Giant temperature span in electrocaloric regenerator.

Cooling devices based on caloric materials have emerged as promising candidates to become the next generation of coolers. Several electrocaloric (EC) heat exchangers have been proposed that use different mechanisms and working principles. However, a prototype that demonstrates a competitive temperature span has been missing. We developed a parallel-plate active EC regenerator based on lead scandium tantalate multilayer capacitors. After optimizing the structural design by using finite element modeling for guidance and to considerably improve insulation, we measured a maximum temperature span of 13.0 kelvin. This temperature span breaks a crucial barrier and confirms that EC materials are promising candidates for cooling applications.

Large electrocaloric effects in oxide multilayer capacitors over a wide temperature range.

Heat pumps based on magnetocaloric and electrocaloric working bodies-in which entropic phase transitions are driven by changes of magnetic and electric field, respectively-use displaceable fluids to establish relatively large temperature spans between loads to be cooled and heat sinks1,2. However, the performance of prototypes is limited because practical magnetocaloric working bodies driven by permanent magnets3-5 and electrocaloric working bodies driven by voltage6-16 display temperature changes of less than 3 kelvin. Here we show that high-quality multilayer capacitors of PbSc0.5Ta0.5O3 display large electrocaloric effects over a wide range of starting temperatures when the first-order ferroelectric phase transition is driven supercritically (as verified by Landau theory) above the Curie temperature of 290 kelvin by electric fields of 29.0 volts per micrometre. Changes of temperature in the large central area of the capacitor peak at 5.5 kelvin near room temperature and exceed 3 kelvin for starting temperatures that span 176 kelvin (complete thermalization would reduce these values from 5.5 to 3.3 kelvin and from 176 to 73 kelvin). If magnetocaloric working bodies were to be replaced with multilayer capacitors of PbSc0.5Ta0.5O3, then the established design principles behind magnetocaloric heat pumps could be repurposed for better performance without bulky and expensive permanent magnets.

Subpopulation Primers Essential for Exhaustive Detection of Diverse Hemagglutinin Genes of H5 Subtype Avian Influenza Viruses by Loop-Mediated Isothermal Amplification Method.

Loop-mediated isothermal amplification (LAMP) is a potential screening test for avian influenza (AI), but its narrow detection spectrum limits its applications. To improve this narrow detection spectrum, 3 types of primers were compared for detection of diverse H5 subtype hemagglutinin (HA) genes. Four and 6 genes, of 10 genetically different H5 HA genes tested, were detected with S primers specific for A/duck/Tsukuba/9/2005 (H5N2) and with M primers (which contained mixed bases), respectively. In contrast, all 10 HA genes became positive with population primers (P primers) (a mixture of primers designed for each subpopulation of 2,202 HA genes). Our study indicated that the P primers for the forward inner primer (FIP) and backward inner primer (BIP) sites were essential for exhaustive detection, whereas those for the F3, forward loop (FL), backward loop (BL), and B3 sites were exchangeable with M primers. A base mismatch experiment demonstrated that HA genes with ≤2 base mismatches per primer site and ≤10 base mismatches per HA gene were amplifiable. Reverse transcription-LAMP was broadly reactive, specific for H5 subtype HA genes, and applicable to field samples, with the sensitivity of real-time PCR. The in silico analysis suggested that most H5 HA genes (2,586 positive genes/2,588 genes tested) registered in the GenBank database might be amplifiable. These results indicate that the use of subpopulation primers in LAMP allows exhaustive detection of diverse HA genes and H5 LAMP can be used as a reliable AI screening test in general diagnostic laboratories.

Ceramide limits phosphatidylinositol-3-kinase C2ß-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid.

