A Theoretical and Empirical Investigation on the Operating Performance of UK Buyout Flotations

The UK has the largest and most mature buyout market in Europe. Regarding the buyout exit, Flotation has been one of the most favourable routes. This dissertation evaluates the post-issue operating performance of UK buyout companies by using a hand-collected dataset of 75 buyouts and 75 matched non-buyouts, which went public during the period between 2000 and 2007. In particular, the performance is considered by profitability, efficiency, sales and employment, from one year before Flotation to five years after Flotation. We find that although both buyouts and non-buyouts exhibit deterioration in profitability after Flotation, their post-issue efficiency, sales and employment all demonstrate improvements. Furthermore, after Flotation, buyouts outperform non-buyouts in profitability, but underperform in sales and employment. There is no significant difference in post-issue efficiency changes between the two groups. Compared with the performance before Flotation, buyouts perform more sustainable and stable than non-buyouts after the issue. We go on to examine the determinants of performance changes. The regression analyses report weak evidence on the positive impact of buyout structures, particularly in efficiency and sales. Even though VC backing plays a positive role, buyout longevity and firm age may negatively related with the performance. Moreover, gearing has a positive association with profitability, but a negative association with sales. In addition, firms coming from high technology industries or floating on AIM may have better performance, while firms floating during hot market periods may perform worse than those floating during normal periods

General Spatial Photonic Ising Machine Based on Interaction Matrix Eigendecomposition Method

The spatial photonic Ising machine has achieved remarkable advancements in solving combinatorial optimization problems. However, it still remains a huge challenge to flexibly mapping an arbitrary problem to Ising model. In this paper, we propose a general spatial photonic Ising machine based on interaction matrix eigendecomposition method. Arbitrary interaction matrix can be configured in the two-dimensional Fourier transformation based spatial photonic Ising model by using values generated by matrix eigendecomposition. The error in the structural representation of the Hamiltonian decreases substantially with the growing number of eigenvalues utilized to form the Ising machine. In combination with the optimization algorithm, as low as 65% of the eigenvalues is required by intensity modulation to guarantee the best probability of optimal solution for a 20-vertex graph Max-cut problem, and this probability decreases to below 20% for zero best chance. Our work provides a viable approach for spatial photonic Ising machines to solve arbitrary combinatorial optimization problems with the help of multi-dimensional optical property

Further development and validation of empirical scoring functions for structure-based binding affinity prediction

New empirical scoring functions have been developed to estimate the binding affinity of a given protein-ligand complex with known three-dimensional structure. These scoring functions include terms accounting for van der Waals interaction, hydrogen bonding, deformation penalty, and hydrophobic effect. A special feature is that three different algorithms have been implemented to calculate the hydrophobic effect term, which results in three parallel scoring functions. All three scoring functions are calibrated through multivariate regression analysis of a set of 200 protein-ligand complexes and they reproduce the binding free energies of the entire training set with standard deviations of 2.2 kcal/mol, 2.1 kcal/mol, and 2.0 kcal/mol, respectively. These three scoring functions are further combined into a consensus scoring function, X-CSCORE. When tested on an independent set of 30 protein-ligand complexes, X-CSCORE is able to predict their binding free energies with a standard deviation of 2.2 kcal/mol. The potential application of X-CSCORE to molecular docking is also investigated. Our results show that this consensus scoring function improves the docking accuracy considerably when compared to the conventional force field computation used for molecular docking.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42967/1/10822_2004_Article_405419.pd

Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts

Generation of induced cardiomyocytes (iCMs) directly from fibroblasts offers a great opportunity for cardiac disease modeling and cardiac regeneration. A major challenge of iCM generation is the low conversion rate. To address this issue, we attempted to identify small molecules that could potentiate the reprogramming ability towards cardiac fate by removing inhibitory roadblocks. Using mouse embryonic fibroblasts as the starting cell source, we first screened 47 cardiac development related epigenetic and transcription factors, and identified an unexpected role of H3K4 methyltransferase Mll1 and related factor Men1 in inhibiting iCM reprogramming. We then applied small molecules (MM408 and MI503) of Mll1 pathway inhibitors and observed an improved efficiency in converting embryonic fibroblasts and cardiac fibroblasts into functional cardiomyocyte-like cells. We further observed that these inhibitors directly suppressed the expression of Mll1 target gene Ebf1 involved in adipocyte differentiation. Consequently, Mll1 inhibition significantly decreased the formation of adipocytes during iCM induction. Therefore, Mll1 inhibitors likely increased iCM efficiency by suppressing alternative lineage gene expression. Our studies show that targeting Mll1 dependent H3K4 methyltransferase activity provides specificity in the process of cardiac reprogramming. These findings shed new light on the molecular mechanisms underlying cardiac conversion of fibroblasts and provide novel targets and small molecules to improve iCM reprogramming for clinical applications

