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Indiana University – Purdue University Indianapolis is the premier urban campus of Indiana University and Purdue University in Indianapolis, Indiana, United States. IUPUI offers undergraduate, graduate and professional degrees from both universities. Wikipedia.

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Kim H.Y.,Indiana University – Purdue University Indianapolis | Walsh P.J.,University of Pennsylvania
Accounts of Chemical Research | Year: 2012

Cyclopropanes occur in a diverse array of natural products, including pheromones, steroids, terpenes, fatty acid metabolites, and amino acids, and compounds that contain cyclopropanes exhibit interesting and important pharmacological properties. These valuable synthetic intermediates can be functionalized, or their rings can be opened, and the synthetic utility and unique biological activity of cyclopropanes have inspired many investigations into their preparation. One of the most powerful methods to generate cyclopropanes is the Simmons-Smith cyclopropanation. Since the original studies in the late 1950s reported that IZnCH2I could transform alkenes into cyclopropanes, researchers have introduced various modifications of the original procedure. Significantly, Furukawa demonstrated that diethylzinc and CH 2I2 react to generate carbenoids, and Shi described more reactive zinc carbenoids that contain electron-withdrawing groups on zinc (XZnCHI2). Despite these advances, the development of catalytic asymmetric Simmons-Smith reactions remains challenging. Although researchers have achieved catalytic asymmetric cyclopropanation of allylic alcohols, these reactions have had limited success. One attractive approach to the synthesis of cyclopropanes involves tandem reactions, where researchers carry out sequential synthetic transformations without the isolation or purification of intermediates. Such a synthetic strategy minimizes difficulties in the handling and purification of reactive intermediates and maximizes yields and the generation of molecular complexity.This Account summarizes our recent effort in the one-pot enantio- and diastereoselective synthesis of cyclopropyl alcohols. In one approach, an asymmetric alkyl addition to α,β-unsaturated aldehydes or asymmetric vinylation of aliphatic or aromatic aldehydes generates allylic zinc alkoxide intermediates. Directed diastereoselective cyclopropanation of the resulting alkoxide intermediates using in situ generated zinc carbenoids provides cyclopropyl or halocyclopropyl alcohols with high enantio-, diastereo-, and chemoselectivity. Other strategies employ bimetallic reagents such as 1-alkenyl-1,1-heterobimetallics or CH2(ZnI) 2 and provide access to di- and trisubstituted cyclopropyl alcohols. These methods enable facile access to skeletally diverse chiral cyclopropyl alcohols in high yields and stereoselectivities without the isolation or purification of the intermediates. © 2012 American Chemical Society.

Presse S.,Indiana University – Purdue University Indianapolis | Ghosh K.,University of Denver | Lee J.,Soongsil University | Dill K.A.,State University of New York at Stony Brook
Reviews of Modern Physics | Year: 2013

The variational principles called maximum entropy (MaxEnt) and maximum caliber (MaxCal) are reviewed. MaxEnt originated in the statistical physics of Boltzmann and Gibbs, as a theoretical tool for predicting the equilibrium states of thermal systems. Later, entropy maximization was also applied to matters of information, signal transmission, and image reconstruction. Recently, since the work of Shore and Johnson, MaxEnt has been regarded as a principle that is broader than either physics or information alone. MaxEnt is a procedure that ensures that inferences drawn from stochastic data satisfy basic self-consistency requirements. The different historical justifications for the entropy S=-Σipilogâ¡pi and its corresponding variational principles are reviewed. As an illustration of the broadening purview of maximum entropy principles, maximum caliber, which is path entropy maximization applied to the trajectories of dynamical systems, is also reviewed. Examples are given in which maximum caliber is used to interpret dynamical fluctuations in biology and on the nanoscale, in single-molecule and few-particle systems such as molecular motors, chemical reactions, biological feedback circuits, and diffusion in microfluidics devices. © 2013 American Physical Society.

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 249.43K | Year: 2015

DESCRIPTION provided by applicant Development of novel lung cancer therapeutics targeting the DNA damage response Abstract Lung tissue is constantly exposed to a wide variety of inhaled chemical agents While the majority of these maybe innocuous those that damage DNA have severe consequences Thus the DNA damage response DDR and DNA repair in these tissues is extremely important The vast majorities of lung cancers are diagnosed in older individuals and can be attributed to complications from tobacco smoke exposure where it has been estimated that one mutation is generated for every cigarettes smoked While we have made significant strides in treatment options for non smoking lung cancer patients with identifiable andquot driverandquot mutations there have been relatively few advances in treatment of smoking induced lung cancers The research in this phase I STTR application exploits two important novel findings The first is data we recently obtained demonstrating that lung cancer patients treated with adjuvant cisplatin chemotherapy after surgery with high XPA xeroderma pigmentosum group A expression correlates with a decrease in overall survival This correlation is unique to XPA and not observed with other DNA repair genes consistent with XPA being the limiting factor in nucleotide excision repair NER These preliminary data serves as the rationale for targeting XPA for adjuvant combination therapy in this patient population The second advance driving this research is our recent development of novel XPA inhibitors XPA inhibitors We originally identified XPA inhibitors with modest activity IC andapos s of M an have recently developed derivatives with IC andapos s in the nM range In a single aim we will exploit our recently discovered structure activity relationships SAR to complete lead optimization to maximize bioavailability potency and specificity of XPA inhibitors We then will interrogate the i vivo effects including PK PD toxicity and efficacy Completion of these studies will provide essential information for IND enabling studies towards the development of a novel therapeutic treatment for smoking induced lung cancer PUBLIC HEALTH RELEVANCE The development of novel cancer therapeutics is directly relevant to human health

