Large Diamagnetism and Electromagnetic Duality in Two-Dimensional Dirac Electron System.

A Dirac electron system in solids mimics relativistic quantum physics that is compatible with Maxwell's equations, with which we anticipate unified electromagnetic responses. We find a large orbital diamagnetism only along the interplane direction and a nearly temperature-independent electrical conductivity of the order of e^{2}/h per plane for the new 2D Dirac organic conductor, α-(BETS)_{2}I_{3}, where BETS is bis(ethylenedithio)tetraselenafulvalene. Unlike conventional electrons in solids whose nonrelativistic effects bifurcate electric and magnetic responses, the observed orbital diamagnetism scales with the electrical conductivity in a wide temperature range. This demonstrates that an electromagnetic duality that is valid only within the relativistic framework is revived in solids.

Coexistence of osteoporosis and atherosclerosis in pheochromocytoma: new insights into its long-term management.

Osteoporosis and atherosclerosis frequently coexist in patients with pheochromocytoma. The presence of osteoporosis may predict that of atherosclerosis and vice versa in patients with PHEO. These findings have implications for the long-term management of the pheochromocytoma and its potential chronic complications. INTRODUCTION: Pheochromocytoma (PHEO), a catecholamine-producing tumor, is often found incidentally, and it may be present for years before it is diagnosed. However, long-term exposure to catecholamines excess may induce chronic complications, such as osteoporosis and atherosclerosis. We aimed to evaluate concomitant osteoporosis and atherosclerosis in patients with PHEO. METHODS: Fifty-one patients with PHEO and 51 patients with a non-functional adrenal tumor were compared radiographically for the prevalence of vertebral fracture (VF), a typical osteoporotic fracture, and abdominal aortic calcification (AAC). RESULTS: In patients with PHEO, the prevalence of AAC was higher in those with VF (58%) than in those without (6%, p < 0.001). AAC was associated with VF after adjusting for age and sex (odds ratio, 1.53; 95% confidence interval, 1.07-2.46; p = 0.003) in patients with PHEO. The degree of catecholamine excess correlated with the presence of VF and AAC (p = 0.007). The prevalence of VF was higher in patients with PHEO (37%) than those with non-functional AT (12%, p = 0.005), but the prevalence of AAC was comparable between the two groups (25% and 19%, p = 0.636). VF and AAC more frequently coexisted in patients with PHEO (22%) than in those with non-functional AT (2%, p = 0.003). CONCLUSION: This study represents the first demonstration that osteoporosis and atherosclerosis frequently coexist in patients with PHEO. The presence of osteoporosis may predict that of atherosclerosis and vice versa in patients with PHEO. These findings have implications for the long-term management of the PHEO and its potential chronic complications.

Anomalous Temperature Behavior of the Chiral Spin Helix in CrNb_{3}S_{6} Thin Lamellae.

Using Lorentz transmission electron microscopy and small-angle electron scattering techniques, we investigate the temperature-dependent evolution of a magnetic stripe pattern period in thin-film lamellae of the prototype monoaxial chiral helimagnet CrNb_{3}S_{6}. The sinusoidal stripe pattern appears due to formation of a chiral helimagnetic order (CHM) in this material. We found that as the temperature increases, the CHM period is initially independent of temperature and then starts to shrink above the temperature of about 90 K, which is far below the magnetic phase transition temperature for the bulk material T_{c} (123 K). The stripe order disappears at around 140 K, far above T_{c}. We argue that this cascade of transitions reflects a three-stage hierarchical behavior of melting in two dimensions.

A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2.

Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is a common disorder of middle-aged individuals characterized by high blood glucose levels which, if untreated, can cause serious medical complications and lead to early death. Genetic factors play an important role in determining susceptibility to this disorder. However, the number of genes involved, their chromosomal location and the magnitude of their effect on NIDDM susceptibility are unknown. We have screened the human genome for susceptibility genes for NIDDM using non-and quasi-parametric linkage analysis methods in a group of Mexican American affected sib pairs. One marker, D2S125, showed significant evidence of linkage to NIDDM and appears to be a major factor affecting the development of diabetes mellitus in Mexican Americans. We propose that this locus be designated NIDDM1.

An in vitro model for cyclosporin A-induced interference of intrathymic clonal elimination.

