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

Electromechanical coupling in free-standing AlGaN/GaN planar structures

The strain and electric fields present in free-standing AlGaN/GaN slabs are examined theoretically within the framework of fully-coupled continuum elastic and dielectric models. Simultaneous solutions for the electric field and strain components are obtained by minimizing the electric enthalpy. We apply constraints appropriate to pseudomorphic semiconductor epitaxial layers and obtain closed-form analytic expressions that take into account the wurtzite crystal anisotropy. It is shown that in the absence of free charges, the calculated strain and electric fields are substantially differently from those obtained using the standard model without electromechanical coupling. It is also shown, however, that when a two-dimensional electron gas is present at the AlGaN/GaN interface, a condition that is the basis for heterojunction field-effect transistors, the electromechanical coupling is screened and the decoupled model is once again a good approximation. Specific cases of these calculations corresponding to transistor and superlattice structures are discussed.Comment: revte

The effect of electromechanical coupling on the strain in AlGaN/GaN heterojunction field effect transistors

The strain in AlGaN/GaN heterojunction field-effect transistors (HFETs) is examined theoretically in the context of the fully-coupled equation of state for piezoelectric materials. Using a simple analytical model, it is shown that, in the absence of a two-dimensional electron gas (2DEG), the out-of-plane strain obtained without electromechanical coupling is in error by about 30% for an Al fraction of 0.3. This result has consequences for the calculation of quantities that depend directly on the strain tensor. These quantities include the eigenstates and electrostatic potential in AlGaN/GaN heterostructures. It is shown that for an HFET, the electromechanical coupling is screened by the 2DEG. Results for the electromechanical model, including the 2DEG, indicate that the standard (decoupled) strain model is a reasonable approximation for HFET calculataions. The analytical results are supported by a self-consistent Schr\"odinger-Poisson calculation that includes the fully-coupled equation of state together with the charge-balance equation.Comment: 6 figures, revte

Direct and indirect control of the initiation of meiotic recombination by DNA damage checkpoint mechanisms in budding yeast

Meiotic recombination plays an essential role in the proper segregation of chromosomes at meiosis I in many sexually reproducing organisms. Meiotic recombination is initiated by the scheduled formation of genome-wide DNA double-strand breaks (DSBs). The timing of DSB formation is strictly controlled because unscheduled DSB formation is detrimental to genome integrity. Here, we investigated the role of DNA damage checkpoint mechanisms in the control of meiotic DSB formation using budding yeast. By using recombination defective mutants in which meiotic DSBs are not repaired, the effect of DNA damage checkpoint mutations on DSB formation was evaluated. The Tel1 (ATM) pathway mainly responds to unresected DSB ends, thus the sae2 mutant background in which DSB ends remain intact was employed. On the other hand, the Mec1 (ATR) pathway is primarily used when DSB ends are resected, thus the rad51 dmc1 double mutant background was employed in which highly resected DSBs accumulate. In order to separate the effect caused by unscheduled cell cycle progression, which is often associated with DNA damage checkpoint defects, we also employed the ndt80 mutation which permanently arrests the meiotic cell cycle at prophase I. In the absence of Tel1, DSB formation was reduced in larger chromosomes (IV, VII, II and XI) whereas no significant reduction was found in smaller chromosomes (III and VI). On the other hand, the absence of Rad17 (a critical component of the ATR pathway) lead to an increase in DSB formation (chromosomes VII and II were tested). We propose that, within prophase I, the Tel1 pathway facilitates DSB formation, especially in bigger chromosomes, while the Mec1 pathway negatively regulates DSB formation. We also identified prophase I exit, which is under the control of the DNA damage checkpoint machinery, to be a critical event associated with down-regulating meiotic DSB 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

Time-dependent photoionization of azulene: Optically induced anisotropy on the femtosecond scale

We measure the photoionization cross-section of vibrationally excited levels in the S2 state of azulene by femtosecond pump-probe spectroscopy. At the wavelengths studied (349-265 nm in the pump) the transient signals exhibit two distinct and well-defined behaviours: (i) Short-term (on the order of a picosecond) polarization dependent transients and (ii) longer (10 ps - 1 ns) time-scale decays. This letter focuses on the short time transient. In contrast to an earlier study by Diau et al.22 [J. Chem. Phys. 110 (1999) 9785.] we unambiguously assign the fast initial decay signal to rotational dephasing of the initial alignment created by the pump transition.Comment: Chemical Physics Letters (2008

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.

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