Targeting cell motility, which is required for dissemination and metastasis, has therapeutic potential for ovarian cancer metastasis, and regulatory mechanisms of cell motility need to be uncovered for developing novel therapeutics. Invasive ovarian cancer cells spontaneously formed protrusions, such as lamellipodia, which are required for generating locomotive force in cell motility. Short interfering RNA screening identified class II phosphatidylinositol 3-kinase C2ß (PI3KC2ß) as the predominant isoform of PI3K involved in lamellipodia formation of ovarian cancer cells. The bioactive sphingolipid ceramide has emerged as an antitumorigenic lipid, and treatment with short-chain C6-ceramide decreased the number of ovarian cancer cells with PI3KC2ß-driven lamellipodia. Pharmacological analysis demonstrated that long-chain ceramide regenerated from C6-ceramide through the salvage/recycling pathway, at least in part, mediated the action of C6-ceramide. Mechanistically, ceramide was revealed to interact with the PIK-catalytic domain of PI3KC2ß and affect its compartmentalization, thereby suppressing PI3KC2ß activation and its driven cell motility. Ceramide treatment also suppressed cell motility promoted by epithelial growth factor, which is a prometastatic factor. To examine the role of ceramide in ovarian cancer metastasis, ceramide liposomes were employed and confirmed to suppress cell motility in vitro. Ceramide liposomes had an inhibitory effect on peritoneal metastasis in a murine xenograft model of human ovarian cancer. Metastasis of PI3KC2ß knocked-down cells was insensitive to treatment with ceramide liposomes, suggesting specific involvement of ceramide interaction with PI3KC2ß in metastasis suppression. Our study identified ceramide as a bioactive lipid that limits PI3KC2ß-governed cell motility, and ceramide is proposed to serve as a metastasis-suppressor lipid in ovarian cancer. These findings could be translated into developing ceramide-based therapy for metastatic diseases.

Transferrin facilitates the formation of DNA double-strand breaks via transferrin receptor 1: the possible involvement of transferrin in carcinogenesis of high-grade serous ovarian cancer.

Fallopian tubal epithelium is a candidate for the origin of high-grade serous ovarian cancer. Transferrin-containing follicular fluid and/or retrograde menstrual blood are possible risk factors for carcinogenesis. Accumulation of DNA double-strand breaks (DNA-DSBs) in the fallopian tubal epithelium is considered to play an important role in the development of cancer. However, the mechanisms by which DNA-DSBs accumulate have not yet been fully elucidated. The hydroxyl radical, which is produced in a Fenton reaction catalyzed by an iron ion, serves as a potent DNA-DSB-inducing molecule, raising the potential of an iron ion transporter of transferrin in the formation of DNA-DSBs. We studied the potential involvement of transferrin in DNA damage and the development of ovarian cancer. Treatment with transferrin facilitated the formation of histone 2AX phosphorylated at Serine 139 (γH2AX), which is known as a DNA-DSB marker, in human fallopian tube secretory epithelial cells and A2780 ovarian cancer cells. Knockdown of transferrin receptor 1 (TfR1), but not transferrin receptor 2, suppressed the transferrin uptake and consequent formation of γH2AX. As hydroxyl radicals in reactive oxygen species (ROS) are involved in DNA-DSBs, the formation of ROS was determined. Treatment with TfR1-specific small interference RNAs significantly diminished transferrin-induced formation of ROS. Moreover, TfR1-dependent uptake of transferrin was revealed to augment the formation of DNA-DSBs in the presence of hydrogen peroxide, which served as a substrate for the Fenton reaction. An ex vivo study with murine fallopian tubes further demonstrated that transferrin treatment introduced DNA-DSBs in the fallopian tubal epithelium. Collectively, these data suggested that the transferrin-TfR1 axis accounts for the induction of DNA-DSBs that potentially lead to DNA damage/genome instability. These findings also suggested that exposure to transferrin initiates and promotes the development of ovarian cancer by aiding the accumulation of DNA-DSBs in the fallopian tubal epithelium.

Eukaryotic elongation factor 2 kinase controls proliferation and migration of vascular smooth muscle cells.

