibits the maturation phase of VLDL assembly via a phosphoinositide 3-kinase-mediated event.

LY 294002 (80 micromol/L), an inhibitor of phosphoinositide 3-kinase, was used to investigate the involvement of this enzyme in the insulin-mediated regulation of very low density lipoprotein (VLDL) apolipoprotein B (apoB) output from cultured rat hepatocytes. Newly synthesized apoB was pulse-labeled with [(35)S]methionine and was then allowed to assemble, via an intermediate precursor stage, into mature VLDL during subsequent chase periods. Brefeldin A (BFA, 0.2 microgram/mL) was used to discriminate between the role of insulin in the regulation of the early, compared with the later, events of VLDL assembly, including apoB degradation. Insulin (78 nmol/L), when present during the pulse-labeling and subsequent chase periods, inhibited the secretion of apoB-100 and apoB-48 as VLDL by 53% and 56%, respectively. Degradation of both was concomitantly increased. Secretion of high density lipoprotein apoB, derived from VLDL precursors, was relatively unaffected under these conditions, as was the net synthesis of apoB-100 and apoB-48. The presence of BFA during the pulse-labeling period and subsequent chase period prevented the maturation of VLDL in the insulin-treated and the non-insulin-treated cells. BFA was then removed, allowing the maturation of VLDL to proceed. Removal of insulin at this stage reversed the overall inhibitory effect of insulin. Furthermore, when insulin remained present during this period, the simultaneous presence of LY 294002 also reversed the inhibitory effect of insulin on VLDL apoB output and abolished the increase in apoB degradation. The results suggest that insulin signaling via phosphoinositide 3-kinase inhibited the maturation phase of VLDL assembly by preventing bulk lipid transfer to a VLDL precursor, thus enhancing the degradation of apoB. There was no inhibition of the conversion of newly synthesized apoB into the VLDL precursor form.

Microsomal membrane-associated apoB is the direct precursor of secreted VLDL in primary cultures of rat hepatocytes.

Brefeldin A (BFA) added to primary cultures of rat hepatocytes, at a concentration of 0.2 microg/ml, prevented the assembly of newly synthesized apolipoprotein B (apoB) into mature, secretory VLDL but did not prevent the secretion of apoB as denser particles (HDL apoB), or of albumin. The unassembled apoB remained associated with the membranes of the cellular microsomal fraction. There was no effect of BFA on the removal of apoB from the lumen of these vesicles. VLDL apoB formed only a minor component of the total apoB in the microsomal lumen. Higher (5 microg/ml) concentrations of BFA were required to prevent the secretion of HDL apoB and albumin. Under these conditions apoB accumulated in the microsomal lumen, as well as in the membranes of these vesicles. Again, apoB VLDL formed only a minor proportion of the total lumenal apoB. ApoB-48 VLDL and apoB-100 VLDL assembly could be restored by removing BFA from the medium. This reactivation of VLDL assembly was accompanied by an increased removal of apoB from the microsomal membranes, but there was no detectable increase in the small quantity of VLDL apoB that was recovered from the microsomal lumen. In the absence of BFA, during pulse-chase experiments the pattern of change in the specific radioactivity of microsomal membrane apoB was similar to that of the secreted VLDL apoB whereas that of the lumenal apoB resembled that of the secreted HDL apoB. The results suggest that membrane-associated apoB is the main direct precursor of secreted VLDL apoB in primary cultures of rat hepatocytes and that VLDL assembly does not involve primarily microsomal lumenal apoB as an intermediate.