Testing and Review of Various Displacement Discontinuity Elements for LEFM Crack Problems

The numerical modeling of hydraulic fractures in unconventional reservoirs presents significant challenges for field applications. There remains a need for accurate models that field personnel can use, yet remains consistent to the underlying physics of the problem [1]. For numerical simulations, several authors have considered a number of issues: the coupling between fracture mechanics and fluid dynamics in the fracture [2], fracture interaction [3-5], proppant transport [6], and others [7-9]. However, the available literature within the oil and gas industry often ignores the importance of the crack tip in modeling applications developed for engineering design. The importance of accurate modeling of the stress induced near the crack tip is likely critical in complex geological reservoirs where multiple propagating crack tips are interacting with natural fractures. This study investigates the influence of various boundary element numerical techniques on the accuracy of the calculated stress intensity factor near the crack tip and on the fracture profile, in general. The work described here is a part of a long-term project in the development of more accurate and efficient numerical simulations for field engineering applications

Inhibitor binding mode and allosteric regulation of Na+-glucose symporters.

Sodium-dependent glucose transporters (SGLTs) exploit sodium gradients to transport sugars across the plasma membrane. Due to their role in renal sugar reabsorption, SGLTs are targets for the treatment of type 2 diabetes. Current therapeutics are phlorizin derivatives that contain a sugar moiety bound to an aromatic aglycon tail. Here, we develop structural models of human SGLT1/2 in complex with inhibitors by combining computational and functional studies. Inhibitors bind with the sugar moiety in the sugar pocket and the aglycon tail in the extracellular vestibule. The binding poses corroborate mutagenesis studies and suggest a partial closure of the outer gate upon binding. The models also reveal a putative Na+ binding site in hSGLT1 whose disruption reduces the transport stoichiometry to the value observed in hSGLT2 and increases inhibition by aglycon tails. Our work demonstrates that subtype selectivity arises from Na+-regulated outer gate closure and a variable region in extracellular loop EL5

Affinity of Talin-1 for the β3-Integrin Cytosolic Domain is Modulated by its Phospholipid Bilayer Environment

Binding of the talin-1 FERM (4.1/ezrin/radixin/moesin) domain to the β3 cytosolic tail causes activation of the integrin αIIbβ3. The FERM domain also binds to acidic phospholipids. Although much is known about the interaction of talin-1 with integrins and lipids, the relative contribution of each interaction to integrin regulation and possible synergy between them remain to be clarified. Here, we examined the thermodynamic interplay between FERM domain binding to phospholipid bilayers and to its binding sites in the β3 tail. We found that although both the F0F1 and F2F3 subdomains of the talin-1 FERM domain bind acidic bilayers, the full-length FERM domain binds with an affinity similar to F2F3, indicating that F0F1 contributes little to the overall interaction. When free in solution, the β3 tail has weak affinity for the FERM domain. However, appending the tail to acidic phospholipids increased its affinity for the FERM domain by three orders of magnitude. Nonetheless, the affinity of the FERM for the appended tail was similar to its affinity for binding to bilayers alone. Thus, talin-1 binding to the β3 tail is a ternary interaction dominated by a favorable surface interaction with phospholipid bilayers and set by lipid composition. Nonetheless, interactions between the FERM domain, the β3 tail, and lipid bilayers are not optimized for a high-affinity synergistic interaction, even at the membrane surface. Instead, the interactions appear to be tuned in such a way that the equilibrium between inactive and active integrin conformations can be readily regulated

De novo design of drug-binding proteins with predictable binding energy and specificity

The de novo design of small molecule-binding proteins has seen exciting recent progress; however, high-affinity binding and tunable specificity typically require laborious screening and optimization after computational design. We developed a computational procedure to design a protein that recognizes a common pharmacophore in a series of poly(ADP-ribose) polymerase-1 inhibitors. One of three designed proteins bound different inhibitors with affinities ranging from <5 nM to low micromolar. X-ray crystal structures confirmed the accuracy of the designed protein-drug interactions. Molecular dynamics simulations informed the role of water in binding. Binding free energy calculations performed directly on the designed models were in excellent agreement with the experimentally measured affinities. We conclude that de novo design of high-affinity small molecule-binding proteins with tuned interaction energies is feasible entirely from computation

Platelet Factor 4 Activity against P. falciparum and Its Translation to Nonpeptidic Mimics as Antimalarials