AIM: Eukaryotic elongation factor 2 kinase (eEF2K), also known as calmodulin (CaM)-dependent protein kinase (CaMK) III, is a unique member of CaMK family protein. We have recently found that expression of eEF2K protein increased in mesenteric artery from spontaneously hypertensive rats. As pathogenesis of hypertension is in part regulated by vascular structural remodelling via proliferation and migration of vascular smooth muscle cells (SMCs), we tested the hypothesis that eEF2K controls SMCs proliferation and migration. METHODSAND RESULTS: In rat mesenteric arterial SMCs, an eEF2K inhibitor, A-484954 (10 µm), significantly inhibited platelet-derived growth factor (PDGF)-BB (10 ng mL(-1) )-induced SMCs proliferation as determined by a cell counting and bromodeoxyuridine incorporation assay. PDGF-BB (10 ng mL(-1) )-induced SMCs migration was significantly inhibited by A-484954 (10 µm) as determined by a Boyden chamber assay. A-484954 (10 µm) significantly inhibited PDGF-BB (10 ng mL(-1) )-induced phosphorylation of eEF2K, extracellular signal-regulated kinase (ERK), Akt, p38 and heat-shock protein (HSP) 27 as determined by Western blotting. It was confirmed that a CaM inhibitor, W-7 (50 µm), inhibited PDGF-BB (10 ng mL(-1) )-induced phosphorylation of eEF2K. In an ex vivo mesenteric arterial ring assay, 10% foetal bovine serum-induced SMCs outgrowth was significantly inhibited by A-484954 (10 µm). CONCLUSION: We for the first time revealed that eEF2K mediates PDGF-BB-induced SMCs proliferation and migration through activating ERK, Akt, p38 and HSP27 signals in a CaM-dependent manner. Our results suggest eEF2K as a novel pharmaceutical target for the prevention of hypertensive cardiovascular diseases.

Observation of quadrupole helix chirality and its domain structure in DyFe3(BO3)4.

Resonant X-ray diffraction (RXD) uses X-rays in the vicinity of a specific atomic absorption edge and is a powerful technique for studying symmetry breaking by motifs of various multipole moments, such as electric monopoles (charge), magnetic dipoles (spin) and electric quadrupoles (orbital). Using circularly polarized X-rays, this technique has been developed to verify symmetry breaking effects arising from chirality, the asymmetry of an object upon its mirroring. Chirality plays a crucial role in the emergence of functionalities such as optical rotatory power and multiferroicity. Here we apply spatially resolved RXD to reveal the helix chirality of Dy 4f electric quadrupole orientations and its domain structure in DyFe3(BO3)4, which shows a reversible phase transition into an enantiomorphic space-group pair. The present study provides evidence for a helix chiral motif of quadrupole moments developed in crystallographic helix chirality.

A subtype prediction score for primary aldosteronism.

Primary aldosteronism (PA) is the most common cause of endocrine hypertension. Although adrenal venous sampling (AVS) is recommended as the gold standard procedure for subtype classification in PA, it is a specialized technique with limited availability. The objective of this study was to develop a scoring system that predicted PA subtype using clinical characteristics. Seventy-one patients with PA were studied. The subjects were diagnosed as having either unilateral (n=32) or bilateral disease (n=39) based on AVS, surgery and/or the postoperative clinical course. Variables associated with laterality in the univariate analysis were entered into multivariable logistic regression models and the regression coefficients were used to construct a subtype prediction score. The diagnostic significance of the score was then evaluated using receiver operating characteristic (ROC) curve analysis. The subtype prediction score was calculated as follows: serum potassium ⩽3.4 mEq l(-1), 2 points; plasma aldosterone concentration ⩾165 pg ml(-1), 3 points; and aldosterone to renin ratio ⩾1000 in a post-captopril challenge test (plasma renin activity in ng ml(-1) h(-1)), 3 points. ROC curve analysis for the ability to discriminate between unilateral and bilateral PA showed that a score of 5 points had 75% sensitivity and 95% specificity, and a score of 3 points had a sensitivity of 97% and a specificity of 59%. The area under the ROC curve was 0.920 (95% confidence interval, 0.859-0.979). Our subtype prediction score could discriminate between unilateral and bilateral PA and is useful for selecting patients who should undergo AVS before surgery.

Brain-derived neurotrophic factor promotes angiogenic tube formation through generation of oxidative stress in human vascular endothelial cells.

