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PubMed2001

Thermodynamics of electron transfer in oxygenic photosynthetic reaction centers: volume change, enthalpy, and entropy of electron-transfer reactions in the intact cells of the cyanobacterium Synechocystis PCC 6803.

The volume and enthalpy changes for charge transfer in the 0.1-10 micros time window in photosynthetic reaction centers of the intact cells of Synechocystis PCC 6803 were determined using pulsed, time-resolved photoacoustics. This required invention of a method to correct for the cell artifact at the temperature of maximum density of water caused by the heterogeneous system. Cells grown under either white or red light had different PS I/PS II molar ratios, approximately 3 and approximately 1.7, respectively, but invariable action spectra and effective antenna sizes of the photosystems. In both cultures, the photoacoustic measurements revealed that their thermodynamic parameters differed strongly in the spectral regions of predominant excitation of PS I (680 nm) and PS II (625 nm). On correcting for contribution of the two photosystems at these wavelengths, the volume change was determined to be -27 +/- 3 and -2 +/- 3 A3 for PS I and PS II, respectively. The energy storage on the approximately 1 micros time scale was estimated to be 80 +/- 15% and 45 +/- 10% per trap in PS I and PS II, respectively. These correspond to enthalpies of -0.33 +/- 0.2 and -1 +/- 0.2 eV for the assumed formation of ion radical pairs P700+F(AB-) and Y(Z*)P680Q(A-), respectively. Taking the free energy of the above reactions as the differences of their redox potentials in situ, apparent entropy changes were estimated to be +0.4 +/- 0.2 and -0.2 +/- 0.2 eV for PS I and PS II, respectively. These values are similar to that obtained in vitro for the purified reaction center complexes on the microsecond time scale [Hou et al. (2001) Biochemistry 40, 7109-7116, 7117-7125]. The constancy of these thermodynamic values over a 2-fold change of the ratio of PS I/PS II is support for this method of in vivo analysis. Our pulsed PA method can correct the "cell" or heterogeneous artifact and thus opens a new route for studying the thermodynamics of electron transfer in vivo.

Calorimetry↗

PubMed2004

A ratiometric expressible FRET sensor for phosphoinositides displays a signal change in highly dynamic membrane structures in fibroblasts.

Phosphoinositides are important signal transduction intermediates in cell growth, survival, and motility. We have invented a fluorescence sensor for polyphosphorylated phosphoinositides based on a peptide derived from the Listeria protein ActA that undergoes a random coil to helix transition upon lipid binding. The sensor, termed CAY, is a fusion protein of cyan and yellow fluorescent proteins flanking the peptide at its N- and C-termini, respectively. CAY displays fluorescence resonance energy transfer in vitro in the absence of phosphorylated phosphoinositides, and this energy transfer is lost upon interaction with these phospholipids. These results demonstrate that a short peptide undergoing a coil to helix transition can be sufficient for the engineering of a FRET-based biosensor. CAY is predominantly localized to the cytoplasm in fibroblasts expressing the sensor but shows loss of fluorescence resonance energy transfer in regions of active actin dynamics such as ruffles that have previously been demonstrated to contain high levels of phosphoinositides.

Amino Acid Sequence↗

PubMedDate not supplied

Hydrocolloid coating of Xenopus laevis embryos.

A novel technology for coating single cells and embryos with thin hydrocolloid (water-soluble polymer) films has been invented and patented. Coating is different from entrapment and immobilization in that the coating around the cell is thinner, comprising only a small fraction of the cell or embryo's diameter. Xenopus laevis embryos were coated with thin films of low-methoxy pectin (LMP), alginate, and iota- and kappa-carrageenans. These gums have different compositions and structures and as such created different coatings around the fertilized cells. All coated embryos appeared to develop normally, similar to noncoated embryos. Elemental detection by ICP-AES spectroscopy revealed that the embryo can control the diffusion of excess ions to which it is exposed during the coating process. The coatings delayed hatching by 18-24 h. Consequently, at hatch the embryos were at a more developed stage than their noncoated counterparts. The hydrocolloid coating reduced the thickness of the natural jelly coating (JC). With the iota-carrageenan coating, percent hatch was maximal, while with LMP it was minimal, as a result of the films' mechanical properties and thicknesses. LMP and alginate created smoother coatings than the carrageenans. Potential interactions between the coating and the natural JC are hypothesized. Overall, coatings appear to be a suitable tool for laboratories interested in performing longer-term experiments with embryos.

