Search

As the cost of high-throughput genomic sequencing technology declines, its application in clinical research becomes increasingly popular. The collected datasets often contain tens or hundreds of thousands of biological features that need to be mined to extract meaningful information. One area of particular interest is discovering underlying causal mechanisms of disease outcomes. Over the past few decades, causal discovery algorithms have been developed and expanded to infer such relationships. However, these algorithms suffer from the curse of dimensionality and multicollinearity. A recently introduced, non-orthogonal, general empirical Bayes approach to matrix factorization has been demonstrated to successfully infer latent factors with interpretable structures from observed variables. We hypothesize that applying this strategy to causal discovery algorithms can solve both the high dimensionality and collinearity problems, inherent to most biomedical datasets. We evaluate this strategy on simulated data and apply it to two real-world datasets. In a breast cancer dataset, we identified important survival-associated latent factors and biologically meaningful enriched pathways within factors related to important clinical features. In a SARS-CoV-2 dataset, we were able to predict whether a patient (1) had COVID-19 and (2) would enter the ICU. Furthermore, we were able to associate factors with known COVID-19 related biological pathways.

A novel oxidative activation of a thiolactam was developed for the preparation of methyltriazolo[1,4]benzodiazepine in a single step. A sulfenic acid (R-SOH) was proposed as the activated intermediate with the concurrent formation of acetylhydrazone from acethydrazide and cyclocondensation to the triazole. A version of the method with 35% peracetic acid was scaled up to 40 kg as a part of the new route for the synthesis of BET inhibitor molibresib (GSK525762). The thiolactam was prepared from commercially available (2-amino-5-methoxyphenyl)(4-chlorophenyl)methanone in two steps in 66% yield. The concise four-step synthesis delivered 52 kg of molibresib of >99.9% ee in an overall 41% yield from the ketone. The condition for the methyltriazole was mild and free of racemization of the sensitive stereocenter. The oxidative method, with several advantages to the known methods, should be applicable to the synthesis of alkyltriazoles from other thiolactams and acylhydrazines.

A combined high-throughput screening and reaction profiling approach to the telescoping of two reductions in the synthesis of Salbutamol is described. Optimization studies revealed the beneficial effect of mildly acidic conditions, and the use of water as a cosolvent. Persistent formation of deoxygenated impurities using a Pd/C catalyst led to the initiation of reaction profiling studies, which revealed that the ketone intermediate formed after rapid debenzylation is the sole source of deoxygenated impurities, indicating that more rapid ketone hydrogenation should minimize this deoxygenation. A dual catalyst approach based on these insights has been developed, with both Pd/Pt and Ru/Pt catalyst systems as more selective than Pd-only systems. Based on reaction profiles that indicate the deoxygenation side reaction is first-order in the concentration of debenzylated ketone intermediate, Pt catalysts for rapid and selective ketone hydrogenation were paired with Pd and Ru catalysts known to perform selective ...

This paper describes the influence of key reaction parameters on the development of a rate model which can be used to forecast starting material conversion independent of scale. A nitro reduction was examined via first principles reaction progress modeling. The reaction parameters, most notably hydrogen partial pressure and agitation rate, influenced the choice of rate model. At lower hydrogen partial pressures, the reaction rate was influenced by gas to liquid mass transfer, hydrogen pore diffusion, and the rate of the surface reaction during the course of the overall reaction. No single model could be generated to explain the rate observations at lower hydrogen partial pressures. At higher hydrogen partial pressures, a kinetic reaction model was used to generate an equation to forecast the substrate concentration as a function of time and reaction parameters. This reaction model was confirmed to be independent of scale provided that the mass transfer coefficient exceeded a minimum threshold value. The m...

An efficient highly diastereo- and enantioselective synthesis of the bis-tetrahydrofuran (bis-THF) alcohol of several HIV protease inhibitors, including Brecanavir and Darunavir, has been achieved utilizing an Evans Mukaiyama aldol reaction of (benzyloxy)acetaldehyde and a silyl ketene acetal. The lactone alcohol intermediate from the catalytic aldol reaction was reduced to a lactol. Palladium catalyzed hydrogenolysis removed the benzyl protection and promoted an in situ cyclization to form the epimer of the bis-THF alcohol in a 98:2 diastereomeric ratio and 97:3 enantiomeric ratio. The alcohol epimer was readily converted to the target in two steps by oxidation to a ketone followed by highly selective reduction to the bis-THF alcohol.