AIM: Brain-derived neurotrophic factor (BDNF), a major type of neurotrophins, plays a role in the regulation of synaptic function. Recent studies suggest that BDNF promotes angiogenesis through its specific receptor, tropomyosin-related kinase B (TrkB). However, the detailed mechanisms for this still remain to be determined. Reactive oxygen species (ROS) generation contributes to the regulation of angiogenesis. Thus, we investigated the mechanisms by which BDNF regulates angiogenesis with focusing on ROS in cultured human vascular endothelial cells (ECs). METHODS AND RESULTS: In human umbilical vein ECs, BDNF increased ROS generation as measured fluorometrically using 2' 7'-dichlorofluorescein diacetate as well as NADPH oxidase (NOX) activity as measured by lucigenin assay. BDNF-induced ROS generation and NOX activity were inhibited by K252a, a TrkB receptor inhibitor. BDNF induced phosphorylation of p47 phox, a regulatory component of NOX, which was inhibited by K252a as measured by Western blotting. BDNF increased angiogenic tube formation in ECs, which was completely inhibited by K252a or gp91ds-tat, a NOX inhibitor. BDNF caused Akt phosphorylation in ECs, which was inhibited by K252a or gp91ds-tat. CONCLUSION: The present results for the first time demonstrate that BDNF induces NOX-derived ROS generation through activation of p47 phox in a TrkB receptor-dependent manner, which leads to the promotion of angiogenic tube formation possibly via Akt activation.

Magnetic phase diagram of CuO via high-resolution ultrasonic velocity measurements.

High-resolution ultrasonic velocity measurements have been used to determine the temperature-magnetic-field phase diagram of the monoclinic multiferroic CuO. A new transition at T(N3)=230 K, corresponding to an intermediate state between the antiferromagnetic noncollinear spiral phase observed below T(N2)=229.3 K and the paramagnetic phase, is revealed. Anomalies associated with a first order transition to the commensurate collinear phase are also observed at T(N1)=213 K. For fields with B || b, a spin-flop transition is detected between 11 T-13 T at lower temperatures. Moreover, our analysis using a Landau-type free energy clearly reveals the necessity for an incommensurate collinear phase between the spiral and the paramagnetic phase. This model is also relevant to the phase diagrams of other monoclinic multiferroic systems.

Quantification of interferon, interleukin, and Toll-like receptor 7 mRNA in quail splenocytes using real-time PCR.

Japanese quail (Coturnix japonica) are farmed worldwide as poultry. Quail have been used as experimental animals in various scientific fields, but their immunological characteristics have not been well characterized. In this study, to develop a method for analyzing the innate immune response of quail to infectious pathogens, we determined the nucleotide sequences of major interleukins (IL) and Toll-like receptor (TLR)-7 of quail and developed quantitative real-time PCR assays. The nucleotide sequences of quail IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-12a, IL-12b, IL-13, IL-18, and TLR-7 were determined based on the sequences of the chicken genes. Specific primers for each of these genes and previously reported interferon (IFN)-α, IFN-γ, and IL-2 genes were designed for quantitative real-time PCR. Standard curves for quantification were established using serial dilutions of external standard plasmids containing real-time PCR products. Then, real-time PCR was performed to monitor the kinetics of quail immune-related gene expression induced in splenocytes stimulated with concanavalin A. After amplification, the r(2) values of the standard curves for all target genes were above 0.980. Melting analysis of real-time PCR revealed specific amplification of each gene that could be visualized clearly as a single peak of melting temperature in a melt peak chart. These data show that the mRNA expressions of quail immune-related genes can be accurately quantified using this real-time PCR assay. In this study, we showed the nucleotide sequences of several quail cytokine mRNA and constructed the quantitative real-time PCR for quail immune-related genes.

Interferon-gamma release assay for diagnosing Mycobacterium tuberculosis infections in patients with systemic lupus erythematosus.

