Nonlinear Kinetic Ion Response to Small Scale Magnetic Islands in Tokamak Plasmas: Neoclassical Tearing Mode Threshold Physics.

A new drift-kinetic theory of the ion response to magnetic islands in tokamak plasmas is presented. Small islands are considered, with widths w much smaller than the plasma radius r, but comparable to the trapped ion orbit width ρ_{bi}. An expansion in w/r reduces the system dimensions from five down to four. In the absence of an electrostatic potential, the ions follow stream lines that map out a drift-island structure that is identical to the magnetic island, but shifted by an amount ∼ few ρ_{bi}. The ion distribution function is flattened across these drift islands, not the magnetic island. For small islands, w∼ρ_{bi}, the shifted drift islands result in a pressure gradient being maintained across the magnetic island, explaining previous simulation results [E. Poli et al., Phys. Rev. Lett. 88, 075001 (2002)PRLTAO0031-900710.1103/PhysRevLett.88.075001]. To maintain quasineutrality an electrostatic potential forms, which then supports a pressure gradient in the electrons also. This influence on the electron physics is shown to stabilize small magnetic islands of width a few ion banana widths, providing a new threshold mechanism for neoclassical tearing modes-a key result for the performance of future tokamaks, including ITER.

Antifungal effect of 405-nm light on Botrytis cinerea.

UNLABELLED: There is very little information on the fungistatic or fungicidal effect of visible light. This study investigated the effect of 405-nm light, generated by a light-emitting diode array, on the economically important fungus Botrytis cinerea. The mycelial growth of B. cinerea was inhibited to the greatest extent by light at 405 and 415 nm and was negligibly inactivated at 450 nm, suggesting the presence of a photosensitizing compound that absorbs light mainly at wavelengths of 405-415 nm. Delta-aminolevulinic acid, a precursor of endogenous photosensitizer porphyrins, was used to determine the role of these porphyrins in 405-nm light-mediated photoinactivation of the fungus. Concentration-dependent inhibition of spore germination by delta-aminolevulinic acid and accumulation of singlet oxygen in the spores was observed when the spores were exposed to 405-nm light. These results suggest that the excitation of endogenous porphyrins and subsequent accumulation of singlet oxygen could partially explain the 405-nm light-mediated photoinactivation of B. cinerea. The development of symptoms in detached tomato leaves inoculated with B. cinerea spores was significantly reduced by irradiation with 405-nm light, indicating that 405-nm light has a potential use for controlling plant diseases caused by B. cinerea. SIGNIFICANCE AND IMPACT OF THE STUDY: Grey mould (Botrytis cinerea) is a very successful necrotroph, causing serious losses in more than 200 crop hosts. This study investigated the antifungal effect of 405-nm light on this pathogen. Our results suggest that the excitation of endogenous porphyrins and subsequent accumulation of singlet oxygen contribute to the 405-nm light-mediated photoinactivation of grey mould. The development of symptoms in detached tomato leaves inoculated with B. cinerea spores was significantly inhibited by irradiation with 405-nm light, indicating that this wavelength of light has a potential use in controlling plant diseases caused by B. cinerea.

Dienogest, a selective progestin, reduces plasma estradiol level through induction of apoptosis of granulosa cells in the ovarian dominant follicle without follicle-stimulating hormone suppression in monkeys.

Dienogest is a selective progestin that has been shown to arrest ovarian follicular development in women, without affecting gonadotropin secretion. As luteal progesterone or exogeneous progestins are known to suppress ovarian folliculogenesis via the inhibition of gonadotropin secretion, this action of dienogest on ovaries seems to be unique. To examine the underlying mechanism of the antifolliculogenic effect of dienogest, female cynomolgus monkeys were treated with a single oral dose of 0.1 mg/kg dienogest on day 7 of the menstrual cycle. Plasma FSH, estradiol (E2), and progesterone levels were measured up to 15 days after dosing. In an additional experiment, ovaries were excised 24 h after dosing for histological examinations. As a result, plasma E2 level declined within 24 h after dosing, while dienogest did not decreased FSH level prior to E2 decline. After decline of E2 level, the low level of E2 was sustained for more than 11 days. It is considered that a single oral dose of dienogest induced atresia of the dominant follicle. In the histological examination, two out of three animals showed decline in E2 level. The ovarian dominant follicles from these animals showed apoptotic changes in granulosa cells with scattered aromatase expression within 24 h after dosing. These results indicate that the induction of atresia of the ovarian dominant follicle by direct action would be a possible mechanism of dienogest to inhibit plasma E2 level.