Animals↗

PubMedDate not supplied

Basic concepts in Q membrane chromatography for large-scale antibody production.

The large-scale production of recombinant human monoclonal antibodies demands economical purification processes with high throughputs. In this article we briefly describe a common antibody process and evaluate the Q membrane adsorber for process-scale antibody production as an alternative to a Q-packed-bed column in a flow-through mode. The scientific concepts underlining Q membrane technology and its application are reviewed. The disadvantages and advantages of using Q membrane chromatography as a purification unit in large-scale production are discussed, including problems initially seen with the Q membrane scale-down model but solved with the invention of a new scale-down model. The new Q-membrane unit operation has a process capacity greater than 3,000 g/m(2) or 10.7 kg/L with a LRV over 5 for four model viruses. In this Review, a cost analysis illustrates that Q membrane chromatography is a viable alternative to Q column chromatography as a polishing step in a flow-through mode for process-scale antibody production.

Animals↗

PubMed1979

An evaluation of the leading patent equivalents services.

Patent equivalent services are useful tools for identifying patent families. A patent family consists of a group of patents in various countries which cover the same invention. The patent equivalents services provided by the three leading suppliers--Chemical Abstracts Service, Derwent Publications Ltd., and INPADOC--have been tested and evaluated for coverage, recall, and accuracy. Results are reported for a test sample consisting of 75 pharmaceutical patent families.

Drug Industry↗

PubMed2001

Catalysis research of relevance to carbon management: progress, challenges, and opportunities.

The goal of the "Opportunities for Catalysis Research in Carbon Management" workshop was to review within the context of greenhouse gas/carbon issues the current state of knowledge, barriers to further scientific and technological progress, and basic scientific research needs in the areas of H2 generation and utilization, light hydrocarbon activation and utilization, carbon dioxide activation, utilization, and sequestration, emerging techniques and research directions in relevant catalysis research, and in catalysis for more efficient transportation engines. Several overarching themes emerge from this review. First and foremost, there is a pressing need to better understand in detail the catalytic mechanisms involved in almost every process area mentioned above. This includes the structures, energetics, lifetimes, and reactivities of the species thought to be important in the key catalytic cycles. As much of this type of information as is possible to acquire would also greatly aid in better understanding perplexing, incomplete/inefficient catalytic cycles and in inventing new, efficient ones. The most productive way to attack such problems must include long-term, in-depth fundamental studies of both commercial and model processes, by conventional research techniques and, importantly, by applying various promising new physicochemical and computational approaches which would allow incisive, in situ elucidation of reaction pathways. There is also a consensus that more exploratory experiments, especially high-risk, unconventional catalytic and model studies, should be undertaken. Such an effort will likely require specialized equipment, instrumentation, and computational facilities. The most expeditious and cost-effective means to carry out this research would be by close coupling of academic, industrial, and national laboratory catalysis efforts worldwide. Completely new research approaches should be vigorously explored, ranging from novel compositions, fabrication techniques, reactors, and reaction conditions for heterogeneous catalysts, to novel ligands and ligation geometries (e.g., biomimetic), reaction media, and activation methods for homogeneous ones. The interplay between these two areas involving various hybrid and single-site supported catalyst systems should also be productive. Finally, new combinatorial and semicombinatorial means to rapidly create and screen catalyst systems are now available. As a complement to the approaches noted above, these techniques promise to greatly accelerate catalyst discovery, evaluation, and understanding. They should be incorporated in the vigorous international research effort needed in this field.

Journal Article↗

PubMed2002

Electron affinities of Al(n) clusters and multiple-fold aromaticity of the square Al4(2-) structure.

