Phonon black-body radiation limit for heat dissipation in electronics.

Thermal dissipation at the active region of electronic devices is a fundamental process of considerable importance. Inadequate heat dissipation can lead to prohibitively large temperature rises that degrade performance, and intensive efforts are under way to mitigate this self-heating. At room temperature, thermal resistance is due to scattering, often by defects and interfaces in the active region, that impedes the transport of phonons. Here, we demonstrate that heat dissipation in widely used cryogenic electronic devices instead occurs by phonon black-body radiation with the complete absence of scattering, leading to large self-heating at cryogenic temperatures and setting a key limit on the noise floor. Our result has important implications for the many fields that require ultralow-noise electronic devices.

Determining phonon mean free paths from observations of quasiballistic thermal transport.

The mean free paths (MFPs) of thermal phonons are mostly unknown in many solids. Recent work indicates that MFPs may be measured using experimental observations of quasiballistic thermal transport, but the precise relationship between the measurements and the MFP distribution remains unclear. Here, we present a method that can accurately reconstruct the MFP distribution from quasiballistic thermal measurements without any assumptions regarding the phonon scattering mechanisms. Our result will enable a substantially improved understanding of thermal transport in many solids, particularly thermoelectrics.

Thermal conductivity spectroscopy technique to measure phonon mean free paths.

Size effects in heat conduction, which occur when phonon mean free paths (MFPs) are comparable to characteristic lengths, are being extensively explored in many nanoscale systems for energy applications. Knowledge of MFPs is essential to understanding size effects, yet MFPs are largely unknown for most materials. Here, we introduce the first experimental technique which can measure MFP distributions over a wide range of length scales and materials. Using this technique, we measure the MFP distribution of silicon for the first time and obtain good agreement with first-principles calculations.

PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-alpha may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR-activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages. Here we show that PPAR-alpha and PPAR-gamma activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxysterol-activated nuclear receptor which induces ABCA1-promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gamma activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.

Intrinsic anharmonic localization in thermoelectric PbSe.

Lead chalcogenides have exceptional thermoelectric properties and intriguing anharmonic lattice dynamics underlying their low thermal conductivities. An ideal material for thermoelectric efficiency is the phonon glass-electron crystal, which drives research on strategies to scatter or localize phonons while minimally disrupting electronic-transport. Anharmonicity can potentially do both, even in perfect crystals, and simulations suggest that PbSe is anharmonic enough to support intrinsic localized modes that halt transport. Here, we experimentally observe high-temperature localization in PbSe using neutron scattering but find that localization is not limited to isolated modes - zero group velocity develops for a significant section of the transverse optic phonon on heating above a transition in the anharmonic dynamics. Arrest of the optic phonon propagation coincides with unusual sharpening of the longitudinal acoustic mode due to a loss of phase space for scattering. Our study shows how nonlinear physics beyond conventional anharmonic perturbations can fundamentally alter vibrational transport properties.

Active Thermal Extraction and Temperature Sensing of Near-field Thermal Radiation.

Recently, we proposed an active thermal extraction (ATX) scheme that enables thermally populated surface phonon polaritons to escape into the far-field. The concept is based on a fluorescence upconversion process that also occurs in laser cooling of solids (LCS). Here, we present a generalized analysis of our scheme using the theoretical framework for LCS. We show that both LCS and ATX can be described with the same mathematical formalism by replacing the electron-phonon coupling parameter in LCS with the electron-photon coupling parameter in ATX. Using this framework, we compare the ideal efficiency and power extracted for the two schemes and examine the parasitic loss mechanisms. This work advances the application of ATX to manipulate near-field thermal radiation for applications such as temperature sensing and active radiative cooling.

Impaired triacylglycerol catabolism in hypertriglyceridemia of the diabetic, cholesterol-fed rabbit: a possible mechanism for protection from atherosclerosis.

