The Ecm11-Gmc2 complex promotes synaptonemal complex formation through assembly of transverse filaments in budding yeast

During meiosis, homologous chromosomes pair at close proximity to form the synaptonemal complex (SC). This association is mediated by transverse filament proteins that hold the axes of homologous chromosomes together along their entire length. Transverse filament proteins are highly aggregative and can form an aberrant aggregate called the polycomplex that is unassociated with chromosomes. Here, we show that the Ecm11-Gmc2 complex is a novel SC component, functioning to facilitate assembly of the yeast transverse filament protein, Zip1. Ecm11 and Gmc2 initially localize to the synapsis initiation sites, then throughout the synapsed regions of paired homologous chromosomes. The absence of either Ecm11 or Gmc2 substantially compromises the chromosomal assembly of Zip1 as well as polycomplex formation, indicating that the complex is required for extensive Zip1 polymerization. We also show that Ecm11 is SUMOylated in a Gmc2-dependent manner. Remarkably, in the unSUMOylatable ecm11 mutant, assembly of chromosomal Zip1 remained compromised while polycomplex formation became frequent. We propose that the Ecm11-Gmc2 complex facilitates the assembly of Zip1 and that SUMOylation of Ecm11 is critical for ensuring chromosomal assembly of Zip1, thus suppressing polycomplex formation

Quantifying extreme behaviour in geomagnetic activity

Understanding the extremes in geomagnetic activity is an important component in understanding just how severe conditions can become in the terrestrial space environment. Extreme activity also has consequences for technological systems. On the ground, extreme geomagnetic behavior has an impact on navigation and position accuracy and the operation of power grids and pipeline networks. We therefore use a number of decades of one-minute mean magnetic data from magnetic observatories in Europe, together with the technique of extreme value statistics, to provide a preliminary exploration of the extremes in magnetic field variations and their one-minute rates of change. These extremes are expressed in terms of the variations that might be observed every 100 and 200 years in the horizontal strength and in the declination of the field. We find that both measured and extrapolated extreme values generally increase with geomagnetic latitude (as might be expected), though there is a marked maximum in estimated extreme levels between about 53 and 62 degrees north. At typical midlatitude European observatories (55–60 degrees geomagnetic latitude), compass variations may reach approximately 3–8 degrees/minute, and horizontal field changes may reach 1000–4000 nT/minute, in one magnetic storm once every 100 years. For storm return periods of 200 years the equivalent figures are 4–11 degrees/minute and 1000–6000 nT/minute

Transport and Magnetic Properties of R1-xAxCoO3 (R=La, Pr and Nd; A=Ba, Sr and Ca)

Transport and magnetic measurements have been carried out on perovskite Co-oxides R1-xAxCoO3 (R=La, Pr, and Nd; A=Ba, Sr and Ca; 0<x<0.5: All sets of the R and A species except Nd1-xBaxCoO3 have been studied.). With increasing the Sr- or Ba-concentration x, the system becomes metallic ferromagnet with rather large magnetic moments. For R=Pr and Nd and A=Ca, the system approaches the metal- insulator phase boundary but does not become metallic. The magnetic moments of the Ca-doped systems measured with the magnetic field H=0.1 T are much smaller than those of the Ba- and Sr-doped systems. The thermoelectric powers of the Ba- and Sr-doped systems decrease from large positive values of lightly doped samples to negative ones with increasing doping level, while those of Ca-doped systems remain positive. These results can be understood by considering the relationship between the average ionic radius of R1-xAx and the energy difference between the low spin and intermediate spin states. We have found the resistivity-anomaly in the measurements of Pr1-xCaxCoO3 under pressure in the wide region of x, which indicates the existence of a phase transition different from the one reported in the very restricted region of x~0.5 at ambient pressure [Tsubouchi et al. Phys. Rev. B 66 (2002) 052418.]. No indication of this kind of transition has been observed in other species of R.Comment: 9 pages, 8 figures. J. Phys. Soc. Jpn. 72 (2003) No.