Structure of the bacterial flagellar protofilament and implications for a switch for supercoiling.

The bacterial flagellar filament is a helical propeller constructed from 11 protofilaments of a single protein, flagellin. The filament switches between left- and right-handed supercoiled forms when bacteria switch their swimming mode between running and tumbling. Supercoiling is produced by two different packing interactions of flagellin called L and R. In switching from L to R, the intersubunit distance ( approximately 52 A) along the protofilament decreases by 0.8 A. Changes in the number of L and R protofilaments govern supercoiling of the filament. Here we report the 2.0 A resolution crystal structure of a Salmonella flagellin fragment of relative molecular mass 41,300. The crystal contains pairs of antiparallel straight protofilaments with the R-type repeat. By simulated extension of the protofilament model, we have identified possible switch regions responsible for the bi-stable mechanical switch that generates the 0.8 A difference in repeat distance.

Mixed venous oxygen saturation as a promising parameter for physiologic control of total artificial heart.

Mixed venous oxygen saturation (SvO2) has been proposed as one of the suitable parameters for physiologic control of a total artificial heart (TAH). To establish the practical application of SvO2, we investigated the response of cardiac output (CO) and SvO2 to step-loaded exercise. A normal calf was surgically equipped with an ultrasonic flowmeter probe and an oximetry catheter in the pulmonary artery to measure CO and SvO2, respectively. Three stage step treadmill exercise tests (1, 2, and 4 km/h) were performed three times. While CO increased from 8.9 L/min at preexercise level to 9.7, 10.2 and 11.4 L/min at 1, 2, and 4 km/h, respectively, SvO2 decreased from 59.6% to 56.8, 55.3, and 52.2%, respectively. There existed a linear correlation between the magnitude of changes in CO and SvO2. CO and SvO2 exhibited a similar course of change, expressing an inverted exponential curve. The time constant of SvO2 was from 19 to 35 seconds, whereas that of CO was from 21 to 39 seconds. We conclude that SvO2 changes in close association with CO during exercise and has good potential to be a parameter for physiologic control of a TAH, by reflecting the recipient's CO demand without conspicuous time delay.

Long-term follow-up of sustained responders to interferon therapy, in patients with chronic hepatitis C.

Interferon (IFN) therapy has been proven to induce the normalization of serum alanine aminotransferase (ALT) levels and to eradicate the hepatitis C virus (HCV) in some patients with chronic hepatitis C, and these patients are usually defined as 'sustained responders'. However, there have been some reports of hepatocellular carcinoma (HCC) in these patients, and the development of HCC remains life-threatening in patients who clear HCV. We analysed the long-term prognoses of patients with chronic hepatitis C in whom HCV was eradicated with IFN. We investigated 392 sustained responders to IFN therapy, from 1,277 patients with chronic HCV infection who received IFN treatment at one of our institutions between April 1989 and March 1999. We analysed the medical records and looked for the development of HCC. About 30% of the sustained responders had been lost to follow-up 3 years after the end of IFN therapy, and the follow-up rate of sustained responders was significantly lower than that of non-sustained responders (P < 0.0001). HCC were found in eight patients: in seven patients HCC developed within 5 years after completion of IFN therapy; but in one patient, a single HCC less than 3 cm in diameter was detected between 7 and 8 years after completion of IFN. Of the five patients who had regular medical follow-up, the HCC was solitary, and the patients survived without any evidence of recurrence. Of the three patients who had not been followed-up, two died from HCC and HCC recurred in the third. These results suggest that HCC can develop in sustained responders and that sustained responders should be followed-up closely after completion of IFN so that HCC may be detected at an early stage. The optimal duration of the follow-up period of the sustained responders remains unclear. Additional prospective studies are required in order to establish an appropriate follow-up protocol for sustained responders to IFN.