The effects of cyclosporin A (CsA) on influencing the intrathymic clonal deletion were investigated by using our established thymic stromal cell clone with capacities to express Ia antigens and to produce a unique T cell growth factor. The following were revealed: (a) T cell clone with a given specificity was killed on the Ia+ stromal cell monolayer in the presence of the relevant antigens, a process depending on T cell receptor (TCR) stimulation; and (b) CsA allowed the T cell clone to continuously proliferate even during TCR stimulation by virtue of the stromal cell-derived T cell growth factor. This paper describes an in vitro model of a mechanism by which CsA is responsible for the generation of normally "forbidden" T cell clones.

Decrease of blood dendritic cells and increase of tissue-infiltrating dendritic cells are involved in the induction of Sjögren's syndrome but not in the maintenance.

We have demonstrated previously that, in primary Sjögren's syndrome (SS), immature myeloid dendritic cells (DCs) are decreased in blood and mature myeloid DCs are accumulated in salivary glands, suggesting recruitment of the myeloid DCs from blood to salivary glands. To verify whether this finding is universal in patients of not only primary SS but also secondary SS, in this study we analysed the blood DCs of secondary SS patients. We examined 24 secondary SS and 29 primary SS patients. A direct correlation between the decreased number of myeloid DCs and the duration of Sicca syndrome in primary and secondary SS was observed; namely, the reduction of myeloid DCs in blood was restored spontaneously with duration time of Sicca syndrome. We also examined the immunohistochemical staining of salivary glands of SS patients with monoclonal antibodies against fascin, CD11c and human leucocyte antigen DR (HLA-DR). Fascin(+) or CD11c(+)/HLA-DR(+) mononuclear cells were present in the salivary glands of secondary SS patients, as in primary SS. However, fascin(+) mononuclear cells were barely detected in the salivary glands of a chronic phase of SS patients. We also found a negative correlation between the frequency of blood myeloid DCs and salivary gland-infiltrating DCs in secondary SS patients, as well as primary SS. Our results suggest that the reduction of blood myeloid DCs and preferential trafficking of myeloid DCs into salivary glands is a common event in the early stage of SS. Myeloid DCs may play essential roles in the pathogenesis of Sicca syndrome of SS by initiating T helper cell immune responses.

Late phase of long-term potentiation induced by co-application of N-methyl-d-aspartic acid and the antagonist of NR2B-containing N-methyl-d-aspartic acid receptors in rat hippocampus.

Activation of N-methyl-d-aspartic acid (NMDA) glutamate receptors (NMDARs) is required for long-term potentiation (LTP) of excitatory synaptic transmission at hippocampal CA1 synapses, the proposed cellular mechanisms of learning and memory. We demonstrate here that a brief bath co-application of a low concentration of NMDA, an agonist of NMDARs, and the selective antagonist of NR2B-containing NMDARs, (alpha R, beta S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidinepropanol (Ro25-6981), to hippocampal slices from young adult rats produced a slowly developing LTP persisting at least for 6 h following a transient depression of synaptic transmission in CA1 synapses. The LTP was likely to occur at postsynaptic site and was initiated by activation of NMDARs, and its development was mediated by cAMP-dependent protein kinase (PKA) activation and protein synthesis. This chemically induced LTP and the tetanus-induced late phase of LTP (L-LTP) were mutually occluding, suggesting a common expression mechanism. Thus, we have demonstrated that a brief bath co-application of NMDA with Ro25-6981 to a slice offers an alternative to electrical stimulation as a stimulation method to induce L-LTP. The chemically induced LTP did not require the low-frequency test stimulation typically used to monitor the strength of synapses during and after drug application. Thus, the LTP may occur at a large fraction of synapses in the slice and not to be confined to a small fraction of the synapses where electrical stimulation can reach and induce LTP. Therefore, this chemically induced LTP may be useful for assessing the biochemical and morphological correlates and the molecular aspects of the expression mechanism for L-LTP that has been proven to correlate to hippocampal long-term memory.

Plasma HHV-6 viral load-guided preemptive therapy against HHV-6 encephalopathy after allogeneic stem cell transplantation: a prospective evaluation.