Preclinical studies of Apogossypolone: a new nonpeptidic pan small-molecule inhibitor of Bcl-2, Bcl-X\u3csub\u3eL \u3c/sub\u3eand Mcl-1 proteins in Follicular Small Cleaved Cell Lymphoma model

Abstract Elevated expression of anti-apoptotic Bcl-2 family proteins have been linked to a poor survival rate of patients with Follicular Lymphoma (FL). This prompted us to evaluate a very potent non-peptidic Small-Molecule Inhibitor (SMI) targeting Bcl-2 family proteins, Apogossypolone (ApoG2) using follicular small cleaved cell lymphoma cell line (WSU-FSCCL) and cell isolated from lymphoma patients. ApoG2 inhibited the growth of WSU-FSCCL significantly with a 50% growth inhibition of cells (IC50) of 109 nM and decreased cell number of fresh lymphoma cells. ApoG2 activated caspases-9, -3, and -8, and the cleavage of Poly (ADP-ribose) polymerase (PARP) and Apoptosis Inducing Factor (AIF). In the WSU-FSCCL-SCID xenograft model, ApoG2 showed a significant anti-lymphoma effect, with %ILS of 84% in the intravenous and 63% in intraperitoneal treated mice. These studies suggest that ApoG2 can be an effective therapeutic agent against FL

Preclinical studies of Apogossypolone: a new nonpeptidic pan small-molecule inhibitor of Bcl-2, Bcl-XL and Mcl-1 proteins in Follicular Small Cleaved Cell Lymphoma model

Elevated expression of anti-apoptotic Bcl-2 family proteins have been linked to a poor survival rate of patients with Follicular Lymphoma (FL). This prompted us to evaluate a very potent non-peptidic Small-Molecule Inhibitor (SMI) targeting Bcl-2 family proteins, Apogossypolone (ApoG2) using follicular small cleaved cell lymphoma cell line (WSU-FSCCL) and cell isolated from lymphoma patients. ApoG2 inhibited the growth of WSU-FSCCL significantly with a 50% growth inhibition of cells (IC50) of 109 nM and decreased cell number of fresh lymphoma cells. ApoG2 activated caspases-9, -3, and -8, and the cleavage of Poly (ADP-ribose) polymerase (PARP) and Apoptosis Inducing Factor (AIF). In the WSU-FSCCL-SCID xenograft model, ApoG2 showed a significant anti-lymphoma effect, with %ILS of 84% in the intravenous and 63% in intraperitoneal treated mice. These studies suggest that ApoG2 can be an effective therapeutic agent against FL

Study on different potato continuous cropping ways on rhizosphere soil nutrients and enzyme activities

To address the problem of food security, China produced potatoes as a staple food in 2015.However, there are increasing problems with continuous cropping production methods, potato continuous cropping has been inevitable.So it is necessary to research under the different potato continuous cropping ways, potato rhizosphere soil nutrients and enzyme activities which can direct potato fertilizer and ease potato continuous cropping obstacle. A two-growing season investigation was carried out during the spring and autumn of 2014 and 2015 to determine the different ways of potato continuous cropping on the overall growth of potatoes, soil nutrients, and enzyme activities. During continuous cropping nitrogen (N) content of rhizosphere soil was reduced; available potassium (Kav) was significantly reduced(p≤5%), especially in spring and autumn continuous cropping; and total phosphorus (Ptot) was reduced during the growth stage. However, the total potassium (Ktot), available phosphorus(Pav), and organic carbon (Ctot) increased before they decreased. For rhizosphere soil enzyme activities, urease initially increased and then decreased, and was lower in continuous cropping than multiple continuous cropping; in spring of 2015, invertase was the highest with continuous cropping. Catalase and polyphenol oxidase decreased initially before increasing. Continuous cropping in spring and autumn consumed more nutrients, especially potassium (K) than in spring. Therefore, potatoes planted in both spring and autumn enhanced the problems of continuous cropping. However, multiple continuous cropping that eased rhizosphere soil nutrient absorption and effectively improves soil nutrients and enzyme activities could provide an effective method for managing the negative impacts associated with continuous cropping