Due to a strong “Can Do” spirit and a well-engrained, albeit simplistic, notion of civilian control over the military, senior military leaders are disinclined to publicly share their disagreement with emerging national security policy. Many senior officers mistakenly believe that there are no alternatives other than just silently executing, resigning, or retiring when confronted with bad policy formulation. There are, however, options available to senior uniformed leaders when confronted with policy formulation that they, in their professional opinion, believe is flawed. Depending on the degree to which the civilian authorities are receptive to military advice and the magnitude of the threat to national security involved in the policy, senior military leaders can choose among many alternatives to widen the policy debate.

The topoisomerase I inhibitor GI147211C (4) was discovered at Glaxo Wellcome and shown to have promising anti-cancer properties. In order to fully assess the clinical potential of 4, an improved synthesis of the drug substance was required. Herein is described a convergent catalytic asymmetric synthesis of 4 which utilizes as key steps, two Heck reactions, a Sharpless asymmetric dihydroxylation reaction, and a Mitsunobu reaction. A 2-chloroquinoline is shown to be a viable substrate for the final Heck reaction to generate the camptothecin nucleus.

Activated carbon-mediated reductive decomposition of several commonly used peracids, peracid salts, and alkyl hydroperoxides was investigated, and oxygen release was measured. Environmentally unfriendly reagents such as dimethyl sulfide, trimethyl phosphite, and triphenyl phosphine were ineffective in reducing the peracid salts. However, the environmentally friendly and waste-minimizing activated carbon proved an effective, simple, and safe method for the decomposition of peracids, peracid salts, and alkyl hydroperoxides.

Presentation from the 2011 Water Peer Review in which the principal investigator discusses project progress to evaluate & optimize the performance, environment, and cost factors of the Free Flow Power hydrokinetic system for Mississippi River commercial deployment

This study focuses on the solution antimicrobial effectiveness of a novel class of copolyoxetanes with quaternary ammonium and PEG-like side chains. A precursor P[(BBOx-m)(ME2Ox)] copolyoxetane was prepared by cationic ring-opening copolymerization of 3-((4-bromobutoxy)methyl)-3-methyloxetane (BBOx) and 3-((2-(2-methoxyethoxy)ethoxy)methyl)-3-methyloxetane (ME2Ox) to give random copolymers with 14-100 (m) mol % BBOx. Reaction of P[(BBOx-m)(ME2Ox)] with dodecyl dimethylamine gave the corresponding quaternary P[(C12-m)(ME2Ox)] polycation salts, designated C12-m, as viscous liquids in 100% yield. BBOx/ME2Ox and C12/ME2Ox ratios were obtained by (1)H NMR spectroscopy. C12-m molecular weights (M(n), 3.5-21.9 kDa) were obtained from (1)H NMR end group analysis. DSC studies up to 150 °C showed only thermal transitions between -69 and -34 °C assigned to T(g) values. Antibacterial activity for the C12-m copolyoxetanes was tested by determining minimum inhibitory concentrations (MICs) against Gram(+) Staphylococcus aureus and Gram(-) Escherichia coli and Pseudomonas aeruginosa . MIC decreased with increasing C12 mol percent, reaching a minimum in the range C12-43 to C12-60. Overall, the antimicrobial with consistently low MICs for the three tested pathogenic bacteria was C12-43: (bacteria, MIC, μg/mL) E. coli (6), S. aureus (5), and P. aeruginosa (33). For C12-43, minimum biocidal concentration (MBC) to reach 99.99% kill in 24 h required 1.5× MIC for S. aureus and 2× MIC for E. coli and P. aeruginosa . At 5× MIC against a challenge of 10(8) cfu/mL, C12-43 kills ≥99% S. aureus , E. coli , and P. aeruginosa within 1 h. C12-m copolyoxetane cytotoxicity toward human red blood cells was low, indicating good prospects for biocompatibility. The tunability of C12-m copolyoxetane compositions, effective antimicrobial behavior against Gram(+) and Gram(-) bacteria, and promising biocompatibility offer opportunities for further modification and potential applications as therapeutic agents.

A practical, chemoenzymatic, four-step synthesis of the LTD4 antagonist MK-0679 is described. The key steps are enzymatic hydrolysis of the prochiral diester to the ester-acid in 99% enantiomeric excess followed by aluminum mediated amidation of the methyl ester to afford MK-0679 in high overall yield. This synthesis is superior to the synthesis of the racemate MK-0571.