The etiology of the hypertriglyceridemia in alloxan-diabetic rabbits was studied by two independent methods. Production and removal rates of VLDL triacylglycerol were measured in diabetic rabbits by injection of [3H]palmitate-labelled VLDL. Similarly, triacylglycerol total removal rates were determined in non-diabetic rabbits which were infused with Intralipid to mimic the plasma triacylglycerol concentrations of diabetic rabbits. Compared to nondiabetic rabbits, triacylglycerol removal rats were decreased in diabetic rabbits, particularly at higher levels of plasma triacylglycerol. During cholesterol and triacylglycerol supplementation of the diet, post-heparin plasma lipoprotein lipase activity of diabetic rabbits with severe hypertriglyceridemia averaged 36% of that of nondiabetics, suggesting an impaired triacylglycerol removal capacity. Furthermore, plasma triacylglycerol was inversely related to post-heparin plasma lipoprotein lipase activity among diabetic rabbits. VLDL triacylglycerol production increased with increasing plasma triacylglycerol concentration among diabetic cholesterol-fed rabbits with moderately severe hypertriglyceridemia, but reached an apparent plateau among rabbits with plasma triacylglycerol concentrations from approx. 2000-9000 mg/dl. Thus, severe hypertriglyceridemia in this model of insulin deficiency can be attributed only partially to VLDL hypersecretion, whereas a removal defect, resulting in saturation of the triacylglycerol removal mechanism, appears to be largely responsible. The impaired removal of plasma triacylglycerol is also related to the presence of cholesterol predominantly in lipoproteins of increased size. The data support the hypothesis that protection against atherosclerosis in cholesterol-fed diabetic rabbits results from exclusion of very large cholesterol-containing lipoproteins from the arterial wall.

Advances in the measurement and computation of thermal phonon transport properties.

Heat conduction by phonons is a ubiquitous process that incorporates a wide range of physics and plays an essential role in applications ranging from space power generation to LED lighting. Heat conduction has been studied for over two hundred years, yet many of the microscopic details have remained unknown in most crystalline solids, including which phonon-phonon interactions are primarily responsible for thermal resistance and how heat is distributed among the broad thermal spectrum. This lack of knowledge was the result of limitations on the available tools to study heat conduction. However, recent advances in both computation and experiment are enabling an unprecedented microscopic view of thermal transport by phonons in both bulk and nanostructured crystals, from the level of atomic bonding to mesoscopic transport in complex devices. In this topical review, we examine these techniques and the microscopic insights gained into the science and engineering of heat conduction.

Stimulation of prostacyclin production in isolated rat adipocytes by angiotensin II, vasopressin, and bradykinin: evidence for two separate mechanisms of prostaglandin synthesis.

We compared the effects of three vasoactive peptides (angiotensin II, vasopressin, and bradykinin) and norepinephrine on the production of prostaglandin I2 [prostacyclin (PGI2)] and PGE2 by isolated rat adipocytes. Angiotensin II, vasopressin, and bradykinin stimulated PGI2 production but had minimal or no effect on PGE2 production or triglyceride lipolysis in isolated rat adipocytes, while norepinephrine stimulated PGI2 production, PGE2 production, and triglyceride lipolysis. The arachidonic acid that serves as substrate for PGI2 production in adipocytes in response to the vasoactive peptides appears to be derived from the cellular phospholipids rather than the triglycerides in these triglyceride-laden cells. The adipocyte contains two separate mechanisms for PG production: 1) a catecholamine-stimulated mechanism for the production of PGI2 and PGE2 that is activated concomitantly with triglyceride lipolysis, and 2) a mechanism activated by vasoactive peptides for the stimulation of PGI2 production independent of triglyceride lipolysis and PGE2 production. These mechanisms may have distinct functions.

Oxidative stress leads to cholesterol accumulation in vascular smooth muscle cells.

The transformation of macrophages and smooth muscle cells into foam cells by modified low-density lipoproteins (LDL) is one of the key events of atherogenesis. Effects of free radicals have mainly been studied in LDL, and other than toxicity, data dealing with direct action of free radicals on cells are scarce. This study focused on the direct effects of free radicals on cholesterol metabolism of smooth muscle cells. A free radical generator, azobis-amidinopropane dihydrochloride, was used, and conditions for a standardized oxidative stress were set up in vascular smooth muscle cells. After free radical action, the cells presented an accumulation of cholesterol that appeared to be the result of: (i) an increase in cholesterol biosynthesis and esterification; (ii) a decrease in cell cholesteryl ester hydrolysis; and (iii) a reduced cholesterol efflux. All these parameters were opposed by antioxidants. In addition, oxidant stress induced an increased degradation of acetyl-LDL, whereas no change was noted for native LDL. From this data, it was concluded that cholesterol metabolism of vascular smooth muscle cells was markedly altered by in vitro treatment with free radicals, although cell viability was unaffected. The resulting disturbance in cholesterol metabolism favors accumulation of cholesterol and cholesteryl esters in vascular cells, and thus may contribute to the formation of smooth muscle foam cells.

Coexisting dysbetalipoproteinemia and familial hypercholesterolemia. Clinical and laboratory observations.