Malkova A.,Indiana University – Purdue University Indianapolis | Ira G.,Baylor College of Medicine
Current Opinion in Genetics and Development | Year: 2013

Break-induced replication (BIR) is the pathway of homologous recombination (HR) conserved from phages to eukaryotes that serves to repair DNA breaks that have only one end. BIR contributes to the repair of broken replication forks and allows telomere lengthening in the absence of telomerase. Nonallelic BIR may lead to translocations and other chromosomal rearrangements. In addition, BIR initiated at sites of microhomology can generate copy number variations (CNVs) and complex chromosomal changes. The level of mutagenesis associated with DNA synthesis in BIR is significantly higher than during normal replication. These features make BIR a likely pathway to promote bursts of genetic changes that fuel cancer progression and evolution. © 2013 Elsevier Ltd.

Joglekar Y.N.,Indiana University – Purdue University Indianapolis
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2011

By investigating a parity- and time-reversal- (PT-) symmetric, N-site lattice with impurities ±iγ and hopping amplitudes t 0(tb) for regions outside (between) the impurity locations, we probe the interimpurity-distance dependence of the critical impurity strength and the origin of maximal PT-symmetry breaking that occurs when the impurities are nearest neighbors. Through a simple and exact derivation, we prove that the critical impurity strength is equal to the hopping amplitude between the impurities, γc=tb, and the simultaneous emergence of N complex eigenvalues is a robust feature of any PT-symmetric hopping profile. Our results show that the threshold strength γc can be widely tuned by a small change in the global profile of the lattice and thus have experimental implications. © 2011 American Physical Society.

Wallace J.M.,Indiana University – Purdue University Indianapolis
Bone | Year: 2012

Scanning probe microscopy (SPM) has been in use for 30. years, and the form of SPM known as atomic force microscopy (AFM) has been around for 25 of those years. AFM has been used to produce high resolution images of a variety of samples ranging from DNA to carbon nanotubes. Type I collagen and many collagen-based tissues (including dentin, tendon, cartilage, skin, fascia, vocal cords, and cornea) have been studied with AFM, but comparatively few studies of bone have been undertaken. The purpose of this review is to introduce the general principles of AFM operation, demonstrate what AFM has been used for in bone research, and discuss the new directions that this technique can take the study of bone at the nanoscale. © 2011 Elsevier Inc.

Filippelli G.M.,Indiana University – Purdue University Indianapolis
Chemosphere | Year: 2011

The role that phosphorite formation, the ultimate source rock for fertilizer phosphate reserves, plays in the marine phosphorus (P) cycle has long been debated. A shift has occurred from early models that evoked strikingly different oceanic P cycling during times of widespread phosphorite deposition to current thinking that phosphorite deposits may be lucky survivors of a series of inter-related tectonic, geochemical, sedimentological, and oceanic conditions. This paradigm shift has been facilitated by an awareness of the widespread nature of phosphogenesis-the formation of authigenic P-bearing minerals in marine sediments that contributes to phosphorite formation. This process occurs not just in continental margin sediments, but in deep sea oozes as well, and helps to clarify the driving forces behind phosphorite formation and links to marine P geochemistry.Two processes come into play to make phosphorite deposits: chemical dynamism and physical dynamism. Chemical dynamism involves the diagenetic release and subsequent concentration of P-bearing minerals particularly in horizons, controlled by a number of sedimentological and biogeochemical factors. Physical dynamism involves the reworking and sedimentary capping of P-rich sediments, which can either concentrate the relatively heavy and insoluble disseminated P-bearing minerals or provide an episodic change in sedimentology to concentrate chemically mobilized P. Both processes can result from along-margin current dynamics and/or sea level variations. Interestingly, net P accumulation rates are highest (i.e., the P removal pump is most efficient) when phosphorites are not forming. Both physical and chemical pathways involve processes not dominant in deep sea environments and in fact not often coincide in space and time even on continental margins, contributing to the rarity of high-quality phosphorite deposits and the limitation of phosphate rock reserves. This limitation is becoming critical, as the human demand for P far outstrips the geologic replacement for P and few prospects exist for new discoveries of phosphate rock. © 2011 Elsevier Ltd.