The bacterial flagellar cap as the rotary promoter of flagellin self-assembly.

The growth of the bacterial flagellar filament occurs at its distal end by self-assembly of flagellin transported from the cytoplasm through the narrow central channel. The cap at the growing end is essential for its growth, remaining stably attached while permitting the flagellin insertion. In order to understand the assembly mechanism, we used electron microscopy to study the structures of the cap-filament complex and isolated cap dimer. Five leg-like anchor domains of the pentameric cap flexibly adjusted their conformations to keep just one flagellin binding site open, indicating a cap rotation mechanism to promote the flagellin self-assembly. This represents one of the most dynamic movements in protein structures.

Effects of reduced pulse pressure to the cerebral metabolism during prolonged nonpulsatile left heart bypass.

We investigated changes in the cerebral metabolism with long-term reduced pulse pressure. Nine goats underwent pulsatile left heart bypass (LHB) for 2 weeks while awake, and nonpulsatile LHB was subsequently conducted for 4 weeks. The average pulse pressure during nonpulsatile LHB (13, 10, 11, and 11 mm Hg at the 1st, 2nd, 3rd, and 4th nonpulsatile LHB week, respectively) was significantly lower than that during pulsatile LHB (36 mm Hg). There were no significant differences in either arterio-jugular venous oxygen differences (AJDO2) and cerebral oxygen extraction ratio between the 2nd pulsatile LHB week and the 1st, 2nd, 3rd, and 4th nonpulsatile LHB weeks. The arterio-jugular venous glucose differences, jugular venous-arterial lactate differences (JAD Lactate), and lactate oxygen indexes (JAD Lactate/AJDO2) also remained unchanged during the entire course of the experiments. In conclusion, the cerebral metabolism during nonpulsatile LHB did not change compared to that during pulsatile LHB.

The changes occurring after the Putti-Platt procedure using magnetic resonance imaging.

The purpose of this study is to evaluate the magnetic resonance imaging (MRI) following Putti-Platt procedure for recurrent anterior dislocation of the shoulder. Six shoulders of six patients who had received Putti-Platt procedure were evaluated by the MRI before and after operation. After the Putti-Platt procedure the subscapularis tendon was thickened and an increased signal area on T2-weighted images were observed in four patients. The area of subscapularis tendons after operation was increased maximally 3.46-fold and the volume was increased on average 1.51-fold. The course of subscapularis muscle fiber before operation was described as a mild arc, but changed to a straight line after the procedure in five patients. The findings in this study suggest that the Putti-Platt procedure leads to a remarkable increase in strength of subscapularis tendon and an improvement of laxity of subscapularis muscle. In conclusion, there is a good possibility that this procedure will increase the stability of the glenohumeral joint and be a successful treatment for recurrent anterior dislocation of the shoulder.

The Jak-STAT pathway.

A variety of important cellular functions are regulated by cytokines. The Jak-STAT pathway is one of the important signaling pathways downstream of cytokine receptors. Following binding of a ligand to its cognate receptor, receptor-associated Jaks are activated. STAT proteins are then in turn activated by tyrosine phosphorylation by Jak kinases, allowing their dimerization and subsequent translocation into the nucleus, where they modulate expression of target genes. Indispensable functions of Jaks and STATs in cytokine signaling in vivo have been revealed through knockout mouse studies. Moreover, the recent discovery of the CIS/SOCS/JAB/SSI family of inhibitors has contributed to understanding how this pathway is negatively regulated.

