Robustness and epistasis in mutation-selection models

We investigate the fitness advantage associated with the robustness of a phenotype against deleterious mutations using deterministic mutation-selection models of quasispecies type equipped with a mesa shaped fitness landscape. We obtain analytic results for the robustness effect which become exact in the limit of infinite sequence length. Thereby, we are able to clarify a seeming contradiction between recent rigorous work and an earlier heuristic treatment based on a mapping to a Schr\"odinger equation. We exploit the quantum mechanical analogy to calculate a correction term for finite sequence lengths and verify our analytic results by numerical studies. In addition, we investigate the occurrence of an error threshold for a general class of epistatic landscape and show that diminishing epistasis is a necessary but not sufficient condition for error threshold behavior.Comment: 20 pages, 14 figure

Human T Cell and Antibody-Mediated Responses to the Mycobacterium tuberculosis Recombinant 85A, 85B, and ESAT-6 Antigens

Tuberculosis remains a major health problem throughout the world causing large number of deaths. Effective disease control and eradication programs require the identification of major antigens recognized by the protective responses against M. tuberculosis. In this study, we have investigated humoral and cellular immune responses to M. tuberculosis-specific Ag85A, Ag85B, and ESAT-6 antigens in Brazilian patients with pulmonary (P, n = 13) or extrapulmonary (EP, n = 12) tuberculosis, patients undergoing chemotherapy (PT, n = 23), and noninfected healthy individuals (NI, n = 7). Compared to NI, we observed increased levels of IgG1 responses to Ag85B and ESAT-6 in P and PT groups. Regarding cellular immunity, Ag85A and ESAT-6 were able to discriminate P, PT, and EP patients from healthy individuals by IFN-γ production and P and PT groups from EP individuals by production of TNF-α. In summary, these findings demonstrate the ability of Ag85A, Ag85B, and ESAT-6 to differentiate TB patients from controls by IgG1, IFN-γ and TNF-α production

Carcinoid heart disease: Two clinical cases and a review

We present two cases of metastatic carcinoid tumours, complicated by carcinoid syndrome and by cardiac valve involvement, a well-known, but infrequent, complication. Carcinoid tumours are generally more indolent than other cancers and may have a long asymptomatic phase. The symptoms of carcinoid syndrome generally manifest only once metastases to the liver have occurred. Cardiac involvement occurs in up to 50% of patients, and heralds a poor prognosis. However, a multidisciplinary team approach has improved the prognosis and quality of life for patients with carcinoid heart disease. Therapy includes somatostatin analogues and treatment for heart failure, removal of primary or metastatic tumour deposits, valve replacement in the presence of valvular involvement, and radioisotopes therapy

The Cdc6p nucleotide-binding motif is required for loading mcm proteins onto chromatin

Cdc6p has an essential function in the mechanism and regulation of the initiation of DNA replication. Budding yeast Cdc6p binds to chromatin near autonomously replicating sequence elements in late M to early G1 phase through an interaction with Origin Recognition Complex or another origin-associated factor. It then facilitates the subsequent loading of the Mcm family of proteins near autonomously replicating sequence elements by an unknown mechanism. All Cdc6p homologues contain a bipartite Walker ATP-binding motif that suggests that ATP binding or hydrolysis may regulate Cdc6p activity. To determine whether these motifs are important for Cdc6p activity, mutations were made in conserved residues of the Walker A and B motifs. Substitution of lysine 114 to alanine (K114A) in the Walker A motif results in a temperature-sensitive phenotype in yeast and slower progression into S phase at the permissive temperature. A K114E mutation is lethal. The Cdc6(K114E) protein binds to chromatin but fails to promote loading of the Mcm proteins, suggesting that ATP binding is essential for this activity. The mutant arrests with a G1 DNA content but retains the ability to restrain mitosis in the absence of DNA replication, unlike depletion of Cdc6p. In contrast, Cdc6p containing a double alanine mutation in the Walker B motif, DE(223, 224)AA, is functional, and the mutant exhibits an apparently normal S phase. These results suggest that Cdc6p nucleotide binding is important for establishing the prereplicative complex at origins of DNA replication and that the amino terminus of Cdc6p is required for blocking entry into mitosis

An n-of-one RCT for intravenous immunoglobulin G for inflammation in hereditary neuropathy with liability to pressure palsy (HNPP).