Type III dysbetalipoproteinemia and familial hypercholesterolemia (FH) are two metabolic disorders giving rise to severe disturbances of lipid homeostasis and premature atherosclerosis. Both metabolic abnormalities have a genetic basis and co-occurrence in the same patient has seldom been described. Because of the unique structure of the French Canadian population, there was an opportunity to observe patients with both dysbetalipoproteinemia (E2/2 homozygotes) and FH (N=14) and to compare their clinical data with that of patients with type III (N=75), patients with FH (N0.7 and the presence of beta-VLDL on electrophoresis. Presence of a low density lipoprotein receptor, LDL-R, mutation should be suspected in a type III patient with a LDL-C level above 3.0 mmol/l and a family history of premature CAD. In the group of patients studied, the coexistence of dysbetalipoproteinemia and heterozygous FH does not appear to increase the prevalence of cardiovascular complications above that observed among control type III or control E3/3-FH patients. Thus, the presence of two epsilon2 alleles in these patients affects the expression of the abnormal LDL-R allele and the resulting phenotype substantiates the non additive effects of alleles at these two loci (epistasis).

Expression of gamma-IFN responsive genes in scavenger receptor over-expressing monocytes is associated with xanthomatosis.

We have recently described an inherited over-expression of the macrophage scavenger receptor (SR) in blood monocytes from members of a kindred, only two of whom displayed extensive xanthomatosis. Using mRNA differential display we demonstrated abnormally high expression of the signal transducer and activator of transcription (STAT1alpha) in monocytes from the proband II-2. Expression of gamma-interferon inducible protein 10 (IP-10), a STAT1alpha-responsive gene and mediator of inflammatory response, was also abnormally expressed in the monocytes from II-2. Over-expression of both genes was restricted to monocytes from II-2 and was not observed in monocytes from the clinically unaffected family members, unlike that of SR. Gel retardation assays with THP-1 cell extracts identified gamma-IFN inducible DNA binding activity to three potential STATI DNA binding elements in the human IP-10 promoter region from nucleotides - 245 to - 188. Taken together these results suggest that gamma-interferon mediated cell activation is responsible for STAT1alpha-induced transcription of the IP-10 gene in THP-1 macrophages as well as in monocytes from II-2. Analysis of monocytes from familial hypercholesterolemic (FH) subjects, who frequently develop xanthomatosis, revealed a significant number of subjects with elevated STAT1alpha and IP-10 expression. Our data suggest that the inflammatory effects of gamma-IFN signaling could play a role in foam cell formation and xanthomatosis.

New methods for rapid detection of low-density lipoprotein receptor and apolipoprotein B gene mutations causing familial hypercholesterolemia.

Due to a genetic founder effect, five mutations in the low-density lipoprotein receptor gene account for approximately 83% of familial hypercholesterolemia (FH) diagnosed in French-Canadians. The most frequent mutation, present in 61% of heterozygotes, is a > 10 kb deletion of the 5' region of the gene that removes the promoter and the first exon, resulting in a null allele. Other less prevalent mutations include a gene deletion of approximately 5 kb, which removes exons 2 and 3 (2% of cases) and three missense mutations: Trp66-->Gly (exon 3) (12%), Glu207-->Lys (exon 4) (3%), and Cys646-->Tyr (exon 14) (6%). The apoB Arg3500-->Gln mutation was absent in 228 French Canadians with the FH phenotype. Taking advantage of the availability of fluorescent DNA detection, we have substantially improved the assays for these mutations.

Lipoprotein lipase gene mutations in coronary artery disease.

BACKGROUND: Genetic lipoprotein disorders are frequently associated with premature coronary artery disease (CAD). Functional mutations of the lipoprotein lipase (LPL) gene are associated with altered plasma lipoprotein profiles and are relatively common in French Canadians. OBJECTIVE: To investigate the prevalence of LPL gene mutations in a group of patients with premature CAD and in a healthy control group. METHODS: A total of 636 subjects (337 [82% men] with angiographically documented CAD and 299 controls [63% men]) were examined for the presence of mutations LPL(Gly188-->Glu), LPL(Pro207-->Leu), LPL(Asp250-->Asn) and LPL(Asn291-->Ser) of the LPL gene. These mutations represent over 97% of LPL mutations in familial hyperchylomicronemia in Quebec. RESULTS: The prevalence of heterozygosity for defective LPL alleles was eight of 337 (2.4%) in the CAD group and five of 299 (1.7%) in the control group (chi(2) = 0.118, P = 0.73; power [P] for alpha = 0.05, P = 0.60). In the six CAD patients heterozygous for LPL(Asn291-->Ser), fasting plasma lipoprotein lipid levels did not differ significantly from those of the rest of the CAD group or markedly from those of control subjects. The two CAD patients heterozygous for the LPL(Gly188-->Glu) mutation, however, had hypertriglyceridemia and low plasma high density lipoprotein levels. No CAD or control subjects were identified with the LPL(Pro207-->Leu) or LPL(Asp250-->Asn) alleles. CONCLUSIONS: In this selected population of premature CAD subjects, the prevalence of heterozygosity for defective LPL alleles was slightly higher (but not significantly so) than that in a group of healthy subjects. The LPL(Gly188-->Glu) and LPL(Asn291-->Ser) mutations may confer genetic susceptibility to premature CAD in a small number (approximately 2.4%) of patients; overall these four LPL alleles do not appear to contribute significantly to CAD risk in French Canadians.