The concept of aromaticity was first invented to account for the unusual stability of planar organic molecules with 4n + 2 delocalized pi electrons. Recent photoelectron spectroscopy experiments on all-metal MAl(4)(-) systems with an approximate square planar Al(4)(2-) unit and an alkali metal led to the suggestion that Al(4)(2-) is aromatic. The square Al(4)(2-) structure was recognized as the prototype of a new family of aromatic molecules. High-level ab initio calculations based on extrapolating CCSD(T)/aug-cc-pVxZ (x = D, T, and Q) to the complete basis set limit were used to calculate the first electron affinities of Al(n)(), n = 0-4. The calculated electron affinities, 0.41 eV (n = 0), 1.51 eV (n = 1), 1.89 eV (n = 3), and 2.18 eV (n = 4), are all in excellent agreement with available experimental data. On the basis of the high-level ab initio quantum chemical calculations, we can estimate the resonance energy and show that it is quite large, large enough to stabilize Al(4)(2-) with respect to Al(4). Analysis of the calculated results shows that the aromaticity of Al(4)(2-) is unusual and different from that of C(6)H(6). Particularly, compared to the usual (1-fold) pi aromaticity in C(6)H(6), which may be represented by two Kekulé structures sharing a common sigma bond framework, the square Al(4)(2-) structure has an unusual "multiple-fold" aromaticity determined by three independent delocalized (pi and sigma) bonding systems, each of which satisfies the 4n + 2 electron counting rule, leading to a total of 4 x 4 x 4 = 64 potential resonating Kekulé-like structures without a common sigma frame. We also discuss the 2-fold aromaticity (pi plus sigma) of the Al(3)(-) anion, which can be represented by 3 x 3 = 9 potential resonating Kekulé-like structures, each with two localized chemical bonds. These results lead us to suggest a general approach (applicable to both organic and inorganic molecules) for examining delocalized chemical bonding. The possible electronic contribution to the aromaticity of a molecule should not be limited to only one particular delocalized bonding system satisfying a certain electron counting rule of aromaticity. More than one independent delocalized bonding system can simultaneously satisfy the electron counting rule of aromaticity, and therefore, a molecular structure could have multiple-fold aromaticity.

Journal Article↗

PubMed2005

Iridium(0) nanocluster, acid-assisted catalysis of neat acetone hydrogenation at room temperature: exceptional activity, catalyst lifetime, and selectivity at complete conversion.

Acetone hydrogenation catalysis is important in applications such as heat pumps and fuel cells or in fulfilling the sizable demand for the product of selective acetone hydrogenation, 2-propanol. Reported herein is the discovery of a superior acetone hydrogenation catalyst--superior in terms of activity at low temperature, selectivity at complete conversion, and total catalyst lifetime. The new catalyst system consists of Ir(0)(n) nanoclusters plus HCl easily and reproducibly formed from commercially available [(1,5-COD)IrCl](2) under H(2). The resultant, room temperature, high activity, and highly selective (2/n)Ir(0)(n) plus 2HCl catalyst system hydrogenates acetone at 22 degrees C and 40 psig of H(2) pressure to 95% 2-propanol and the rest diisopropyl ether at 100% conversion with 16400 total catalytic turnovers and with an initial turnover frequency of 1.9 s(-1) at 22 degrees C. When molecular sieves are added, the catalyst system becomes even more selective and long-lived, providing the complete and selective conversion of acetone to 100% 2-propanol with 188000 total turnovers. Also reported are initial kinetic, D-labeling and other mechanistic studies, a summary section detailing the four main findings, the "green chemistry" aspects, and the current main drawback (a limited catalytic lifetime due to nanocluster precipitation) of the present invention. A review of the extensive literature of acetone hydrogenation is also tabulated as part of the Supporting Information.

Journal Article↗

PubMed2004

Direct coupling of indoles with carbonyl compounds: short, enantioselective, gram-scale synthetic entry into the hapalindole and fischerindole alkaloid families.

The invention of a method for the direct union of indoles and carbonyl compounds (ketones, amides, esters) is described. Using this new method, a short, enantioselective, gram-scale and protecting group-free synthetic entry to the fischerindole and hapalindole indole alkaloid family has been achieved from carvone and indole. Total syntheses of (+)-hapalindole Q and (-)-12-epi-fischerindole U isothiocyanate are reported. The absolute stereochemistry of the latter natural product has also been determined.

Aldehydes↗

PubMed2005

Enantioselective organo-cascade catalysis.

