Therapeutic modulation of liver ischaemia reperfusion injury

Liver Ischaemia Reperfusion Injury (IRI) leads to production of reactive oxygen species and cytokines, which affects hepatocellular function following liver resection and transplantation. This thesis examines 2 hypotheses: 1) The role of intravenous glycine in amelioration of liver IRI in a in vivo animal model of partial lobar liver IRI. 2) Does prophylactically administered N-acetylcysteine prevent liver IRI in patients undergoing elective liver resection. Materials and Methods 1) A rabbit model of hepatic lobar IRI was used to evaluate glycine. 3 groups (n=6) Sham group (laparotomy alone), ischaemia reperfusion (I/R) group (1 hour ischaemia and 6 hours of reperfusion), and glycine I/R group (IV glycine 5 mg/kg prior to the I/R protocol) were used. Portal blood flow, bile flow and bile was analysed by H1NMR spectroscopy. Hepatic microcirculation, intracellular tissue oxygenation, serum TNFα, IL-8, ALT, AST were measured at 1, 2, 4 and 6 hours following reperfusion. 2) A randomised double blind clinical trial was conducted to assess the effect of NAC on liver IRI following liver resections. The main outcomes were: morbidity and mortality, ICAM-1 expression in liver tissue, liver function tests. Patients were randomised to receive NAC as IV infusion (NACG) or a placebo group (PG) which received 5% dextrose only. Immunohistochemistry for ICAM-1 was carried out on perioperative liver biopsies. Results 1) Glycine normalised the bile flow, reduced phosphatidylcholine shedding, lactate surge, and stimulated bile acid, pyruvate, glucose and acetoacetate release. Glycine improved portal blood flow, hepatic microcirculation by the 2nd hour, and hepatic intracellular tissue oxygenation by the 4th hour of reperfusion. Glycine ameliorated serum TNFα at 1, 2 and 4 hours and serum Il- 8, AST and ALT up to 6 hours post reperfusion as compared to the I/R alone group. 2) Of the 43 patients, 15 received NAC, 16 were randomised to the PG, 12 were excluded due to inoperable tumours. Serum ALT was reduced in NACG (p=0.001), while serum ALP was higher in the NACG (p=0.003). ICAM-1 expression was up-regulated in 6/16 patients in the PG and in 3/15 patients in NACG. ICAM-1 was down-regulated in 1/15 patients in the NACG and none in the PG, the difference was not significant. Conclusions 1) Glycine ameliorated liver IRI, improved bile flow and composition. 2) NAC ameliorated parenchymal liver injury and enhanced liver regeneration in patients undergoing elective liver resection

On the Distribution of Haloes, Galaxies and Mass

The stochasticity in the distribution of dark haloes in the cosmic density field is reflected in the distribution function $P_V(N_h|\delta_m)$ which gives the probability of finding $N_h$ haloes in a volume $V$ with mass density contrast $\delta_m$. We study the properties of this function using high-resolution $N$-body simulations, and find that $P_V(N_n|\delta_m)$ is significantly non-Poisson. The ratio between the variance and the mean goes from $\sim 1$ (Poisson) at $1+\delta_m\ll 1$ to $<1$ (sub-Poisson) at $1+\delta_m\sim 1$ to $>1$ (super-Poisson) at $1+\delta_m\gg 1$. The mean bias relation is found to be well described by halo bias models based on the Press-Schechter formalism. The sub-Poisson variance can be explained as a result of halo-exclusion while the super-Poisson variance at high $\delta_m$ may be explained as a result of halo clustering. A simple phenomenological model is proposed to describe the behavior of the variance as a function of $\delta_m$. Galaxy distribution in the cosmic density field predicted by semi-analytic models of galaxy formation shows similar stochastic behavior. We discuss the implications of the stochasticity in halo bias to the modelling of higher-order moments of dark haloes and of galaxies.Comment: 10 pages, 6 figures, Latex using MN2e style. Minor changes. Accepted for publication in MNRA