Apolipoprotein E, synaptic plasticity and Alzheimer's disease.

Apolipoprotein E (apoE) has been studied extensively with regard to its role in plasma lipoprotein lipid transport. A role for apoE in the transport of membrane cholesterol and phospholipid in the central and peripheral nervous system has also been studied. Entorhinal cortex-lesioned rats have been used extensively to examine the molecular mechanisms associated with deafferentation and reinnervation in the CNS; studies of the role of apoE in this process using this animal model are described. In all human populations examined, three common apoE isoforms, apoE2, apoE3 and apoE4, result from multiple alleles epsilon 2, epsilon 3 and epsilon 4 at a single apoE genetic locus. These isoforms impart well-characterized functional differences in plasma lipoprotein transport, which are reviewed herein. Also discussed are less well-studied possible apoE-isoform specific differences in central nervous system function. These are currently of critical importance due to numerous recent studies showing an association of epsilon 4 with increased risk for Alzheimer's disease. Diverse hypotheses as to the molecular basis for this association, as well as the supporting experimental evidence, are reviewed.

A novel explanation for the reduced LDL cholesterol in severe hypertriglyceridemia.

When [3H]cholesteryl ester-labeled low density (LDL) and intermediate density lipoproteins (IDL) from a normotriglyceridemic, hypercholesterolemic rabbit were injected into severely hypertriglyceridemic, hypercholesterolemic rabbits, 60% of the label appeared in very low density lipoproteins (VLDL) at 3 hr. A similar experiment showed that 40% of injected 131I-protein-labeled LDL appeared in the IDL fraction at 4 hr. Taken together, these data suggest that the exchange of LDL cholesteryl ester for VLDL triglyceride results in a density shift of injected LDL to the IDL density range. Furthermore, the percent of injected 131I-labeled LDL from normotriglyceridemic rabbits that appeared in the IDL fraction increased in rabbits with increasing levels of plasma triglyceride. This LDL density shift was reproduced in vitro by incubating iodinated LDL from normotriglyceridemic, hypercholesterolemic rabbits with concentrations of VLDL from hypertriglyceridemic, hypercholesterolemic rabbits similar to those in plasma. With such a system, it was shown that the percentage of LDL that appeared in the IDL fraction increased with time, was enhanced fourfold by the addition of plasma lipid transfer protein, increased with increasing molar ratio of triglyceride to cholesteryl ester in VLDL, but apparently did not increase with increasing VLDL particle number. These studies suggest that a pronounced decrease in density of lipoproteins that would normally appear in the LDL density range, resulting from loss of cholesteryl ester in exchange for VLDL triglyceride, may explain, at least in part, the reduced LDL levels in severe hypertriglyceridemia.

A potent PPARalpha agonist stimulates mitochondrial fatty acid beta-oxidation in liver and skeletal muscle.

The proposed mechanism for the triglyceride (TG) lowering by fibrate drugs is via activation of the peroxisome proliferator-activated receptor-alpha (PPARalpha). Here we show that a PPARalpha agonist, ureido-fibrate-5 (UF-5), approximately 200-fold more potent than fenofibric acid, exerts TG-lowering effects (37%) in fat-fed hamsters after 3 days at 30 mg/kg. In addition to lowering hepatic apolipoprotein C-III (apoC-III) gene expression by approximately 60%, UF-5 induces hepatic mitochondrial carnitine palmitoyltransferase I (CPT I) expression. A 3-wk rising-dose treatment results in a greater TG-lowering effect (70%) at 15 mg/kg and a 2.3-fold elevation of muscle CPT I mRNA levels, as well as effects on hepatic gene expression. UF-5 also stimulated mitochondrial [3H]palmitate beta-oxidation in vitro in human hepatic and skeletal muscle cells 2.7- and 1.6-fold, respectively, in a dose-related manner. These results suggest that, in addition to previously described effects of fibrates on apoC-III expression and on peroxisomal fatty acid (FA) beta-oxidation, PPARalpha agonists stimulate mitochondrial FA beta-oxidation in vivo in both liver and muscle. These observations suggest an important mechanism for the biological effects of PPARalpha agonists.