A new strategy for organocatalysis based on the biochemical blueprints of biosynthesis has enabled a new laboratory approach to cascade catalysis. Imidazolidinone-based catalytic cycles, involving iminium and enamine activation, have been successfully combined to allow a large diversity of nucleophiles (furans, thiophenes, indoles, butenolides, hydride sources, tertiary amino lactone equivalents) and electrophiles (fluorinating and chlorinating reagents) to undergo sequential addition with a wide array of alpha,beta-unsaturated aldehydes. These new cascade catalysis protocols allow the invention of enantioselective transformations that were previously unknown, including the asymmetric catalytic addition of the elements of HF across a trisubstituted olefin. Importantly, these domino catalysis protocols can be mediated by a single imidazolidinone catalyst or using cycle-specific amine catalysts. In the latter case, cascade catalysis pathways can be readily modulated to provide a required diastereo- and enantioselective outcome via the judicious selection of the enantiomeric series of the amine catalysts. A central benefit of combining multiple asymmetric organocatalytic events into one sequence is the intrinsic requirement for enantioenrichment in the second induction cycle, as demonstrated by the enantioselectivities obtained throughout this study (>/=99% ee in all cases).

Aldehydes↗

PubMed2006

Total synthesis of (+/-)-haouamine A.

The first total synthesis of the highly complex and potent anticancer agent haouamine A is reported through an eight-step sequence. Brevity of the sequence and complete control of chemo-, position-, and stereoselectivity (both planar and axial chirality) were possible through the invention of chemistry specifically tailored for the problems at hand, namely a cascade annulation proceeding via a hitherto unknown chemical entity for the indeno-tetrahydropyridine ring system as well as a pyrone-assisted stitching of the daunting bent-aromatic ring.

Alkylation↗

PubMed2002

Identification of a pharmacophore for thrombopoietic activity of small, non-peptidyl molecules. 2. Rational design of naphtho[1,2-d]imidazole thrombopoietin mimics.

The invention of a new class of naphtho[1,2-d]imidazole thrombopoietin mimics based on a pharmacophore hypothesis for small-molecule thrombopoietic agonists is discussed. Parallel array synthesis and purification techniques allowed for the rapid exploration of structure-activity relationships within this class and for the improvement in TPO mimetic potencies and efficacies.

Antigens, CD34↗

PubMed2005

CoMFA and CoMSIA investigations revealing novel insights into the binding modes of dopamine D3 receptor agonists.

As an extension of a series of dopamine D(3) receptor agonists involving FAUC 54, ex-chiral pool synthesis, and biological evaluation of 3-substituted 7-aminotetrahydroindolizines was performed. Considering the structural features of both series of enantiomers, we developed a novel alignment hypothesis for D(3) agonists, allowing for the placement of the aromatic moieties on two alternative, adjacent positions. CoMFA and CoMSIA analyses yielded significant cross-validated q(2) values of 0.726 and 0.590, respectively, when a newly invented program application (IRAS) controlling the alignment selection proved to be useful. Employing the CoMFA/CoMSIA contribution maps, we were able to transform a previously constructed homology model of the D(3) receptor from an inactive into an activate state. Besides the established ionic interactions, we propose pi-stacking with Phe6.51 and a hydrogen bond between His6.55 and the acyl moiety to be primarily involved in the D(3) receptor binding of FAUC 54 and its analogues.

Animals↗

PubMed2005

Structure and transport properties of nanostructured materials.

In the present manuscript, we have presented the simulation of nanoporous aluminum oxide using a molecular-dynamics approach with recently developed dynamic charge transfer potential using serial/parallel programming techniques (Streitz and Mintmire Phys. Rev. B 1994, 50, 11996). The structures resembling recently invented ordered nanoporous crystalline material, MCM-41/SBA-15 (Kresge et al. Nature 1992, 359, 710), and inverted porous solids (hollow nanospheres) with up to 10 000 atoms were fabricated and studied in the present work. These materials have been used for separation of gases and catalysis. On several occasions including the design of the reactor, the knowledge of surface diffusion is necessary. In the present work, a new method for estimating surface transport of gases based on a hybrid Monte Carlo method with unbiased random walk of tracer atom on the pore surface has been introduced. The nonoverlapping packings used in the present work were fabricated using an algorithm of very slowly settling rigid spheres from a dilute suspension into a randomly packed bed. The algorithm was modified to obtain unimodal, homogeneous Gaussian and segregated bimodal porous solids. The porosity of these solids was varied by densification using an arbitrary function or by coarsening from a highly densified pellet. The surface tortuosity for the densified solids indicated an inverted bell shape curve consistent with the fact that at very high porosities there is a reduction in the connectivity while at low porosities the pores become inaccessible or dead-end. The first passage time distribution approach was found to be more efficient in terms of computation time (fewer tracer atoms needed for the linearity of Einstein's plot). Results by hybrid discrete-continuum simulations were close to the discrete simulations for a boundary layer thickness of 5lambda.

