Retinol-binding protein 4 (RBP4) transports retinol from the liver to extrahepatic tissues, and RBP4 lowering is reported to improve insulin sensitivity in mice. We have identified A1120, a high affinity (K i ‫؍‬ 8.3 nM) non-retinoid ligand for RBP4, which disrupts the interaction between RBP4 and its binding partner transthyretin. Analysis of the RBP4-A1120 co-crystal structure reveals that A1120 induces critical conformational changes at the RBP4-transthyretin interface. Administration of A1120 to mice lowers serum RBP4 and retinol levels but, unexpectedly, does not improve insulin sensitivity. In addition, we show that Rpb4 ؊/؊ mice display normal insulin sensitivity and are not protected from high fat diet-induced insulin resistance. We conclude that lowering RBP4 levels does not improve insulin sensitivity in mice. Therefore, RBP4 lowering may not be an effective strategy for treating diabetes. RBP42 is a serum protein that transports retinol (vitamin A) from the liver to extrahepatic tissues (1). The majority of RBP4 is expressed in the liver, with ϳ15-20% expressed in adipose (2). In the serum, RBP4 is present as a complex with transthyretin (TTR), which effectively increases the molecular weight of RBP4 and protects it from glomerular filtration. Thus disruption of the RBP4⅐TTR complex in vivo by administration of the synthetic retinoid fenretinide (N-(4-hydroxyphenyl)retinamide) results in a rapid reduction in serum RBP4 levels (3, 4).Although the major physiological ligand for RBP4 appears to be retinol, RBP4 can bind to other endogenous and synthetic retinoids. For example, using biochemical assays, RBP4 has been shown to bind to retinol, all-trans-and 13-cis-retinoic acid, retinyl acetate, N-(ethyl)retinamide, and fenretinide (4 -6). In addition, x-ray diffraction analysis of a variety of RBP4-retinoid co-crystal structures has demonstrated that these retinoids bind to the same site as retinol, with the cyclohexene ring buried within the internal cavity and the polar head group pointing toward the exterior of the protein (7-9). The loop regions of RBP4 surrounding the entrance of the binding cavity form the binding site for TTR, with the binding of retinol (in particular the presence of the hydroxyl group) increasing the affinity of RBP4 for TTR by a factor of ϳ4 (10). The binding of fenretinide, however, has the opposite effect. Through a combination of steric hindrance (from the bulky phenylamide head group) and changes in the position of the loop regions of RBP4 located at the TTR binding interface, fenretinide completely disrupts the binding of RBP4 to TTR (4, 9).Recent reports have suggested that, in addition to its role in vitamin A transport, RBP4 may also be involved in the development of insulin resistance. For example, Yang et al. reported that mice overexpressing an RBP4 transgene and mice injected with recombinant RBP4 protein become insulin-resistant, and that reduction of RBP4 levels in mice either by gene ablation or treatment with fenretinide improves insulin sensitivity (11). In huma...

Two new proton magnetic resonance techniques, relaxation spectra and relaxation selective imaging, have been used to investigate the distribution of water in samples of normal white spruce sapwood, heartwood, and juvenile wood as well as two rehydrated heartwood samples containing incipient decay and compression wood respectively. It is demonstrated that the spin-spin (T2) relaxation behavior in wood is best presented as a continuous spectrum of relaxation times. Spectra of T 2 for white spruce show separate peaks corresponding to the different water environments. Bound water gives a peak with an T 2 time of about 1 ms and lumen water gives a distribution of T 2 times in the range of 10 to 100 ms. The lumen water T 2 time is a function of the wood cell radius. Consequently, the different cell lumen radii distributions for spruce sapwood, juvenile wood, and compression wood are readily distinguishable by the shape of their T 2 spectra. Water environments which are separable on a T 2 spectrum may be imaged separately. Imaging has been carried out in one dimension for bound water and lumen water of a spruce sapwood sample at four different moisture contents ranging from 100% to 17%. For the first time, we demonstrate that above the fibre saturation point the moisture density profile of the bound water is largely independent of moisture content. The feasibility and utility of using these techniques for internal scanning of logs and lumber is discussed. These techniques should provide new insights into the wood drying process.

Combined RFA and cementoplasty appears to be safe, practical and effective in the palliative treatment of painful neoplastic lesions.

exchangers exhibit a common Ca 2ϩ -dependent regulatory mechanism, whereby their activity requires the presence of low concentrations of Ca 2ϩ on their intracellular surface, and their activity is augmented in parallel with elevated intracellular Ca 2ϩ levels (3). This important regulatory property may permit the timely coupling of exchange function to alterations in intracellular Ca 2ϩ concentrations to meet the continuous needs for overall Ca 2ϩ balance. The general similarities of exchange function and regulatory properties within the large NCX protein family are ascribed to their conserved structural arrangements: nine predicted transmembrane (TM) segments form the ion translocation pathway and a large loop of ϳ500 amino acid residues splits TM helix-5 and -6 on the intracellular side of the molecule (4). Ca 2ϩ -dependent regulation is attributed exclusively to Ca 2ϩ interactions on the intracellular loop (5). A pair of Ca 2ϩ binding domains (CBD1 and -2), called CALX-␤ motifs, has been identified (6). Sequence analysis revealed that CBD1 has conserved Ca 2ϩ binding sites throughout the NCX family, whereas greater sequence diversity and/or Ca 2ϩ binding capabilities occurs in CBD2 (7,27). Given that CBD1 exhibits a higher Ca 2ϩ affinity than CBD2 (8), it has been suggested that CBD1 acts as the primary sensor in the pair of CBDs. Mutations of carboxylate residues at CBD1 result in a pronounced reduction of the affinity for functional Ca 2ϩ regulation (9). The Ca 2ϩ -bound structures of CBD1 of NCX1 have recently been determined by NMR, and more recently by x-ray crystallography (8,11