Lagrangian bias in the local bias model

It is often assumed that the halo-patch fluctuation field can be written as a Taylor series in the initial Lagrangian dark matter density fluctuation field. We show that if this Lagrangian bias is local, and the initial conditions are Gaussian, then the two-point cross-correlation between halos and mass should be linearly proportional to the mass-mass auto-correlation function. This statement is exact and valid on all scales; there are no higher order contributions, e.g., from terms proportional to products or convolutions of two-point functions, which one might have thought would appear upon truncating the Taylor series of the halo bias function. In addition, the auto-correlation function of locally biased tracers can be written as a Taylor series in the auto-correlation function of the mass; there are no terms involving, e.g., derivatives or convolutions. Moreover, although the leading order coefficient, the linear bias factor of the auto-correlation function is just the square of that for the cross-correlation, it is the same as that obtained from expanding the mean number of halos as a function of the local density only in the large-scale limit. In principle, these relations allow simple tests of whether or not halo bias is indeed local in Lagrangian space. We discuss why things are more complicated in practice. We also discuss our results in light of recent work on the renormalizability of halo bias, demonstrating that it is better to renormalize than not. We use the Lognormal model to illustrate many of our findings.Comment: 14 pages, published on JCA

The Mass Function of Dark Halos in Superclusters and Voids

A modification of the Press-Schechter theory allowing for presence of a background large-scale structure (LSS) - a supercluster or a void, is proposed. The LSS is accounted as the statistical constraints in form of linear functionals of the random overdensity field. The deviation of the background density within the LSS is interpreted in a pseudo-cosmological sense. Using the constraints formalism may help us to probe non-trivial spatial statistics of haloes, e.g. edge and shape effects on boundaries of the superclusters and voids. Parameters of the constraints are connected to features of the LSS: its mean overdensity, a spatial scale and a shape, and spatial momenta of higher orders. It is shown that presence of a non-virialized LSS can lead to an observable deviation of the mass function. This effect is exploited to build a procedure to recover parameters of the background perturbation from the observationally estimated mass function.Comment: 23 pages, 6 figures; to be appeared in Astronomy Reports, 2014, Vol. 58, No. 6, pp. 386-39

Study Of Phenothiazine On p53 Core Domain Mutant Y220C: Finding The Anti-tumor Activity Of Phenothiazine

The tumor suppressor protein p53 is a transcription factor that plays a key role in the prevention of cancer development. The p53 cancer mutation Y220C induces formation of a cavity on the protein&#x27;s surface that can accommodate stabilizing small molecules. We have attempted with the help of virtual screening and molecular docking approach using Lamarckian Genetic Algorithm to elucidate the extent of specificity of p53 cancer mutation Y220C towards different class of Phenothiazines (an anti-cancer agent). &#xd;&#xa;&#xd;&#xa;The 393 residue p53 tumor suppressor protein exists in a dynamic equilibrium to form homotetramers. Each chain comprises several functional domains. The N terminal part of the protein consists of the trans-activation domain (residues 1&#x2013;63) followed by a proline rich region (64&#x2013; 92). The central (core) domain (p53 core domain) is responsible for binding. The C terminal part of p53 contains the tetramerization domain (residues 326&#x2013;355) and the negative regulatory domain at the extreme C terminus (363&#x2013;393), which contains phosphorylation and acetylation sites and regulates the DNA binding activity of p53.&#xd;&#xa;&#xd;&#xa;The docking result of the study of 2,000 Phenothiazines demonstrated that the binding energies were in the range of -10.54 kcal/mol to -1.14 kcal/mol, with 8 molecules showing hydrogen bonds with the active site residues (Lys 164). All the selected 2000 inhibitors were selected on the basis of the structural specificity to the enzyme towards its substrate and inhibitors. Our research provides a blueprint for the design of more potent and specific drugs that rescue p53-Y220C

