Estimating novel potential drug targets of Plasmodium falciparum by analysing the metabolic network of knock-out strains in silico

Malaria is one of the world’s most common and serious diseases causing death of about 3 million people each year. Its most severe occurrence is caused by the protozoan Plasmodium falciparum. Biomedical research could enable treating the disease by effectively and specifically targeting essential enzymes of this parasite. However, the parasite has developed resistance to existing drugsmaking it indispensable to discover new drugs. We have established a simple computational tool which analyses the topology of the metabolic network of P. falciparum to identify essential enzymes as possible drug targets.Weinvestigated the essentiality of a reaction in the metabolic network by deleting (knocking-out) such a reaction in silico. The algorithmselected neighbouring compounds of the investigated reaction that had to be produced by alternative biochemical pathways. Using breadth first searches, we tested qualitatively if these products could be generated by reactions that serve as potential deviations of the metabolic flux. With this we identified 70 essential reactions. Our results were compared with a comprehensive list of 38 targets of approved malaria drugs. When combining our approach with an in silico analysis performed recently [Yeh, I., Hanekamp, T., Tsoka, S., Karp, P.D., Altman, R.B., 2004. Computational analysis of Plasmodium falciparum metabolism: organizing genomic information to facilitate drug discovery. Genome Res. 14, 917–924] we could improve the precision of the prediction results. Finally we present a refined list of 22 new potential candidate targets for P. falciparum, half of which have reasonable evidence to be valid targets against micro-organisms and cancer

Program on stimulating operational private sector use of Earth observation satellite data

There are no author-identified significant results in this report

Simplified Triceps Surae Muscle Volume Assessment in Older Adults

Triceps surae (TS) muscle volume can be estimated in young adults by only considering the maximal anatomical cross-sectional area (ACSAmax) and the length of the muscle due to the presence of a constant muscle-specific shape factor. This study aimed to investigate if this simplified muscle volume assessment is also applicable in older adults or if muscle-specific shape changes with aging. MRI sequences were taken from the dominant leg of 21 older female adults. The boundaries of all three TS muscles (SOL, soleus; GM, gastrocnemius medialis; GL, gastrocnemius lateralis) were manually outlined in transverse image sequences, and muscle volume for each muscle was calculated as the integral of the obtained cross-sectional areas of the contours along the whole length of the muscle (measured volume) and, in addition, by using the average muscle-specific shape factors of each muscle obtained from the ratio of the measured volume and the product of ACSAmax and the muscle length (estimated volume). There were no differences in the measured and estimated muscle volumes (SOL: 357.7 ± 61.8 vs. 358.8 ± 65.3 cm3; GM: 179.5 ± 32.8 vs. 179.8 ± 33.3 cm3; GL: 90.2 ± 15.9 vs. 90.4 ± 14.8 cm3). However, when using the reported shape factors of younger adults instead, we found a significant (p < 0.05) overestimation of muscle volume for SOL and GM with average RMS differences of 6.1 and 7.6%, respectively. These results indicate that corrections of muscle-specific shape factors are needed when using the previously proposed simplified muscle volume assessment as aging may not only be accompanied with muscle atrophy but also changes in the shape of skeletal muscle

Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival

Recent evidence suggests CML stem cells are insensitive to kinase inhibitors and responsible for minimal residual disease in treated patients. We investigated whether CML stem cells, in a transgenic mouse model of CML-like disease or derived from patients, are dependent on Bcr-Abl. In the transgenic model, following re-transplantation, donor-derived CML stem cells in which Bcr-Abl expression had been induced and subsequently shut off, were able to persist in vivo and re-initiate leukemia in secondary recipients upon Bcr-Abl re-expression. Bcr-Abl knockdown in human CD34+ CML cells cultured for 12 days in physiological growth factors achieved partial inhibition of Bcr-Abl and downstream targets p-CrkL and p-STAT5, inhibition of proliferation and colony forming cells, but no reduction of input cells. The addition of dasatinib further inhibited p-CrkL and p-STAT5, yet only reduced input cells by 50%. Complete growth factor withdrawal plus dasatinib further reduced input cells to 10%, however the surviving fraction was enriched for primitive leukemic cells capable of growth in long-term culture initiating cell assay and expansion upon removal of dasatinib and addition of growth factors. Together these data suggest that CML stem cell survival is Bcr-Abl kinase independent and suggest curative approaches in CML must focus on kinase-independent mechanisms of resistance

Thermal Re-emission Model

Starting from a continuum description, we study the non-equilibrium roughening of a thermal re-emission model for etching in one and two spatial dimensions. Using standard analytical techniques, we map our problem to a generalized version of an earlier non-local KPZ (Kardar-Parisi-Zhang) model. In 2+1 dimensions, the values of the roughness and the dynamic exponents calculated from our theory go like $\alpha \approx z \approx 1$ and in 1+1 dimensions, the exponents resemble the KPZ values for low vapor pressure, supporting experimental results. Interestingly, Galilean invariance is maintained althrough.Comment: 4 pages, minor textual corrections and typos, accepted in Physical Review B (rapid