Human herpesvirus 6 (HHV-6) causes life-threatening encephalopathy in recipients of allogeneic SCT, but no consensus has been reached regarding appropriate preventive methods. This study evaluated a plasma HHV-6 viral load-guided preemptive approach against HHV-6-associated encephalopathy. Plasma real-time PCR assay was performed once a week. Among 29 patients, 19 developed positive plasma HHV-6 DNA. Median maximum plasma HHV-6 DNA was 4593.5 copies/ml plasma (range, 150.0-127 891.0 copies/ml plasma). In one of eight events with low-level HHV-6 DNA (defined as <1000 copies/ml plasma) and four of seven events with mid-level HHV-6 DNA (1000-9999.5 copies/ml plasma), HHV-6 loads in plasma subsequently continued increasing. Ganciclovir was administered against six of nine patients with high-level HHV-6 DNA (> or =10,000 copies/ml plasma). High-level HHV-6 DNA resolved similarly in both groups with or without ganciclovir therapy. Among the nine patients with high-level HHV-6 DNA two developed encephalopathy. As encephalopathy developed before the detection of high-level HHV-6 DNA in plasma, these two patients had not received preemptive ganciclovir therapy. In conclusion, our preemptive approach against HHV-6-associated encephalopathy cannot prevent all cases of HHV-6 encephalopathy in SCT recipients due to the dynamic kinetics of plasma HHV-6 viral load.

The ZZ/ZW sex-determining mechanism originated twice and independently during evolution of the frog, Rana rugosa.

The Japanese frog, Rana rugosa, has two distinct sex chromosome types, XX/XY and ZZ/ZW. These two types are found in localized groups, separated geographically by a boundary area predicted to lie somewhere around Lake Biwa in central Japan. To determine this precise boundary, the heterogametic sex of 18 populations around Lake Biwa was examined by genotyping sex-linked genes. Phylogenetic relationships between the populations were also analyzed using mitochondrial 12S rRNA gene. Results showed that the Suzuka-Kii mountain range located east of Lake Biwa separated the XX/XY populations from the ZZ/ZW populations. Unexpectedly, from a phylogenetic perspective, the ZZ/ZW populations around Lake Biwa belonged not to the main ZW group but to the XY group. The authors propose that the ZZ/ZW populations around Lake Biwa diverged secondarily from the XX/XY group through a change of heterogametic sex, eventually forming a new group. This group was thus named the 'Neo-ZW group'. As the main ZW group inhabiting northwestern Japan is known to have a different male heterogametic origin, this finding shows that change of heterogametic sex from male to female may have occurred twice, and independently, during the frog speciation.

ADAMTS-1: a metalloproteinase-disintegrin essential for normal growth, fertility, and organ morphology and function.

A disintegrin and metalloproteinase (ADAM) represents a protein family possessing both metalloproteinase and disintegrin domains. ADAMTS-1, an ADAM family member cloned from cachexigenic colon adenocarcinoma, is unusual in that it contains thrombospondin type I motifs and anchors to the extracellular matrix. To elucidate the biological role of ADAMTS-1, we developed ADAMTS-1-null mice by gene targeting. Targeted disruption of the mouse ADAMTS-1 gene resulted in growth retardation with adipose tissue malformation. Impaired female fertilization accompanied by histological changes in the uterus and ovaries also resulted. Furthermore, ADAMTS-1(-/-) mice demonstrated enlarged renal calices with fibrotic changes from the ureteropelvic junction through the ureter, and abnormal adrenal medullary architecture without capillary formation. ADAMTS-1 thus appears necessary for normal growth, fertility, and organ morphology and function. Moreover, the resemblance of the renal phenotype to human ureteropelvic junction obstruction may provide a clue to the pathogenesis of this common congenital disease.

Effect of slow movement and stretch-shortening cycle on lower extremity muscle activity and joint moments during squat.