The unusual distribution of molecular gas and star formation in Arp 140

We investigate the atomic and molecular interstellar medium and star formation of NGC 275, the late-type spiral galaxy in Arp 140, which is interacting with NGC 274, an early-type system. The atomic gas (HI) observations reveal a tidal tail from NGC 275 which extends many optical radii beyond the interacting pair. The HI morphology implies a prograde encounter between the galaxy pair approximately 1.5 x 10**8 years ago. The Halpha emission from NGC 275 indicates clumpy irregular star-formation, clumpiness which is mirrored by the underlying mass distribution as traced by the Ks-band emission. The molecular gas distribution is striking in its anti-correlation with the {HII regions. Despite the evolved nature of NGC 275's interaction and its barred potential, neither the molecular gas nor the star formation are centrally concentrated. We suggest that this structure results from stochastic star formation leading to preferential consumption of the gas in certain regions of the galaxy. In contrast to the often assumed picture of interacting galaxies, NGC 275, which appears to be close to merger, does not display enhanced or centrally concentrated star formation. If the eventual merger is to lead to a significant burst of star formation it must be preceded by a significant conversion of atomic to molecular gas as at the current rate of star formation all the molecular gas will be exhausted by the time the merger is complete.Comment: 13 paper, accepted my Monthly Notices of the Royal Astronomical Societ

The Pairwise Peculiar Velocity Dispersion of Galaxies: Effects of the Infall

We study the reliability of the reconstruction method which uses a modelling of the redshift distortions of the two-point correlation function to estimate the pairwise peculiar velocity dispersion of galaxies. In particular, the dependence of this quantity on different models for the infall velocity is examined for the Las Campanas Redshift Survey. We make extensive use of numerical simulations and of mock catalogs derived from them to discuss the effect of a self-similar infall model, of zero infall, and of the real infall taken from the simulation. The implications for two recent discrepant determinations of the pairwise velocity dispersion for this survey are discussed.Comment: minor changes in the discussion; accepted for publication in ApJ; 8 pages with 2 figures include

The Stellar Mass Fundamental Plane: The virial relation and a very thin plane for slow-rotators

Early-type galaxies -- slow and fast rotating ellipticals (E-SRs and E-FRs) and S0s/lenticulars -- define a Fundamental Plane (FP) in the space of half-light radius $R_e$, enclosed surface brightness $I_e$ and velocity dispersion $\sigma_e$. Since $I_e$ and $\sigma_e$ are distance-independent measurements, the thickness of the FP is often expressed in terms of the accuracy with which $I_e$ and $\sigma_e$ can be used to estimate sizes $R_e$. We show that: 1) The thickness of the FP depends strongly on morphology. If the sample only includes E-SRs, then the observed scatter in $R_e$ is $\sim 16\%$, of which only $\sim 9\%$ is intrinsic. Removing galaxies with $M_*<10^{11}M_\odot$ further reduces the observed scatter to $\sim 13\%$ ($\sim 4\%$ intrinsic). The observed scatter increases to the $\sim 25\%$ usually quoted in the literature if E-FRs and S0s are added. If the FP is defined using the eigenvectors of the covariance matrix of the observables, then the E-SRs again define an exceptionally thin FP, with intrinsic scatter of only $5\%$ orthogonal to the plane. 2) The structure within the FP is most easily understood as arising from the fact that $I_e$ and $\sigma_e$ are nearly independent, whereas the $R_e-I_e$ and $R_e-\sigma_e$ correlations are nearly equal and opposite. 3) If the coefficients of the FP differ from those associated with the virial theorem the plane is said to be `tilted'. If we multiply $I_e$ by the global stellar mass-to-light ratio $M_*/L$ and we account for non-homology across the population by using S\'ersic photometry, then the resulting stellar mass FP is less tilted. Accounting self-consistently for $M_*/L$ gradients will change the tilt. The tilt we currently see suggests that the efficiency of turning baryons into stars increases and/or the dark matter fraction decreases as stellar surface brightness increases.Comment: 13 pages, 9 figures, 3 tables, accepted for publication in MNRA