SummaryPlasmodium falciparum pathogenesis is affected by various cell types in the blood, including platelets, which can kill intraerythrocytic malaria parasites. Platelets could mediate these antimalarial effects through human defense peptides (HDPs), which exert antimicrobial effects by permeabilizing membranes. Therefore, we screened a panel of HDPs and determined that human platelet factor 4 (hPF4) kills malaria parasites inside erythrocytes by selectively lysing the parasite digestive vacuole (DV). PF4 rapidly accumulates only within infected erythrocytes and is required for parasite killing in infected erythrocyte-platelet cocultures. To exploit this antimalarial mechanism, we tested a library of small, nonpeptidic mimics of HDPs (smHDPs) and identified compounds that kill P. falciparum by rapidly lysing the parasite DV while sparing the erythrocyte plasma membrane. Lead smHDPs also reduced parasitemia in a murine malaria model. Thus, identifying host molecules that control parasite growth can further the development of related molecules with therapeutic potential

Synthetic approaches to structurally complex molecules by photo- and non-photochemical methods

This dissertation details the development and investigation of three independent research projects. These aims show a progressive evolution from ground state chemistry to excited state chemistry and finally supramolecular chemistry in construction and design of structurally complex molecules. The first section shows the synthetic approaches toward a potent microtubule stabilizing natural product, elutherobin, utilizing tandem Diels-Alder reaction/Grob-type fragmentation reaction as key steps. During the course of these studies, large scale preparation of bis-diene and successful activation of the secondary alcohol were achieved. Due to the difficulty in SmI 2 fragmentation and the capricious nature of the tandem Diels-Alder reaction, our original route did not prove amenable to an efficient synthesis of eleutherobin. A revised route using a β-elimination pathway was subsequently investigated. The following section has its foundation based upon a serendipitous discovery in the Winkler group. In an effort to explore the scope of the photoreaction, we found a novel desulfurative photocycloaddition from investigation of enone-benzothiazoline photochemistry and its mechanistic rationale was studied to suggest enecarbamate could be an intermediate that was generated from its episulfide precursor. The formation of N,S-acetal photoproduct could be also utilized in the synthesis of another natural product, discorhabdin A. The concluding section deals with a synthetic design of chiral molecular tweezers based upon the natural alkaloid calycanthine. A number of synthetic strategies on the extended dimer of calycanthine were investigated and monobromocalycanthine was successfully prepared from a semi-synthetic approach. The future directions of this project based on dimethylcalycanthine are presented

Mechanical behavior of concentric and eccentric casing, cement, and formation using analytical and numerical methods

textThe first main goal of this research is to develop comprehensive analytical and numerical models for the stress distribution around an inclined cased wellbore by considering all wellbore processes and to amend erroneous models of most previous work. The second main goal is to apply the developed models to explain near wellbore phenomena such as cement failure and sand production. To achieve these goals, this work checked the eligibility of using simple elastic approaches for the system by using a poroelastic undrained condition and a steady state condition for stresses induced by wellbore temperature variation. It utilized the generalized plane strain to compensate for the limitation of the plane strain which most previous work had used. In addition, this research developed comprehensive models to improve previous work by using superposing principles. For applying the developed models to cement failure, Mogi-Coulomb criterion for shear failure instead of Mohr-Coulomb and Drucker-Prager criteria was used to properly consider the intermediate stress. Additionally, ABAQUSr was utilized for numerical models with the "model change" option to simulate and combine all individual wellbore processes while MATLABr was used for analytical models. For predicting sand production, fully coupled poroelastic solutions for an inclined open wellbore were modified to obtain the stress distribution around a perforation tunnel after perforating. Then, modified Lade failure criterion was used to calculate the critical drawdown when sand production occurs, that is, when the perforation tunnel starts failure. This research obtained the following results. For developing models, the analytical models improved the previous research. However, the numerical results under a vertical tectonic stress showed discrepancies because of the difference between the generalized plane strain and numerical models. For cement failure, Young's modulus of cement, wellbore pressure and wellbore temperature variation could affect shear failure more significantly than the other factors. The numerical results showed closer to the failure envelopes than the analytical results. For predicting sand production, well completion affected sand production near wellbore and the critical drawdown converged to asymptotic values. In addition, perforating along the minimum horizontal stress direction was most preferable in a vertical cased wellbore under a normal stress regime.Petroleum and Geosystems Engineerin