Obesity-related cardiovascular disease (CVD) involves increased sympathetic activity in men and male animals. Although women exhibit increased visceral fat, metabolic disorders, inflammation and CVD with obesity, whether body weight gain affects autonomic control of cardiovascular function in females remain unknown. Due to the lack of adequate model to mimic the human pathology, this study aimed to develop a murine model, which would allow studying the sex-specificity of the response of the autonomic nervous system to obesity and identifying the origin of potential sex-differences. We tested the hypothesis that sexual dimorphisms in the autonomic response to obesity disappear in mice matched for changes in body weight, metabolic and inflammatory disorders. Male and female C57Bl/6 mice were submitted to control (CD) or high fat diet (HFD) for 24 weeks. Female mice gained more adipose mass and lost more lean mass than males but reached similar visceral adipose mass and body weight, as males, at the end of the diet. 24 weeks of HFD matched male and female mice for visceral adiposity, glycaemia, plasma insulin, lipids, and inflammatory cytokines levels, demonstrating the suitability of the model to study human pathology. HFD did not elevate BP, but similarly increased heart rate (HR) in males (CD: 571 ± 9 vs. HFD: 631 ± 14 bpm, P < 0.05) and females (CD: 589 ± 19 vs. HFD: 642 ± 6 bpm, P < 0.05). Indices of autonomic control of BP and HR were obtained by measuring BP and HR response to ganglionic blockade, β-adrenergic, and muscarinic receptors antagonists. HFD increased vascular but reduced cardiac sympathetic drive in males (CD: –43 ± 4 and HFD: –60 ± 7% drop in BP, P < 0.05). HFD did not alter females' vascular or cardiac sympathetic drive. HFD specifically reduced aortic α-adrenergic constriction in males and lowered HR response to muscarinic receptor antagonism in females. These data suggest that obesity-associated increases in HR could be caused by a reduced cardiac vagal tone in females, while HR increases in males may compensate for the reduced vascular adrenergic contractility to preserve baseline BP. These data suggest that obesity impairs autonomic control of cardiovascular function in males and females, via sex-specific mechanisms and independent of fat distribution, metabolic disorder or inflammation.

Aluminum-rich AlGaN is the ideal material system for emerging solid-state deep-ultraviolet (DUV) light sources. Devices operating in the near-UV spectral range have been realized; to date, however, the achievement of high-efficiency light-emitting diodes (LEDs) operating in the UV-C band (200-280 nm specifically) has been hindered by the extremely inefficient p-type conduction in AlGaN and the lack of DUV-transparent conductive electrodes. Here, we show that these critical challenges can be addressed by Mg dopant-free Al(Ga)N/h-BN nanowire heterostructures. By exploiting the acceptor-like boron vacancy formation, we have demonstrated that h-BN can function as a highly conductive, DUV-transparent electrode; the hole concentration is ∼10 cm at room temperature, which is 10 orders of magnitude higher than that previously measured for Mg-doped AlN epilayers. We have further demonstrated the first Al(Ga)N/h-BN LED, which exhibits strong emission at ∼210 nm. This work also reports the first achievement of Mg-free III-nitride LEDs that can exhibit high electrical efficiency (80% at 20 A/cm).

Image-guided musculoskeletal (MSK) biopsies are safe and effective procedures that yield diagnostic accuracies up to 97%. When performed in conjunction with a multidisciplinary team, they provide crucial information that will affect patient care and outcome. Computed tomography and ultrasound are the main modalities used to carry out MSK biopsies, and various needles and techniques are available to help the radiologist perform these procedures safely.

Ex vivo heart perfusion (EVHP) may facilitate resuscitation of discarded donor hearts and expand the donor pool; however, a reliable means of demonstrating organ viability prior to transplantation is required. Therefore, we sought to identify metabolic and functional parameters that predict myocardial performance during EVHP. To evaluate the parameters over a broad spectrum of organ function, we obtained hearts from 9 normal pigs and 37 donation after circulatory death pigs and perfused them ex vivo. Functional parameters obtained from a left ventricular conductance catheter, oxygen consumption, coronary vascular resistance, and lactate concentration were measured, and linear regression analyses were performed to identify which parameters best correlated with myocardial performance (cardiac index: mL·min(-1)·g(-1)). Functional parameters exhibited excellent correlation with myocardial performance and demonstrated high sensitivity and specificity for identifying hearts at risk of poor post-transplant function (ejection fraction: R(2) = 0.80, sensitivity = 1.00, specificity = 0.85; stroke work: R(2) = 0.76, sensitivity = 1.00, specificity = 0.77; minimum dP/dt: R(2) = 0.74, sensitivity = 1.00, specificity = 0.54; tau: R(2) = 0.51, sensitivity = 1.00, specificity = 0.92), whereas metabolic parameters were limited in their ability to predict myocardial performance (oxygen consumption: R(2) = 0.28; coronary vascular resistance: R(2) = 0.20; lactate concentration: R(2) = 0.02). We concluded that evaluation of functional parameters provides the best assessment of myocardial performance during EVHP, which highlights the need for an EVHP device capable of assessing the donor heart in a physiologic working mode.