BCKDH: the missing link in apicomplexan mitochondrial metabolism is required for full virulence of Toxoplasma gondii and Plasmodium berghei

While the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii are thought to primarily depend on glycolysis for ATP synthesis, recent studies have shown that they can fully catabolize glucose in a canonical TCA cycle. However, these parasites lack a mitochondrial isoform of pyruvate dehydrogenase and the identity of the enzyme that catalyses the conversion of pyruvate to acetyl-CoA remains enigmatic. Here we demonstrate that the mitochondrial branched chain ketoacid dehydrogenase (BCKDH) complex is the missing link, functionally replacing mitochondrial PDH in both T. gondii and P. berghei. Deletion of the E1a subunit of T. gondii and P. berghei BCKDH significantly impacted on intracellular growth and virulence of both parasites. Interestingly, disruption of the P. berghei E1a restricted parasite development to reticulocytes only and completely prevented maturation of oocysts during mosquito transmission. Overall this study highlights the importance of the molecular adaptation of BCKDH in this important class of pathogens

170 Nanometer Nuclear Magnetic Resonance Imaging using Magnetic Resonance Force Microscopy

We demonstrate one-dimensional nuclear magnetic resonance imaging of the semiconductor GaAs with 170 nanometer slice separation and resolve two regions of reduced nuclear spin polarization density separated by only 500 nanometers. This is achieved by force detection of the magnetic resonance, Magnetic Resonance Force Microscopy (MRFM), in combination with optical pumping to increase the nuclear spin polarization. Optical pumping of the GaAs creates spin polarization up to 12 times larger than the thermal nuclear spin polarization at 5 K and 4 T. The experiment is sensitive to sample volumes containing $\sim 4 \times 10^{11}$ $^{71}$Ga$/\sqrt{Hz}$. These results demonstrate the ability of force-detected magnetic resonance to apply magnetic resonance imaging to semiconductor devices and other nanostructures.Comment: Submitted to J of Magnetic Resonanc

Seismicity and fault interaction, Southern San Jacinto Fault Zone and adjacent faults, southern California: Implications for seismic hazard

The southern San Jacinto fault zone is characterized by high seismicity and a complex fault pattern that offers an excellent setting for investigating interactions between distinct faults. This fault zone is roughly outlined by two subparallel master fault strands, the Coyote Creek and Clark-San Felipe Hills faults, that are located 2 to 10 km apart and are intersected by a series of secondary cross faults. Seismicity is intense on both master faults and secondary cross faults in the southern San Jacinto fault zone. The seismicity on the two master strands occurs primarily below 10 km; the upper 10 km of the master faults are now mostly quiescent and appear to rupture mainly or solely in large earthquakes. Our results also indicate that a considerable portion of recent background activity near the April 9, 1968, Borrego Mountain rupture zone (M_L=6.4) is located on secondary faults outside the fault zone. We name and describe the Palm Wash fault, a very active secondary structure located about 25 km northeast of Borrego Mountain that is oriented subparallel to the San Jacinto fault system, dips approximately 70° to the northeast, and accommodates right-lateral shear motion. The Vallecito Mountain cluster is another secondary feature delineated by the recent seismicity and is characterized by swarming activity prior to nearby large events on the master strand. The 1968 Borrego Mountain and the April 28, 1969, Coyote Mountain (M_L=5.8) events are examples of earthquakes with aftershocks and subevents on these secondary and master faults. Mechanisms from those earthquakes and recent seismic data for the period 1981 to 1986 are not simply restricted to strike-slip motion; dipslip motion is also indicated. Teleseismic body waves (long-period P and SH) of the 1968 and 1969 earthquakes were inverted simultaneously for source mechanism, seismic moment, rupture history, and centroid depth. The complicated waveforms of the 1968 event (M_o=1.2 × 10^(19) Nm) are interpreted in terms of two subevents; the first caused by right-lateral strike-slip motion in the mainshock along the Coyote Creek fault and the second by a rupture located about 25 km away from the master fault. Our waveform inversion of the 1969 event indicates that strike-slip motion predominated, releasing a seismic moment of 2.5 × 10^(17) Nm. Nevertheless, the right-lateral nodal plane of the focal mechanism is significantly misoriented (20°) with respect to the master fault, and hence the event is not likely to be associated with a rupture on that fault. From this and other examples in southern California, we conclude that cross faults may contribute significantly to seismic hazard and that interaction between faults has important implications for earthquake prediction

New apparatus for DTA at 2000 bar: thermodynamic studies on Au, Ag, Al and HTSC oxides

A new DTA (Differential Thermal Analysis) device was designed and installed in a Hot Isostatic Pressure (HIP) furnace in order to perform high-pressure thermodynamic investigations up to 2 kbar and 1200C. Thermal analysis can be carried out in inert or oxidising atmosphere up to p(O2) = 400 bar. The calibration of the DTA apparatus under pressure was successfully performed using the melting temperature (Tm) of pure metals (Au, Ag and Al) as standard calibration references. The thermal properties of these metals have been studied under pressure. The values of DV (volume variation between liquid and solid at Tm), ROsm (density of the solid at Tm) and ALPHAm (linear thermal expansion coefficient at Tm) have been extracted. A very good agreement was found with the existing literature and new data were added. This HP-DTA apparatus is very useful for studying the thermodynamics of those systems where one or more volatile elements are present, such as high TC superconducting oxides. DTA measurements have been performed on Bi,Pb(2223) tapes up to 2 kbar under reduced oxygen partial pressure (p(O2) = 0.07 bar). The reaction leading to the formation of the 2223 phase was found to occur at higher temperatures when applying pressure: the reaction DTA peak shifted by 49C at 2 kbar compared to the reaction at 1 bar. This temperature shift is due to the higher stability of the Pb-rich precursor phases under pressure, as the high isostatic pressure prevents Pb from evaporating.Comment: 6 figures, 3 tables, Thermodynamics, Thermal property, Bi-2223, fundamental valu