Unexpected consequences of deletion of the first two repeats of the ligand-binding domain from the low density lipoprotein receptor. Evidence from a human mutation.

Heterozygosity for a 5-kilobase (kb) deletion of the first two ligand-binding repeats (exons 2 and 3) of the low density lipoprotein (LDL) receptor (R) gene (LDL-R delta 5kb) confers familial hypercholesterolemia (FH). The FH phenotype is unexpected based on previous site-directed mutagenesis showing that deletion of exons 2 and 3 resulted in little or no defect in LDL-R activity. In the present study, we took unique advantage of the ability to distinguish the LDL-R delta 5kb from the normal receptor on the basis of size, in order to resolve this apparent discrepancy. Fibroblasts from heterozygotes for the LDL-R delta 5kb displayed 50% of normal capacity to bind LDL and beta-VLDL, apparently due to lower receptor number. Cellular mRNA for the delta 5kb allele was at least as abundant as that for the normal allele. Immunoblotting and cell binding assays with anti-LDL-R antibody IgG-4A4 demonstrated normal synthesis and transport of the delta 5kb receptor. Ligand blotting demonstrated that the delta 5kb receptor displayed minimal or no ability to bind LDL or beta-VLDL. Thus, in contrast to transfected cell lines, in human fibroblasts, the first two cysteine rich repeats of the LDL-R appear functionally necessary. These characteristics of the LDL-R delta 5kb in human fibroblasts explain the in vivo phenotype of carriers.

G-->A substitution at position -75 of the apolipoprotein A-I gene promoter. Evidence against a direct effect on HDL cholesterol levels.

The present study sought to resolve the contradictory evidence as to whether the G-->A substitution at position -75 of the apoA-I gene promoter raises HDL cholesterol (HDL-C) levels by examining the effect of this polymorphism in French Canadians, a relatively genetically homogeneous population. Among 308 women, carriers of the A allele displayed 12% and 10% higher mean plasma HDL-C and apoA-I concentrations, respectively, than did noncarriers. Among 345 men, no effect of the A allele was noted. The frequency distribution of HDL-C levels in women carrying the A but not the G allele appeared bimodal, with one peak corresponding to the mean of the noncarriers and a second to higher HDL-C. Thus it appears that only a subset of A alleles confers high HDL-C levels. This hypothesis was supported by data from four kindreds within which some but not all A alleles segregated with hyperalphalipoproteinemia. The data suggest that the A substitution in the apoA-I gene promoter does not directly confer high HDL-C levels but may be in linkage disequilibrium with other sequence polymorphism(s) at this locus in a subset of alleles that raise HDL-C levels.

Characterization of inherited scavenger receptor overexpression and abnormal macrophage phenotype in a normolipidemic subject with planar xanthomas.

It is proposed that, in hyperlipidemia, foam cells develop in cutaneous xanthomas from the uptake by the macrophage scavenger receptor (SR) of low density lipoproteins (LDL) that are modified due to increased residence time in plasma. We have observed extensive xanthelasmas and planar xanthomas in the absence of hyperlipidemia in two siblings. In blood monocytes from one sibling, 125I-labeled acetylated LDL (Ac-LDL) degradation and SR mRNA were 4 and 7 times higher, respectively, than in four control subjects. Among monocytes from these five individuals, variation in Ac-LDL degradation was completely accounted for by SR mRNA levels (R2 = 0.98, P < 0.001). Monocyte SR mRNA was induced upon maturation into macrophages during 7 days in culture. Mean monocyte and macrophage SR mRNA values from one sibling and six additional family members were elevated 5- and 4-fold compared to that of 16 control subjects, and elevated monocyte SR mRNA was associated with abnormally high cell-surface expression of SR epitopes. Monocytes from eight of nine family members examined displayed an unusual phenotype characterized by increased adhesion and rapid maturation into large macrophages which overaccumulated lipids. Monocyte-macrophage SR overexpression relative to control persisted even in the absence of autologous serum, consistent with a cellular abnormality. This is the first demonstration of an inherited abnormality in scavenger receptor expression and its occurrence in association with planar xanthomas.