Both stat5a and stat5b are required for antigen-induced eosinophil and T-cell recruitment into the tissue.

Antigen-induced eosinophil recruitment into the airways of sensitized mice is mediated by CD4(+) T cells and their cytokines, especially IL-5. In this study, we found that the antigen-induced airway eosinophilia was diminished in Stat5a-deficient (Stat5a(-/-)) mice and Stat5b-deficient (Stat5b(-/-)) mice. We also found that antigen-induced CD4(+) T-cell infiltration and IL-5 production in the airways were diminished in Stat5a(-/- )mice and Stat5b(-/-) mice. Moreover, antigen-induced proliferation of splenocytes was diminished in Stat5a(-/- )mice and Stat5b(-/-) mice, suggesting that the generation of antigen-primed T cells may be compromised in Stat5a(-/-) mice and Stat5b(-/-) mice and this defect may account for the diminished antigen-induced T-cell infiltration into the airways. Interestingly, IL-4 and IL-5 production from anti-CD3-stimulated splenocytes was diminished in Stat5a(-/-) mice and Stat5b(-/-) mice. However, antigen-specific IgE and IgG1 production was diminished in Stat5a(-/-) mice but not in Stat5b(-/-) mice, whereas antigen-specific IgG2a production was increased in Stat5a(-/-) mice, suggesting the enhanced Th1 responses in Stat5a(-/-) mice. Finally, we found that eosinophilopoiesis induced by the administration of recombinant IL-5 was also diminished in Stat5a(-/-) mice and Stat5b(-/-) mice. Together, these results indicate that both Stat5a and Stat5b are essential for induction of antigen-induced eosinophil recruitment into the airways and that the defects in antigen-induced eosinophil recruitment in Stat5a(-/-) mice and Stat5b(-/-) mice result from both impaired IL-5 production in the airways and diminished IL-5 responsiveness of eosinophils. (Blood. 2000;95:1370-1377)

Activation of human progelatinase A/promatrix metalloproteinase 2 by Escherichia coli-derived serine proteinase.

Treatment of human uterine cervical fibroblasts with commercial lipopolysaccharide (LPS) preparations from different serotypes of Escherichia coli effectively augmented the processing of mammalian progelatinase A/promatrix metalloproteinase (proMMP)-2 to a 62-kDa form of MMP-2. When purified proMMP-2 was incubated with LPS preparations, the proenzyme was similarly processed into the 62-kDa active MMP-2 in a time- and dose-dependent manner. By contrast, progelatinase B/proMMP-9 and prostromelysin 1/proMMP-3 were not activated. A serine proteinase inhibitor, phenylmethylsulfonyl fluoride, completely interfered with this LPS-mediated activation of proMMP-2. This is novel evidence that E. coli serine proteinase is a specific activator of proMMP-2. Thus, it is very likely that E. coli infection plays a crucial role in the degradation of connective tissues via the activation of proMMP-2, and the resultant active MMP-2 participates in the dysfunction of connective tissues such as in the preterm rupture of fetal membranes.

Crystallization of the F41 fragment of flagellin and data collection from extremely thin crystals.

Flagellin, which constructs supercoiled filaments of the bacterial flagellum, is very difficult to crystallize because of its strong tendency to polymerize. We therefore crystallized the F41 fragment of flagellin, which does not polymerize because terminal regions that play important roles in polymerization are cleaved off. F41 was crystallized by the hanging drop vapor diffusion method in a mixture of polyethylene glycol, glycerol, and isopropanol, with a reservoir solution covered with silicon oil. The two key factors for success in growing sufficiently large crystals were isopropanol and silicon oil, which worked well to reduce the otherwise very high nucleation rate that resulted in hundreds of tiny crystals. The crystals were grown to very thin plates with thickness less than 10 microm, which made the collection of diffraction data very difficult. Freezing and annealing of the crystals and irradiation at synchrotron beamlines had to be carried out by specific methods and under specific conditions for its structure analysis at 2.0-A resolution.