Quantum Heisenberg antiferromagnet on low-dimensional frustrated lattices

Using a lattice-gas description of the low-energy degrees of freedom of the quantum Heisenberg antiferromagnet on the frustrated two-leg ladder and bilayer lattices we examine the magnetization process at low temperatures for these spin models. In both cases the emergent discrete degrees of freedom implicate a close relation of the frustrated quantum Heisenberg antiferromagnet to the classical lattice gas with finite nearest-neighbor repulsion or, equivalently, to the Ising antiferromagnet in a uniform magnetic field. Using this relation we obtain analytical results for thermodynamically large systems in the one-dimensional case. In the two-dimensional case we perform classical Monte Carlo simulations for systems of up to $100 \times 100$ sites.Comment: Submitted to Teoreticheskaya i Matematicheskaya Fizika (special issue dedicated to the 90th anniversary of Professor Sergei Vladimirovich Tyablikov

Histone degradation in response to DNA damage enhances chromatin dynamics and recombination rates

Nucleosomes are essential for proper chromatin organization and the maintenance of genome integrity. Histones are post-translationally modified and often evicted at sites of DNA breaks, facilitating the recruitment of repair factors. Whether such chromatin changes are localized or genome-wide is debated. Here we show that cellular levels of histones drop 20-40% in response to DNA damage. This histone loss occurs from chromatin, is proteasome-mediated and requires both the DNA damage checkpoint and the INO80 nucleosome remodeler. We confirmed reductions in histone levels by stable isotope labeling of amino acids in cell culture (SILAC)-based mass spectrometry, genome-wide nucleosome mapping and fluorescence microscopy. Chromatin decompaction and increased fiber flexibility accompanied histone degradation, both in response to DNA damage and after artificial reduction of histone levels. As a result, recombination rates and DNA-repair focus turnover were enhanced. Thus, we propose that a generalized reduction in nucleosome occupancy is an integral part of the DNA damage response in yeast that provides mechanisms for enhanced chromatin mobility and homology search.</p

In search of lost hybridity: the French Daniel Deronda

Starting from a set of examples of borrowings from French in George Eliot’s Daniel Deronda, I explore the various ways in which the characters’ and narrator’s use of mixed English–French utterances generates inferences which make the transcending of their mono-cultural self possible. I go on to argue that in Jumeau’s recent French translation of the novel, the reader is not given access to those inferences, resulting in the erasing of an Anglo-European, cosmopolitan identity

Quaternary structure predictions of transmembrane proteins starting from the monomer: a docking-based approach

BACKGROUND: We introduce a computational protocol for effective predictions of the supramolecular organization of integral transmembrane proteins, starting from the monomer. Despite the demonstrated constitutive and functional importance of supramolecular assemblies of transmembrane subunits or proteins, effective tools for structure predictions of such assemblies are still lacking. Our computational approach consists in rigid-body docking samplings, starting from the docking of two identical copies of a given monomer. Each docking run is followed by membrane topology filtering and cluster analysis. Prediction of the native oligomer is therefore accomplished by a number of progressive growing steps, each made of one docking run, filtering and cluster analysis. With this approach, knowledge about the oligomerization status of the protein is required neither for improving sampling nor for the filtering step. Furthermore, there are no size-limitations in the systems under study, which are not limited to the transmembrane domains but include also the water-soluble portions. RESULTS: Benchmarks of the approach were done on ten homo-oligomeric membrane proteins with known quaternary structure. For all these systems, predictions led to native-like quaternary structures, i.e. with C(α)-RMSDs lower than 2.5 Å from the native oligomer, regardless of the resolution of the structural models. CONCLUSION: Collectively, the results of this study emphasize the effectiveness of the prediction protocol that will be extensively challenged in quaternary structure predictions of other integral membrane proteins

Erinnerung an W. Thielmann und Willingshausen

While the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii are thought to primarily depend on glycolysis for ATP synthesis, recent studies have shown that they can fully catabolize glucose in a canonical TCA cycle. However, these parasites lack a mitochondrial isoform of pyruvate dehydrogenase and the identity of the enzyme that catalyses the conversion of pyruvate to acetyl-CoA remains enigmatic. Here we demonstrate that the mitochondrial branched chain ketoacid dehydrogenase (BCKDH) complex is the missing link, functionally replacing mitochondrial PDH in both T. gondii and P. berghei. Deletion of the E1a subunit of T. gondii and P. berghei BCKDH significantly impacted on intracellular growth and virulence of both parasites. Interestingly, disruption of the P. berghei E1a restricted parasite development to reticulocytes only and completely prevented maturation of oocysts during mosquito transmission. Overall this study highlights the importance of the molecular adaptation of BCKDH in this important class of pathogens