Journal Article↗

PubMed2005

The puzzle of contrast inversion in DNA STM imaging.

DNA has been at the center of an imaging effort since the invention of the scanning tunneling microscope (STM). In some of the STM imaging reports the molecules appeared with negative contrast, i.e., "submerged" under the metal background and darker. We demonstrate the phenomenon of contrast inversion in DNA STM imaging by controlled and spontaneous contrast inversions and by the dependence of the DNA apparent height with respect to the surface on the imaging bias voltage. Using these characterizations, we formulate a model explaining the above phenomenon by resonant tunneling through virtual states in the vacuum between the STM tip and the DNA molecule.

DNA↗

PubMed2006

Better chemistry through ceramics: the physical bases of the outstanding chemistry of ORMOSIL.

Twenty years after their invention, sol-gel organically modified silicates (ORMOSIL) are finding a number of impressive applications that range from efficient deliver of genes into mouse brains to self-ordered helices of interest to fields as diverse as optics, catalysis, molecular recognition, and chromatography. The physical bases of this mulifaceted chemistry, therefore, are of immense importance to scientists working toward new applications such as photovoltaics and catalysis that are crucially important in making sustainable global development. The purpose of this article is to provide a general picture of ORMOSIL's physical chemistry that will be useful in the creative development of new materials capable to solve a number of relevant open problems.

Journal Article↗

PubMed1992

Strategies and tactics for the synthesis of oxygenated natural products.

The total synthesis of the ansa antibiotic macbecin I [1] is described exploiting an approach that features the oxidative transformation of furans into hydropyrans that then serve as conformationally biased templates for stereoselective refunctionalization and elaboration. A novel variant of the Mitsunobu reaction was developed that may be applied to the inversion of hindered secondary alcohols. In work directed toward the total synthesis of the antifungal antibiotic ambruticin [3], new and general methods have been invented for the asymmetric synthesis of functionalized cyclopropanes by intramolecular cyclopropanations of omega-unsaturated diazoacetates and the convergent stereoselective synthesis of trisubstituted alkenes.

Alcohols↗

PubMed2002

Applicability of a modified Edman procedure for measurement of protein adducts: mechanisms of formation and degradation of phenylthiohydantoins.

Adducts to N-terminal valine residues in hemoglobin (Hb) are used for monitoring in vivo doses of electrophiles and are quantitated by means of a modified Edman procedure, the "N-alkyl Edman procedure". In the reaction with pentafluorophenyl isothiocyanate, N-alkylated valines cyclize and detach from the protein as pentafluorophenylthiohydantoins (PFPTHs) much more efficiently than do unsubstituted N-terminal valine residues. The mechanisms of this reaction, and of possible degradation reactions, have been studied with model compounds using phenyl- and pentafluorophenyl isothiocyanate. The rapid cyclization to N-alkylvaline-PTHs occurs as a consequence of the influence of substituents on ring formation. This facilitated cyclization favors a direct attack by the thiocarbamoyl nitrogen atom on valine-C-1, and is also observed to occur slowly at unsubstituted N-terminal valines. Such cyclization is favored in protic solvents. Under alkaline conditions and in the presence of air, hydrolytic and oxidative processes give rise to degradation products. The PTH derivatives of N-alkylvaline are less apt to undergo such reactions than are the corresponding derivatives of unsubstituted valine. We conclude that the presence of an N-substituent exerts a greater influence on the cyclization process than the structure of the amino acid or of the Edman reagent. For adducts of different structures, the method has broad applicability, for which the limits, however, are not yet explored. The knowledge from the studies is valid not only for the N-alkyl Edman procedure, but also, to some extent, for the classical Edman degradation reaction. The oxidative side reaction gave rise to the invention of a novel synthesis route for insertion of nucleophiles at carbon-5 in thiohydantoins. The present investigation provides a basis for the N-alkyl Edman procedure, facilitating new toxicological applications.

Alkylation↗