AIM: The purpose of the present study was to compare activity patterns of 8 muscles that cross the ankle, knee and hip joints under different conditions of squatting. METHODS: Ten male athletes performed squats at 3 different speeds (slow, normal, quick). Variables such as net moment and power about the joint were calculated during the descending and ascending phases of each squat. Using surface electrodes placed over the 8 lower extremity muscles, %iEMG was calculated during the ascending phase of each squat. RESULTS: In the descending phase, activities of the following 7 muscles were significantly greater for the quick squat (QS) than the normal squat (NS) or slow squat (SS): erector spinae (ES), gluteus maximus (Gmax), gluteus medius (Gmed), rectus femoris (RF), biceps femoris (BF), adductor longus (AL), and vastus lateralis (VL). Median frequency (MDF) of the Gmax muscle was significantly lower for NS than QS, and activity of the BF was significantly lower for NS than QS or SS. Mean moment of the hip joint was significantly lower for SS than QS. In the ascending phase, activities of the following 7 muscles were significantly greater for QS and NS than SS: ES, Gmax, Gmed, RF, BF, AL, and VL. MDF of the Gmax muscle was significantly lower for NS than QS, and the activity of the BF was significantly lower for NS than QS or SS. Mean moment of the hip joint was significantly higher for QS than SS or NS. Mean moment of the knee was significantly lower for SS than NS or QS. CONCLUSIONS: For QS, a stretch-shortening cycle increased the load on the Gmax. Mean muscle activity was less for SS than NS, and MDF was greater for SS than NS. These results suggest that SS mobilizes type-2 muscle fibers, despite the slow movement involved and the low risk of injury.

Clinical characteristics and outcome of human herpesvirus-6 encephalitis after allogeneic hematopoietic stem cell transplantation.

In this retrospective analysis using the Transplant Registry Unified Management Program, we identified 145 patients with human herpesvirus (HHV)-6 encephalitis among 6593 recipients. The cumulative incidences of HHV-6 encephalitis at 100 days after transplantation in all patients, recipients of bone marrow or PBSCs and recipients of cord blood were 2.3%, 1.6% and 5.0%, respectively. Risk factors identified in multivariate analysis were male sex, type of transplanted cells (relative risk in cord blood transplantation, 11.09, P<0.001; relative risk in transplantation from HLA-mismatched unrelated donor, 9.48, P<0.001; vs transplantation from HLA-matched related donor) and GvHD prophylaxis by calcineurin inhibitor alone. At 100 days after transplantation, the overall survival rate was 58.3% and 80.5% among patients with and without HHV-6 encephalitis, respectively (P<0.001). Neuropsychological sequelae remained in 57% of 121 evaluated patients. With both foscarnet and ganciclovir, full-dose therapy (foscarnet ⩾180 mg/kg, ganciclovir ⩾10 mg/kg) was associated with better response rate (foscarnet, 93% vs 74%, P=0.044; ganciclovir, 84% vs 58%, P=0.047). HHV-6 encephalitis is not rare not only in cord blood transplant recipients but also in recipients of HLA-mismatched unrelated donors. In this study, development of HHV-6 encephalitis was associated with a poor survival rate, and neurological sequelae remained in many patients.

Expression of high-affinity interleukin 4 receptors on murine sarcoma cells and receptor-mediated cytotoxicity of tumor cells to chimeric protein between interleukin 4 and Pseudomonas exotoxin.

The presence of interleukin 4 receptor (IL-4R) on methylcholanthrene (MCA-106, MCA-102, and MC-38)- and viral DNA (G-2TS and 14-2TS)-induced murine sarcoma cells was demonstrated. MCA-106 tumor cells express about 500 to 1348 (median, 800) interleukin 4 (IL-4) binding sites/cell with a dissociation constant (Kd) of 115 +/- 26 pM (mean +/- SD, n = 4). By Northern blot analysis, tumor cells exhibited a single mRNA species of 3.9 kilobases. Other murine sarcoma (MCA-102), colon adenocarcinoma (MC-38), G-2TS, and 14-2TS tumor cells express low numbers of IL-4R. By immunoperoxidase staining, 81 to 92% of the cells from fresh MCA-106 tumors were positive for IL-4 receptors, while only 7 to 10% of tumor-infiltrating cells were Thy 1.2 and less than 1% Mac-1 positive. Using a chimeric protein composed of IL-4 and Pseudomonas exotoxin (IL-4-PE40), we observed that IL-4-PE40 was cytotoxic (determined by inhibition of protein synthesis by [3H]leucine uptake) to MCA-106 tumor cells in a dose-dependent manner. A nonchimeric protein (PE40) that cannot bind to the IL-4R did not inhibit protein synthesis in tumor cells. A chimeric mutant protein (IL4-PE40 asp553) that can bind to IL-4 receptors but does not have the capability to inhibit protein synthesis was not cytotoxic to tumor cells. These studies strongly suggest that IL-4R on murine MCA-106 sarcoma cells is internalized when occupied by IL-4 PE40. Furthermore, a neutralizing antibody (11B11) to IL-4 completely abolished the protein synthesis-inhibitory activity of IL-4-PE40. G-2TS tumor cells which expressed low numbers of IL-4 receptors were not vulnerable to cytotoxicity by IL-4-PE40. Taken together, these data suggest that IL-4 receptor may be a target for IL-4-toxin therapy.