The preparation and characterization of N,N-dimethylammonium dialkylaluminum chloride and the use of these complexes in the synthesis of the LTD 4 antagonist MK-0679 is described

A practical, chemoenzymatic, four-step synthesis of the LTD4 antagonist MK-0679 is described. The key steps are enzymatic hydrolysis of the prochiral diester to the ester-acid in 99% enantiomeric excess followed by aluminum mediated amidation of the methyl ester to afford MK-0679 in high overall yield. This synthesis is superior to the synthesis of the racemate MK-0571.

A formal synthesis of (2R-cis)-4-methyl-1-(2,3,4,5-tetrahydro-5-methyl-[2,3′-bifuran]-2-pentanone, or ipomeamarone (1) [494-23-5] was accomplished from 3-furaldehyde 5 and ethyl-2-bromocrotonate 4. The key step involved the formation of the dihydrofuran ring in 2 via a vinyloxirane rearrangement of 3 in the [2+3] dihydrofuran annulation. Mechanistic duality of reactions of those tetrahydrofurans possessing acidic hydrogens adjacent to the ring is addressed.

The infinite matrices in Witten's vertex are easy to diagonalize. It just requires some SL(2,R) lore plus a Watson-Sommerfeld transformation. We calculate the eigenvalues of all Neumann matrices for all scale dimensions s, both for matter and ghosts, including fractional s which we use to regulate the difficult s=0 limit. We find that s=1 eigenfunctions just acquire a p term, and x gets replaced by the midpoint position., 24 pages, 2 figures, RevTeX style, typos corrected

The preparation and characterization of N,N-dimethylammonium dialkylaluminum chloride and the use of these complexes in the synthesis of the LTD 4 antagonist MK-0679 is described

This paper examines the role of the World Bank in the development and application of key ideas and approaches to address issues related to malnutrition. The World Bank's commitment to human development can be seen on how its resources have been applied, and the difference it has made on the lives of the people. Their health, nutrition and population activity is comprised of 225 projects in 89 countries that have contributed directly to the fulfillment of the economic and social rights of millions of people. Furthermore, the Bank's project known as Comprehensive Development Framework reflects its understanding of the two-way relationship between development and human rights. Lastly, the Bank's comprehensive approach, which consists of support for governance reform and equitable economic growth, is intended to strengthen human rights culture.

The Department of Defense (DoD) has launched an ambitious planning initiative that could have a major impact upon how resources are allocated among the military departments and the combatant commands. This monograph addresses how well Theater Engagement Planning methodology has been designed and implemented and offers recommendations to improve the existing process.

The following speech was presented at the Society of NASA Flight Surgeon's annual luncheon meeting on May 11, 1995 in Anaheim, CA. The Randolph C. Lovelace Award is presented annually by the Society. Stanley C. White, M.D., had a very distinguished career in Aerospace Medicine, including working with the Air Force's Man-In-Space and Man-In-Space-Soonest Programs, and, later, as the first Flight Surgeon assigned to the NASA Space Task Group. For these, and numerous other contributions, Dr. White was chosen to receive the Society of NASA Flight Surgeons' 1995 Lovelace Award at the 66th Annual Scientific Meeting of the Aerospace Medical Association. Dr. White, who was a personal acquaintance of Dr. Randy Lovelace for whom the award is named, then captivated the audience with a fascinating speech about Dr. Lovelace. Furthermore, he admonished us to remember the legacy of Dr. Lovelace and the many lessons his wisdom still teaches us today. The following is Dr. White's presentation.

Adiabatic perturbation theory works for non-conserved dilation operators. At each effective coupling, all renormalization group functions are dilation eigenvalues of a “tangent” field theory, which preserves scale invariance instead of translation invariance. The adiabatic expansion reconstructs the true field theory from this tangent bundle. For complex angular momentum, the short and long distance expansions mix indecomposably at certain turning points. By connecting the UV and IR limits across them, the adiabatic method determines Regge intercepts from integrals over the renormalization group. Fixed Regge cuts or accumulations of poles are insensitive to the IR region.

Ordinary second-quantized field theories are rearranged to look like first-quantized strings expanded around an unstable classical vacuum. The β function of the field theory becomes the tadpole amplitude of the string, the anomalous dimensions become the string mass matrix. This map should be useful in both directions: it gives a new picture of renormalization, and it shows how to do spontaneous symmetry breaking for strings. Dynamical symmetry breaking, where string loop divergences cancel against those of the 2D field theory, is also conceivable.

BRST anomalies arising from modular integrations can be cancelled between different genus world-sheets at the price of moving the world-sheet σ-model away from its conformal fixed point. We have fully implemented this procedure for the lowest-loop corrections to the type-I superstring. The associated conformal invariance violations are responsible for important corrections to the background field equations including both the coupling of the gauge field to gravity and the anomaly-cancelling interactions of the antisymmetric tensor field.