Our aim was to analyze the performance of an interferon-gamma release assay, QuantiFERON-TB Gold (QFT-2G), for diagnosing Mycobacterium tuberculosis (MTB) infection in patients with systemic lupus erythematosus (SLE). We performed the QFT-2G and tuberculin skin test (TST) in 71 SLE patients. The QFT-2G results of 279 patients with other connective tissue diseases (CTD) and 35 healthy controls were analyzed. Of the 71 SLE patients, two (2.8%) were positive and 46 (64.8%) were negative by QFT-2G. All SLE patients had no evidence of active MTB infection, apart from one. QFT-2G produced a significantly higher number of indeterminate results in patients with SLE (23/71, 32.4%) compared with those with other CTD (5.7%) or healthy controls (0%) (p < 0.0001 and p < 0.0001). Decreased lymphocyte counts and high SLEDAI scores in SLE patients were shown to be risk factors for indeterminate results by multivariate analysis (p = 0.02 and p = 0.04). Among all patients with CTD, SLE itself and lymphocytopenia were found to be independent risks for indeterminate results (p = 0.00000625 and p = 0.000107). In conclusion, QFT-2G may have more potential to assist in the diagnosis of active and latent MTB infection than TST in SLE patients. However, because of the high frequency of indeterminate results, caution must be used when interpreting the results of QFT-2G among SLE patients, especially those who have parallel or subsequent flares.

LBH589, a deacetylase inhibitor, induces apoptosis in adult T-cell leukemia/lymphoma cells via activation of a novel RAIDD-caspase-2 pathway.

Adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm etiologically associated with human T-lymphotropic virus type-1 (HTLV-1), is resistant to treatment. In this study, we examined the effects of a new inhibitor of deacetylase enzymes, LBH589, on ATLL cells. LBH589 effectively induced apoptosis in ATLL-related cell lines and primary ATLL cells and reduced the size of tumors inoculated in SCID mice. Analyses, including with a DNA microarray, revealed that neither death receptors nor p53 pathways contributed to the apoptosis. Instead, LBH589 activated an intrinsic pathway through the activation of caspase-2. Furthermore, small interfering RNA experiments targeting caspase-2, caspase-9, RAIDD, p53-induced protein with a death domain (PIDD) and RIPK1 (RIP) indicated that activation of RAIDD is crucial and an event initiating this pathway. In addition, LBH589 caused a marked decrease in levels of factors involved in ATLL cell proliferation and invasion such as CCR4, IL-2R and HTLV-1 HBZ-SI, a spliced form of the HTLV-1 basic zipper factor HBZ. In conclusion, we showed that LBH589 is a strong inducer of apoptosis in ATLL cells and uncovered a novel apoptotic pathway initiated by activation of RAIDD.

Pinguecula and contact lenses.

PURPOSE: To assess the relationship between age and the incidence and severity (determined by a grading system) of pinguecula in contact lens (CL) wearers, and to compare the grade of pinguecula between CL wearers and non-wearers. METHODS: A total of 600 CL wearers (94 wore hard CLs (HCLs) and 506 wore soft CLs (SCLs)) aged 11-60 years and 579 non-wearers aged 10-60 years were enrolled. The age, gender, medical history, ocular history, and grade of pinguecula at two locations (nasal and temporal) were determined in all subjects. RESULTS: There was an age-related increase in the grade of pinguecula among both CL wearers and non-wearers. The grade of pinguecula at the temporal conjunctiva was higher in CL wearers than in non-wearers (P=0.01907), whereas it was higher in HCL wearers than SCL wearers at both the nasal and temporal conjunctiva (P<0.00001 and P<0.00001). CONCLUSIONS: This was the first assessment of the severity of pinguecula in a large consecutive series of CL wearers. Our results suggest that the use of CLs is an important risk factor for pinguecula.

The development of a non-contact screening system for rapid medical inspection at a quarantine depot using a laser Doppler blood-flow meter, microwave radar and infrared thermography.

In order to conduct fast screening of passengers with infections such as severe acute respiratory syndrome (SARS) or pandemic influenza at a quarantine depot, we developed a non-contact screening system with self-produced program to conduct a human screening within five seconds, via a linear discriminant function from non-contact derived variables, i.e. palmer pulse derived from a laser Doppler blood-flow meter, respiration rate determined by a 10-GHz microwave radar, and facial temperature measured by thermography. The system evaluation was conducted on seven healthy male subjects (23 +/- 1 years). In order to achieve a pseudo-infection condition, the subjects maintained an ergometer exercise load (100 W, 10 minutes). Before (normal condition) and after (pseudo-infection condition) exercise, a significant linear discriminant function (p < 0.001) was determined to distinguish pseudo-infection condition from normal condition (Mahalanobis D-square = 20.3, classification error rate <5%). The proposed system appears promising for future application in fast screening of infection at a quarantine depot.