Particular types of tumor cells have the capacity to convert transforming growth factor beta from a latent to an active form.

We investigated the capacities of various tumor types to generate an active versus latent form of transforming growth factor beta (TGF-beta) in its culture supernatants (SNs). Tumor cell lines were divided into three types depending on the form and magnitude of TGF-beta detected in their culture SNs: some (2 of 7 lines) generated mostly an active form (Type A); others (4 of 7) generated exclusively a latent form (Type B); and the remaining line (1 of 7) produced only marginal levels of active/latent TGF-beta (Type C). When Type A tumor cells were cultured at lower numbers, cultures failed to generate active TGF-beta. However, the addition of Type B tumor cell culture SNs containing only a latent form of TGF-beta resulted in the generation of the potent activity of active TGF-beta. This capacity was observed for another Type A tumor but not for other types (Type B and Type C). An active form of TGF-beta was detected in culture SNs of Type A tumor cells as early as 3-6 h after the addition of Type B tumor culture SNs. The emergence of an active form of TGF-beta was also observed in cultures of Type A tumor cells, the protein synthesis of which was almost completely inhibited by pretreatment with cycloheximide. Moreover, the Type B tumor SN used for the induction of active TGF-beta activity was found to contain latent TGF-beta with an apparent molecular weight of about 200,000. Type A tumor cells were also capable of generating active TGF-beta by the addition of recombinant TGF-beta of latent form with a small molecular weight (about 60,000), although the generation of active TGF-beta was much weaker after the addition of small latent TGF-beta than after the addition of large latent TGF-beta. Taken collectively, these results indicate that particular types of tumor cells have the capacity to generate an active form of TGF-beta and that such capacity can be attributed to their potential to convert TGF-beta from a latent (mainly large type) to an active form.

The transmembrane protein tyrosine phosphatase RPTPsigma modulates signaling of the epidermal growth factor receptor in A431 cells.

Attenuation of epidermal growth factor receptor signaling by the ganglioside G(M3) has previously been found to involve activation of an unknown protein-tyrosine phosphatase (PTP). In transient expression experiments we tested different PTPs for activation towards EGF receptor by G(M3). The transmembrane PTP RPTPsigma but not RPTPalpha or the SH2-domain PTP SHP-1 exhibited elevated activity towards EGF receptor in G(M3)-treated cells. The possible relevance of RPTPsigma for regulation of EGF receptor signaling activity was further explored in stable A431 cells lines inducibly expressing RPTPsigma or RPTPsigma antisense RNA. RPTPsigma expression clearly reduced EGF receptor phosphorylation. Also, soft agar colony formation of respective cell lines was reduced upon RPTPsigma expression whereas RPTPsigma antisense RNA expression augmented both, EGF receptor phosphorylation and soft agar colony formation. In addition, RPTPsigma antisense RNA expression rendered A431 cells resistant to inhibition of EGF receptor phosphorylation by G(M3). We propose that RPTPsigma participates in EGF receptor dephosphorylation in A431 cells, becomes activated by G(M3) via an unknown mechanism and is thereby capable to mediate attenuation of EGF receptor phosphorylation by G(M3).

Enzymic hydrolysis of diol lipids by pancreatic lipase.