Transport and Magnetic Studies on the Spin State Transition of Pr1-xCaxCoO3 up to High Pressure

Transport and magnetic measurements and structural and NMR studies have been carried out on (Pr1-yR'y)1-xAxCoO3 {R'=(rare earth elements and Y); A=(Ca, Ba and Sr)} at ambient pressure or under high pressure. The system exhibits a phase transition from a nearly metallic to an insulating state with decreasing temperature T, where the low spin (LS) state of Co3+ is suddenly stabilized. For y=0, we have constructed a T-x phase diagram at various values of the external pressure p. It shows that the (T, x) region of the low temperature phase, which is confined to a very narrow region around x=0.5 at ambient pressure, expands as p increases, suggesting that the transition is not due to an order-disorder type one. For the occurrence of the transition, both the Pr and Ca atoms seem to be necessary. The intimate relationship between the local structure around the Co ions and the electronic (or spin) state of Co3+ ions is discussed: For the smaller unit cell volume or the smaller volume of the CoO6 octahedra and for the larger tilting angle of the octahedra, the temperature of the transition becomes higher. The role of the carriers introduced by the doping of the A atoms, is also discussed. By analyzing the data of 59Co-NMR spectra and magnetic susceptibilities of Pr1-xCaxCoO3 the energy separations among the different spin states of Co3+ and Co4+ are roughly estimated.Comment: 15 pages, 15 figures, 2 tables, submitted to J. Phys. Soc. Jp

Evidence that MEK1 positively promotes interhomologue double-strand break repair

During meiosis there is an imperative to create sufficient crossovers for homologue segregation. This can be achieved during repair of programmed DNA double-strand breaks (DSBs), which are biased towards using a homologue rather than sister chromatid as a repair template. Various proteins contribute to this bias, one of which is a meiosis specific kinase Mek1. It has been proposed that Mek1 establishes the bias by creating a barrier to sister chromatid repair, as distinct from enforcing strand invasion with the homologue. We looked for evidence that Mek1 positively stimulates strand invasion of the homologue. This was done by analysing repair of DSBs induced by the VMA1-derived endonuclease (VDE) and flanked by directly repeated sequences that can be used for intrachromatid single-strand annealing (SSA). SSA competes with interhomologue strand invasion significantly more successfully when Mek1 function is lost. We suggest the increase in intrachromosomal SSA reflects an opportunistic default repair pathway due to loss of a MEK1 stimulated bias for strand invasion of the homologous chromosome. Making use of an inhibitor sensitive mek1-as1 allele, we found that Mek1 function influences the repair pathway throughout the first4–5 h of meiosis. Perhaps reflecting a particular need to create bias for successful interhomologue events before chromosome pairing is complete

Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety

<p>Abstract</p> <p>Background</p> <p>Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti-apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule.</p> <p>Methods</p> <p>Potential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m²/day) intravenously for 12 to 14 days.</p> <p>Results</p> <p>We established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF.</p> <p>Conclusions</p> <p>Intravenous rh-HGF at a dose of 0.6 mg/m²was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose.</p

Essential and checkpoint functions of budding yeast ATM and ATR during meiotic prophase are facilitated by differential phosphorylation of a meiotic adaptor protein, Hop1

A hallmark of the conserved ATM/ATR signalling is its ability to mediate a wide range of functions utilizing only a limited number of adaptors and effector kinases. During meiosis, Tel1 and Mec1, the budding yeast ATM and ATR, respectively, rely on a meiotic adaptor protein Hop1, a 53BP1/Rad9 functional analog, and its associated kinase Mek1, a CHK2/Rad53-paralog, to mediate multiple functions: control of the formation and repair of programmed meiotic DNA double strand breaks, enforcement of inter-homolog bias, regulation of meiotic progression, and implementation of checkpoint responses. Here, we present evidence that the multi-functionality of the Tel1/Mec1-to-Hop1/Mek1 signalling depends on stepwise activation of Mek1 that is mediated by Tel1/Mec1 phosphorylation of two specific residues within Hop1: phosphorylation at the threonine 318 (T318) ensures the transient basal level Mek1 activation required for viable spore formation during unperturbed meiosis. Phosphorylation at the serine 298 (S298) promotes stable Hop1-Mek1 interaction on chromosomes following the initial phospho-T318 mediated Mek1 recruitment. In the absence of Dmc1, the phospho-S298 also promotes Mek1 hyper-activation necessary for implementing meiotic checkpoint arrest. Taking these observations together, we propose that the Hop1 phospho-T318 and phospho-S298 constitute key components of the Tel1/Mec1- based meiotic recombination surveillance (MRS) network and facilitate effective coupling of meiotic recombination and progression during both unperturbed and challenged meiosis