Paroxysmal Cerebral Disorder

Off-line production of intense 7,10Be+^{7,10}Be^{+} beams

$^7$Be and $^{10}$Be were produced by 590~MeV proton bombardment of a graphite target at PSI. Parts of this graphite target were transferred into an ISOLDE target and ion source unit and ionized with the ISOLDE resonance ionization laser ion source (RILIS). Thus intense radioactive ion beams of 300~nA of $^{7,10}$Be$^+$ were produced off-line

Evolutionary dynamics of the most populated genotype on rugged fitness landscapes

We consider an asexual population evolving on rugged fitness landscapes which are defined on the multi-dimensional genotypic space and have many local optima. We track the most populated genotype as it changes when the population jumps from a fitness peak to a better one during the process of adaptation. This is done using the dynamics of the shell model which is a simplified version of the quasispecies model for infinite populations and standard Wright-Fisher dynamics for large finite populations. We show that the population fraction of a genotype obtained within the quasispecies model and the shell model match for fit genotypes and at short times, but the dynamics of the two models are identical for questions related to the most populated genotype. We calculate exactly several properties of the jumps in infinite populations some of which were obtained numerically in previous works. We also present our preliminary simulation results for finite populations. In particular, we measure the jump distribution in time and find that it decays as $t^{-2}$ as in the quasispecies problem.Comment: Minor changes. To appear in Phys Rev

Differential cross section for electron impact excitation of metastable helium measured by the atomic time-of-flight method

The authors have measured the differential cross section for the inelastic process He(11S0)+e- to He(23S1)+e- just above threshold by bombarding a beam of helium atoms with electrons from a pulsed electron gun and measuring the times of flight of the excited metastable atoms to a distant detector. Since each time of flight corresponds to a definite value of the electron scattering angle, the angular distribution of electrons scattered over the entire range 0-180 degrees is deduced from the data.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48848/2/jbv10i2pL43.pd

Magnetically Controlled Accretion Flows onto Young Stellar Objects

(abridged) Accretion from disks onto young stars is thought to follow magnetic field lines from the inner disk edge to the stellar surface. The accretion flow thus depends on the geometry of the magnetic field. This paper extends previous work by constructing a collection of orthogonal coordinate systems, including the corresponding differential operators, where one coordinate traces the magnetic field lines. This formalism allows for an (essentially) analytic description of the geometry and the conditions required for the flow to pass through sonic points. Using this approach, we revisit the problem of magnetically controlled accretion flow in a dipole geometry, and then generalize the treatment to consider magnetic fields with multiple components, including dipole, octupole, and split monopole contributions. This approach can be generalized further to consider more complex magnetic field configurations. Observations indicate that accreting young stars have substantial dipole and octupole components, and that accretion flow is transonic. If the effective equation of state for the fluid is too stiff, the flow cannot pass smoothly through the sonic points in steady state. For a multipole field of order \ell, we derive a constraint on the polytropic index, n>\ell+3/2, required for steady transonic flow to reach free-fall velocities. For octupole fields, inferred on surfaces of T Tauri stars, n>9/2, so that the flow must be close to isothermal. The inclusion of octupole field components produces higher densities at the stellar surface and smaller hot spots, which occur at higher latitudes; the magnetic truncation radius is also modified. This contribution thus increases our understanding of magnetically controlled accretion for young stellar objects and can be applied to a variety of additional astrophysical problems.Comment: 50 pages, 8 figures, accepted to Ap

In the absence of ATPase activity, pre-RC formation is blocked prior to MCM2-7 hexamer dimerization

The origin recognition complex (ORC) of Saccharomyces cerevisiae binds origin DNA and cooperates with Cdc6 and Cdt1 to load the replicative helicase MCM2–7 onto DNA. Helicase loading involves two MCM2–7 hexamers that assemble into a double hexamer around double-stranded DNA. This reaction requires ORC and Cdc6 ATPase activity, but it is unknown how these proteins control MCM2–7 double hexamer formation. We demonstrate that mutations in Cdc6 sensor-2 and Walker A motifs, which are predicted to affect ATP binding, influence the ORC–Cdc6 interaction and MCM2–7 recruitment. In contrast, a Cdc6 sensor-1 mutant affects MCM2–7 loading and Cdt1 release, similar as a Cdc6 Walker B ATPase mutant. Moreover, we show that Orc1 ATP hydrolysis is not involved in helicase loading or in releasing ORC from loaded MCM2–7. To determine whether Cdc6 regulates MCM2–7 double hexamer formation, we analysed complex assembly. We discovered that inhibition of Cdc6 ATPase restricts MCM2–7 association with origin DNA to a single hexamer, while active Cdc6 ATPase promotes recruitment of two MCM2–7 hexamer to origin DNA. Our findings illustrate how conserved Cdc6 AAA+ motifs modulate MCM2–7 recruitment, show that ATPase activity is required for MCM2–7 hexamer dimerization and demonstrate that MCM2–7 hexamers are recruited to origins in a consecutive process