Infrared magneto-optical properties of (III,Mn)V ferromagetic semiconductors

We present a theoretical study of the infrared magneto-optical properties of ferromagnetic (III,Mn)V semiconductors. Our analysis combines the kinetic exchange model for (III,Mn)V ferromagnetism with Kubo linear response theory and Born approximation estimates for the effect of disorder on the valence band quasiparticles. We predict a prominent feature in the ac-Hall conductivity at a frequency that varies over the range from 200 to 400 meV, depending on Mn and carrier densities, and is associated with transitions between heavy-hole and light-hole bands. In its zero frequency limit, our Hall conductivity reduces to the $\vec k$-space Berry's phase value predicted by a recent theory of the anomalous Hall effect that is able to account quantitatively for experiment. We compute theoretical estimates for magnetic circular dichroism, Faraday rotation, and Kerr effect parameters as a function of Mn concentration and free carrier density. The mid-infrared response feature is present in each of these magneto-optical effects.Comment: 11 pages, 5 figure

INDEPENDENT DISCOVERIES IN GRAPH THEORY *

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72829/1/j.1749-6632.1979.tb17761.x.pd

Topological semimetal in a fermionic optical lattice

Optical lattices play a versatile role in advancing our understanding of correlated quantum matter. The recent implementation of orbital degrees of freedom in chequerboard and hexagonal optical lattices opens up a new thrust towards discovering novel quantum states of matter, which have no prior analogs in solid state electronic materials. Here, we demonstrate that an exotic topological semimetal emerges as a parity-protected gapless state in the orbital bands of a two-dimensional fermionic optical lattice. The new quantum state is characterized by a parabolic band-degeneracy point with Berry flux $2\pi$, in sharp contrast to the $\pi$ flux of Dirac points as in graphene. We prove that the appearance of this topological liquid is universal for all lattices with D$_4$ point group symmetry as long as orbitals with opposite parities hybridize strongly with each other and the band degeneracy is protected by odd parity. Turning on inter-particle repulsive interactions, the system undergoes a phase transition to a topological insulator whose experimental signature includes chiral gapless domain-wall modes, reminiscent of quantum Hall edge states.Comment: 6 pages, 3 figures and Supplementary Informatio

Improved bone defect healing by a superagonistic GDF5 variant derived from a patient with multiple synostoses syndrome

Multiple synostoses syndrome 2 (SYNS2) is a rare genetic disease characterized by multiple fusions of the joints of the extremities, like phalangeal joints, carpal and tarsal joints or the knee and elbows. SYNS2 is caused by point mutations in the Growth and Differentiation Factor 5 (GDF5), which plays an essential role during skeletal development and regeneration. We selected one of the SYNS2-causing GDF5 mutations, p.N445T, which is known to destabilize the interaction with the Bone Morphogenetic Protein (BMP) antagonist NOGGIN (NOG), in order to generate the superagonistic GDF5 variant GDF5(N445T). In this study, we tested its capacity to support regeneration in a rat critical-sized defect model in vivo. MicroCT and histological analyses indicate that GDF5(N445T)-treated defects show faster and more efficient healing compared to GDF5 wild type (GDF5(wt))-treated defects. Microarray-based gene expression and quantitative PCR analyses from callus tissue point to a specific acceleration of the early phases of bone healing, comprising the inflammation and chondrogenesis phase. These results support the concept that disease-deduced growth factor variants are promising lead structures for novel therapeutics with improved clinical activities

Excited states of linear polyenes

We present density matrix renormalisation group calculations of the Pariser- Parr-Pople-Peierls model of linear polyenes within the adiabatic approximation. We calculate the vertical and relaxed transition energies, and relaxed geometries for various excitations on long chains. The triplet (3Bu+) and even- parity singlet (2Ag+) states have a 2-soliton and 4-soliton form, respectively, both with large relaxation energies. The dipole-allowed (1Bu-) state forms an exciton-polaron and has a very small relaxation energy. The relaxed energy of the 2Ag+ state lies below that of the 1Bu- state. We observe an attraction between the soliton-antisoliton pairs in the 2Ag+ state. The calculated excitation energies agree well with the observed values for polyene oligomers; the agreement with polyacetylene thin films is less good, and we comment on the possible sources of the discrepencies. The photoinduced absorption is interpreted. The spin-spin correlation function shows that the unpaired spins coincide with the geometrical soliton positions. We study the roles of electron-electron interactions and electron-lattice coupling in determining the excitation energies and soliton structures. The electronic interactions play the key role in determining the ground state dimerisation and the excited state transition energies.Comment: LaTeX, 15 pages, 9 figure