Aldehydes were found to undergo facile stereoselective vinyloxiranation with the lithium dienolate of ethyl 2-bromocrotonate (12) at low temperature. The resulting vinyloxiranes were transformed thermolytically to functionalized dihydrofurans. An operational comparison of this heterocyclic annulation is made with its carbocyclic counterpart, the [2+3] cyclopentene annulation, and the potential for a general dihydrofuran synthesis in either a racemic or an asymmetric fashion is addressed.

We calculate the orbit volumes of the local gauge group, for U(N) theories on lattices of any size and dimension. As N → ∞ one orbit always grows relative to all others. This is the strong coupling limit of Witten's master field.

Cycloaddition d'azido-8 oxo-6 octadiene-2,4oate de methyle en hydroxy-4 aza-1bicyclo [3.1.0] hexaneacrylate-6 de methyle que l'on transforme ensuite en oxo-7 pyrrolizinecarboxylates-1

We study the problem of finding the beta functions, and the associated spacetime effective action, for interacting open and closed strings propagating in background fields. String loop divergences play a crucial role in this problem. Cancelling them against sigma model divergences gives a consistent set of loop-corrected beta functions, which can be derived from a simple generalization of the string-tree-level effective action. This suggests the existence of new string theories which are conformally invariant only after all world sheets have been summed.

We prove that corresponding O( N ), U( N ), and Sp( N ) lattice gauge theories give the same Wilson loops as N → ∞. Therefore, magnetic monopoles cannot be significant in this limit.

We examine the splice loss occurring along a multimode fiber regenerator span and compare the results to a "standard" laboratory test condition. Large variations in the splice loss sensitivity to transverse offset of a "reference" splice were seen 1) at the ends of 5 different 8.9-km fiber concatenations and 2) at various locations along one 8.9-km path. These data indicate that significant variations in the modal power distribution exist even at the receiver end of a regenerator span. This is explained by the long coupling lengths (long compared to splice spacing) of low loss fibers and the random amount of mode coupling introduced by the concatenation splices. Splice loss measurements made with an "overfilled" launch condition and a 3-turn 20-mm mandrel wrap mode filter (commonly used in fiber loss measurements) accurately approximated the average splice loss sensitivity along the span for offsets less than 4 μm. i.e., losses less than 0.2 dB. For offsets greater than 4 μm, the mandrel wrap mode filter configuration yields a pessimistic estimate, but is within 30 percent of the average "system" loss for most cases of interest. This demonstrates the usefulness of the mode filter in establishing splice measurement conditions that yield results representative of those seen in a regenerator span.

We try to find the most general conditions for Lorentz covariance of particles with ghost-free internal structure. Applied to string models, they become finite matrix equations for the reduced structure constants of the gauge superalgebra. At least all low-order solutions are direct sums of the known algebras. This greatly limits the possibilities for new dual models. We assume no restriction on either conformal invariant, so our no-go theorem applies to Nahm's conjectured partition functions. A byproduct is a general functional method for calculating Schwinger terms of any superalgebra.

SU(N) gauge systems are attracted to large orbits of the global gauge group by an invariant and calculable potential. In models the wave function becomes increasingly localized near the maximal orbit as N → ∞, which explains the success of semiclassical methods. Picturing the links Ui of the lattice as particles on an SU(N) group manifold, the effect favors large moments of inertia about U = 1. It thus opposes the magnetic interaction, and tends to destabilize the perturbative vacuum.

By a new method, we show that the asymptotically free o 6 3 field theory has a point of accumulation of Regge poles but no fixed cut. It is plausible that nonabelian gauge theories have an analogous singularity at j = 1.

An expansion of the Regge trajectories for large energy is derived for singular and nonsingular potentials. The Pade approximant is introduced in order to sum these asymptotic expansions. Further calculations for a Yukawa potential are reported with emphasis on the analytic properties of the trajectories. All the trajectories investigated have singularities not present in theS-matrix itself. We conclude that one can analytically continue from one trajectory to another.

Our 1967 CERN-EXP phase-shift analysis has been redone with 212 times more experimental data (11550 points). The results differ mainly in being even smoother. Most of previous resonance candidates are strengthened, and four possible new ones above 2 GeV suggested. However, the D13(1700) required by the quark model is still absent.

Assuming only dispersion relations, backward πp elastic scattering experiments give an F ratio probability of 108 : 1 for the presence of a ππ So wave and require it to have a broad σ resonance.