An MDM2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals

<p>Abstract</p> <p>Background</p> <p>MI-319 is a synthetic small molecule designed to target the MDM2-P53 interaction. It is closely related to MDM2 antagonists MI-219 and Nutlin-3 in terms of the expected working mechanisms. The purpose of this study was to evaluate anti-lymphoma activity of MI-319 in WSU-FSCCL, a B-cell follicular lymphoma line. For comparison purpose, MI-319, MI-219 and Nutlin-3 were assessed side by side against FSCCL and three other B-cell hematological tumor cell lines in growth inhibition and gene expression profiling experiments.</p> <p>Results</p> <p>MI-319 was shown to bind to MDM2 protein with an affinity slightly higher than that of MI-219 and Nutlin-3. Nevertheless, cell growth inhibition and gene expression profiling experiments revealed that the three compounds have quite similar potency against the tumor cell lines tested in this study. <it>In vitro</it>, MI-319 exhibited the strongest anti-proliferation activity against FSCCL and four patient cells, which all have wild-type p53. Data obtained from Western blotting, cell cycle and apoptosis analysis experiments indicated that FSCCL exhibited strong cell cycle arrest and significant apoptotic cell death; cells with mutant p53 did not show significant apoptotic cell death with drug concentrations up to 10 μM, but displayed weaker and differential cell cycle responses. In our systemic mouse model for FSCCL, MI-319 was tolerated well by the animals, displayed effectiveness against FSCCL-lymphoma cells in blood, brain and bone marrow, and achieved significant therapeutic impact (p < 0.0001) by conferring the treatment group a > 28% (%ILS, 14.4 days) increase in median survival days.</p> <p>Conclusion</p> <p>Overall, MI-319 probably has an anti-lymphoma potency equal to that of MI-219 and Nutlin-3. It is a potent agent against FSCCL <it>in vitro </it>and <it>in vivo </it>and holds the promises to be developed further for the treatment of follicular lymphoma that retains wild-type p53.</p

Design of the Firstâ inâ Class, Highly Potent Irreversible Inhibitor Targeting the Meninâ MLL Proteinâ Protein Interaction

The structureâ based design of Mâ 525 as the firstâ inâ class, highly potent, irreversible smallâ molecule inhibitor of the meninâ MLL interaction is presented. Mâ 525 targets cellular menin protein at subâ nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLLâ regulated gene expression in MLL leukemia cells. Mâ 525 demonstrates high cellular specificity over nonâ MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and coâ crystal structure of Mâ 525 in complex with menin firmly establish its mode of action. A single administration of Mâ 525 effectively suppresses MLLâ regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize Mâ 525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.Irreversible inhibitor Mâ 525 targets the meninâ MLL interaction. It is demonstrated that irreversible inhibition of menin is a promising therapeutic strategy for the treatment of MLL leukemia and may have advantages over reversible inhibitors.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141532/1/anie201711828.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141532/2/anie201711828-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141532/3/anie201711828_am.pd

Design of the Firstâ inâ Class, Highly Potent Irreversible Inhibitor Targeting the Meninâ MLL Proteinâ Protein Interaction

The structureâ based design of Mâ 525 as the firstâ inâ class, highly potent, irreversible smallâ molecule inhibitor of the meninâ MLL interaction is presented. Mâ 525 targets cellular menin protein at subâ nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLLâ regulated gene expression in MLL leukemia cells. Mâ 525 demonstrates high cellular specificity over nonâ MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and coâ crystal structure of Mâ 525 in complex with menin firmly establish its mode of action. A single administration of Mâ 525 effectively suppresses MLLâ regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize Mâ 525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.Der irreversible Inhibitor Mâ 525 greift an der Meninâ MLLâ Wechselwirkung an. Die irreversible Inhibition von Menin erweist sich als vielversprechende Strategie für die Behandlung von MLLâ Leukämie, mit möglichen Vorteilen gegenüber dem Einsatz reversibler Inhibitoren.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141701/1/ange201711828_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141701/2/ange201711828.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141701/3/ange201711828-sup-0001-misc_information.pd