Chain length and positional specificities of pancreatic lipase for diol lipids have been examined by use of the synthetic substrates such as the diol esters and related esters that contain C6--C20 even-numbered saturated acids and oleic acid as fatty acids, and ethylene glycol, 1,2- and 1,3-propanediols, 1,3-, 1,4-, and 2,3-butanediols, monohydric alcohols, and glycerol as alcohols. No remarkable difference in the degree of hydrolysis was observed in the case of diol esters having C14--C20 fatty acids at least during 30-min digestion, though hydrolysis reached a maximum in diol diotanoates after the same period. Pancreatic lipase specifically released only the fatty acids esterified with the primary hydroxyl groups of diols.

Approximately 70% of fucose-labeled glycopeptides from the cell surface and cellular material of rat.

Approximately 70% of fucose-labeled glycopeptides from the cell surface and cellular material of rat fibroblasts (3Y1B cells) were hydrolyzed by endo-beta-N-acetylglucosaminidase D in the presence of neuraminidase, beta-galactosidase and beta-N-acetylglucosaminidase. Structure of the susceptible glycopeptides were found to be very similar to non-membrane glycopeptides of the complex heteropolysaccharide unit, such as the sialylated glycopeptides of thyroglobulin. On the other hand, the resistant glycopeptides were also refractory toward endo-beta-N-acetylglucosaminidase H and alpha-mannosidase, and appeared to be a mixture of glycopeptides with unique structures.

Mutations in the hepatocyte nuclear factor-1alpha/MODY3 gene in Japanese subjects with early- and late-onset NIDDM.

Recent studies have shown that mutations in the hepatocyte nuclear factor (HNF)-1alpha gene are the cause of maturity-onset diabetes of the young type 3 (MODY3). We have screened 193 unrelated Japanese subjects with NIDDM for mutations in this gene: 83 with early-onset NIDDM (diagnosis at <30 years of age) and 110 with late-onset NIDDM (diagnosis > or = 30 years of age). All of the members of the latter group also had at least one sibling with NIDDM. The 10 exons, flanking introns, and promoter region were amplified using polymerase chain reaction and were sequenced directly. Mutations were found in 7 of the 83 (8%) unrelated subjects with early-onset NIDDM. The mutations were each different and included four missense mutations (L12H, R131Q, K205Q, and R263C) and three frameshift mutations (P379fsdelCT, T392fsdelA, and L584S585fsinsTC). One of the 110 subjects with late-onset NIDDM was heterozygous for the missense mutation G191D. This subject, who was diagnosed with NIDDM at 64 years of age, also had a brother with NIDDM (age at diagnosis, 54 years) who carried the same mutation, suggesting that this mutation contributed to the development of NIDDM in these two siblings. None of these mutations were present in 50 unrelated subjects with normal glucose tolerance (100 normal chromosomes). Mutations in the HNF-1alpha gene occur in Japanese subjects with NIDDM and appear to be an important cause of early-onset NIDDM in this population. In addition, they are present in about 1% of subjects with late-onset NIDDM.

Mutations in the coding region of the neurogenin 3 gene (NEUROG3) are not a common cause of maturity-onset diabetes of the young in Japanese subjects.

Mutations in transcription factors that play a role in the development of the endocrine pancreas, such as insulin promoter factor-1 and NeuroD1/BETA2, have been associated with diabetes. Cell type-specific members of the basic helix-loop-helix (bHLH) family of transcription factors play essential roles in the development and maintenance of many differentiated cell types, including pancreatic beta-cells. Neurogenin 3 is a bHLH transcription factor that is expressed in the developing central nervous system and the embryonic pancreas. Mice lacking this transcription factor fail to develop any islet endocrine cells and die postnatally from diabetes. Because neurogenin 3 is required for the development of beta-cells and other pancreatic islet cell types, we considered it a candidate diabetes gene. We screened the coding region of the human neurogenin 3 gene (NEUROG3) for mutations in a group of unrelated Japanese subjects with maturity-onset diabetes of the young (MODY). We found three sequence variants: a deletion of 2-bp in the 5'-untranslated region (NEUROG3-g.-44-45delCA), a G-to-A substitution in codon 167 (g.499G/ A), resulting in a Gly-to-Arg replacement (G/R167), and a T-to-C substitution in codon 199 (g.596T/C), resulting in a Phe/Ser polymorphism F/S199. These polymorphisms were not associated with MODY, thereby suggesting that mutations in NEUROG3 are not a common cause of MODY in Japanese patients.