Ou Z.Y.,Indiana University – Purdue University Indianapolis
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2012

A nonlinear interferometer uses nonlinear elements as beam splitters to split and to recombine optical waves for interference. As a result, the interference fringe size has a nonlinear dependence on the intensity of the field for phase sensing and leads to an enhanced phase signal. In this paper, a practical scheme of nonlinear interferometry for precision phase measurement is analyzed with parametric amplifiers as the nonlinear beam splitters. It is found that the signal due to phase shift is enhanced by a factor of the amplification gain as compared to a linear interferometer with the same phase-sensing light intensity while the quantum noise is kept at the vacuum level, thus, effectively increasing the signal-to-noise ratio (SNR) beyond the standard quantum limit. Furthermore, the scheme is not as sensitive to the detection loss as the linear scheme with a squeezed state for noise reduction. However, losses inside the interferometer limit the enhancement factor in SNR. We apply the concept to a Michelson interferometer but with parametric amplifiers involved for gravitational-wave detection. We find that effective power is increased by the gain of the amplifiers without actually increasing the cycling power inside the interferometer. Furthermore, the full benefits with squeezed input and variational output or the combination of a quantum nondemolition interferometer for sensitivity beyond the standard quantum limit apply here with even better results. Such a nonlinear interferometer will find wide applications in precision measurements. © 2012 American Physical Society.

Malkova A.,Indiana University – Purdue University Indianapolis | Haber J.E.,Rosenstiel Basic Medical science Research Center
Annual Review of Genetics | Year: 2012

Mutations stimulate evolutionary change and lead to birth defects and cancer in humans as well as to antibiotic resistance in bacteria. According to the classic view, most mutations arise in dividing cells and result from uncorrected errors of S-phase DNA replication, which is highly accurate because of the involvement of selective DNA polymerases and efficient error-correcting mechanisms. In contrast, studies in bacteria and yeast reveal that DNA synthesis associated with repair of double-strand chromosomal breaks (DSBs) by homologous recombination is highly inaccurate, thus making DSBs and their repair an important source of mutations. Different error-prone mechanisms appear to operate in different repair scenarios. In the filling in of single-stranded DNA regions, error-prone translesion DNA polymerases appear to produce most errors. In contrast, in gene conversion gap repair and in break-induced replication, errors are independent of translesion polymerases, and many mutations have the signatures of template switching during DNA repair synthesis. DNA repair also appears to create complex copy-number variants. Overall, homologous recombination, which is traditionally considered a safe pathway of DSB repair, is an important source of mutagenesis that may contribute to human disease and evolution. © 2012 by Annual Reviews.

Agency: National Science Foundation | Branch: | Program: STTR | Phase: Phase I | Award Amount: 222.04K | Year: 2014

The broader impact/commercial potential of this project lies in the ability of the Extended Analog Computer (EAC) to perform filtering operations not possible with current technology. The low power, near instantaneous filtering of complex analog signals, differentiates the EAC technology from DSP products currently in the marketplace. The development of prosthetics with advanced control characteristics is reaching a computational limit due to the need for neuromuscular waveform recognition and classification in the context of real-time, low power, small form factor computation. EACs promise to surmount these challenges, improving functionality of prosthetics and the quality of life for amputees. In 2010, the global prosthetics market was $3 billion and is expected to reach $4.5 billion by 2017, with myoelectric prosthetics representing a small, but growing fraction of this market. While the myoelectric prosthetics industry represents an initial customer base, this generic computing technology's financial upside can best be estimated by segmenting the multi-billion dollar market for digital signal processing and analog computing devices. The intent is to solve computing problems in niche markets within this broad potential marketplace. This Small Business Technology Transfer Research (STTR) Phase I project is focused on the development of the Extended Analog Computer (EAC) for application to myoelectric prosthetics. New myoelectric interface techniques, such as targeted muscle reinnervation (TMR) are simplifying the use of advanced multi-degree of freedom prosthetics by amputees. However, the dramatic increase in the number and density of electrode sites, and need to implant multi-electrode structures into targeted muscles will increase the signal processing requirements beyond the capacity of traditional mobile digital signal processing (DSP). The EAC is a radical departure from the digital computer, deriving its computational power by taking advantage of the intrinsic solutions to partial differential equations represented as an analog voltage manifold in space. The proposed research aims to implement automatic machine learning/training methods to automatically configure networks of EAC sheets in a radial basis function network (RBFN). The research also explores the effect of the geometry of the input and output points on the sheet to optimize them for the TMR application. Finally, a physical instantiation enabling stand-alone, real-time operation of an EAC-RBFN will be developed. Using recorded data from intramuscular electrode arrays, the performance of the EAC will be tested against standard DSP techniques.

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