Development of a non-contact screening system for rapid medical inspection at a quarantine depot using a laser Doppler blood-flow meter, microwave radar and infrared thermography.

In order to conduct fast screening of passengers with infections such as severe acute respiratory syndrome (SARS) or pandemic influenza at a quarantine depot, we developed a non-contact screening system with a self-produced program to conduct a human screening within five seconds, via a linear discriminant function from non-contact derived variables, i.e. palmer pulse derived from a laser Doppler blood-flow meter, respiration rate determined by a 10-GHz microwave radar, and facial temperature measured by a thermography. The system evaluation was conducted on seven healthy male subjects (23+1 years). In order to achieve a pseudo-infection condition, the subjects maintained an ergo-meter exercise load (100 W, 10 minutes). Before (normal condition) and after (pseudo-infection condition) exercise, a significant linear discriminant function (p50.001) was determined to distinguish the pseudo-infection condition from the normal condition (Mahalanobis D-square 1/4 20.3, classification error rate55%). The proposed system appears promising for future application in fast screening of infection at a quarantine depot.

Relationship between refraction and allergic conjunctivitis.

PURPOSE: External allergens are the main causative factor in the pathogenesis of allergic diseases; however, little is known about internal factors such as the biometrical structure of the eye. We investigated the relationship between refractive error and allergic conjunctivitis in order to reveal possible insights into the pathogenesis in 1015 subjects. METHODS: The patients were divided into four groups: contact lens wearers with allergic conjunctivitis (n=73), contact lens wearers without allergic conjunctivitis (n=59), non-contact lens wearers with allergic conjunctivitis (n=224), and non-contact lens wearers without allergic conjunctivitis (n=659). The spherical power, cylindrical power, corneal radius, and minimum and maximum corneal refractive powers were measured in all subjects. RESULTS: In the non-contact lens wearers, the spherical equivalent and spherical power were significantly lower in patients with allergic conjunctivitis than in patients without allergic conjunctivitis (-3.01+/-3.83 D vs-1.36+/-3.08 D, P<0.0001, and -2.64+/-3.63 D vs-1.05+/-2.88 D, P<0.0001, respectively), while there was no significant difference in any of the parameters between the contact lens wearers with and without allergic conjunctivitis. CONCLUSION: Refractive error may be a risk factor for allergic conjunctivitis.

Longitudinal analysis of corneal topography in suspected keratoconus.

AIMS: To examine the incidence of progression of suspected keratoconus to true keratoconus and compare quantitative descriptors of corneal topography between eyes with and without progression. METHODS: 34 eyes with suspected keratoconus were retrospectively reviewed in 34 patients. Their age at the initial examination was 13 to 40 years (24.1 (7.5), mean (SD)), and the follow-up periods ranged from 3 to 10 years (6.0 (2.2) years). Suspected keratoconus was defined as the fellow eye of a clinically apparent keratoconus but that had no slit-lamp signs of keratoconus (Fleischer ring, Vogt striae and Munson sign) with a best spectacle-corrected visual acuity of 20/20 or better. Eyes were monitored for the progression of apparent slit-lamp findings of keratoconus during the follow-up period. Using a Fourier analysis of the corneal topography data, regular astigmatism, asymmetry component and higher-order irregularity component were calculated in the central 3 mm zone. Quantitative descriptors of corneal topography were compared between eyes which progressed to true keratoconus and those which did not. RESULTS: Five eyes (14.7%) progressed to apparent keratoconus from suspected keratoconus (progression group), and 29 eyes did not (non-progression group). On average, it took 5.2 years for the eyes to develop apparent slit-lamp findings of keratoconus. The cumulative incidence of progression by Kaplan-Meier analysis was 21.5% in 6 years. The asymmetry component and regular astigmatism by Fourier analysis at the initial examination were significantly larger in the progression group than in the non-progression group. CONCLUSION: In our retrospective study, approximately 20% of eyes with suspected keratoconus progressed to true keratoconus in 6 years, and these eyes had presented greater asymmetry and regular astigmatism at the initial examination.