Molecular fingerprint and machine learning to accelerate design of high-performance homochiral metal–organic frameworks

Computational screening was employed to calculate the enantioseparation capabilities of 45 functionalized homochiral metal–organic frameworks (FHMOFs), and machine learning (ML) and molecular fingerprint (MF) techniques were used to find new FHMOFs with high performance. With increasing temperature, the enantioselectivities for (R,S)-1,3-dimethyl-1,2-propadiene are improved. The “glove effect” in the chiral pockets was proposed to explain the correlations between the steric effect of functional groups and performance of FHMOFs. Moreover, the neighborhood component analysis and RDKit/MACCS MFs show the highest predictive effect on enantioselectivities among the four ML classification algorithms with nine MFs that were tested. Based on the importance of MF, 85 new FHMOFs were designed, and a newly designed FHMOF, NO₂-NHOH-FHMOF, with high similarity to the optimal MFs achieved improved chiral separation performance, with enantioselectivities of 85%. The design principles and new chiral pockets obtained by ML and MFs could facilitate the development of new materials for chiral separation.     

Cyp1 Inhibition Prevents Doxorubicin-Induced Cardiomyopathy in a Zebrafish Heart-Failure Model

Doxorubicin is a highly effective chemotherapy agent used to treat many common malignancies. However, its use is limited by cardiotoxicity, and cumulative doses exponentially increase the risk of heart failure. To identify novel heart failure treatment targets, a zebrafish model of doxorubicin-induced cardiomyopathy was previously established for small-molecule screening. Using this model, several small molecules that prevent doxorubicin-induced cardiotoxicity both in zebrafish and in mouse models have previously been identified. In this study, exploration of doxorubicin cardiotoxicity is expanded by screening 2271 small molecules from a proprietary, target-annotated tool compound collection. It is found that 120 small molecules can prevent doxorubicin-induced cardiotoxicity, including 7 highly effective compounds. Of these, all seven exhibited inhibitory activity towards cytochrome P450 family 1 (CYP1). These results are consistent with previous findings, in which visnagin, a CYP1 inhibitor, also prevents doxorubicin-induced cardiotoxicity. Importantly, genetic mutation of cyp1a protected zebrafish against doxorubicin-induced cardiotoxicity phenotypes. Together, these results provide strong evidence that CYP1 is an important contributor to doxorubicin-induced cardiotoxicity and highlight the CYP1 pathway as a candidate therapeutic target for clinical cardioprotection.     

Ethnography,CSCW and Ethnomethodology

Computer Supported Cooperative Work (CSCW) - This paper documents some details and some examples of the influence of ethnomethodological work in the fieldwork tradition associated with European...     

Morphology,adipocyte size,and fatty acid analysis of dairy cattle digital cushions,and the effect of body condition score and age

The digital cushion is an essential part of maintaining a healthy foot, working to dissipate foot strike and body weight forces and lameness from claw horn disruption lesions. Despite the importance of the digital cushion, little is known about the basic anatomy, adipocyte morphology, and fatty acid composition in relation to age, limb position, and body condition score. In total, 60 claws (from 17 cows) were selected and collected from a herd, ensuring that body condition score data and computed micro-tomography were known for each animal. Digital cushion tissue underwent histological staining combined with stereology, systematic random sampling, and cell morphology analysis, in addition to lipid extraction followed by fatty acid analysis. The results describe digital cushion architecture and adipocyte sizes. Adipocyte size was similar across all 4 claws (distal left lateral and medial and distal right lateral and medial) and across the ages (aged 2–7 yr); however, animals with body condition score of 3.00 or more at slaughter had a significantly increased cell size in comparison to those with a score of less than 2.50. Of 37 fatty acid methyl esters identified, 5 differed between either the body condition score or different age groups. C10:0 capric acid, C14:0 myristic acid, C15:0 pentadecanoic acid, and C20:0 arachidic acid percentages were all lesser in lower body condition score cows, whereas C22:1n-9 erucic acid measurements were lesser in younger cows. Saturated fatty acid, monounsaturated fatty acid, and polyunsaturated fatty acid percentages were not altered in the different claws, ages, or body condition score groups. Triglyceride quantities did not differ for claw position or age but had decreased quantities in lower body condition score animals. Digital cushion anatomy, cellular morphology, and fatty acid composition have been described in general and also in animals with differing ages, body condition scores, and in the differing claws. Understanding fat deposition, mobilization, and composition are essential in not only understanding the roles that the digital cushion plays but also in preventing disorders and maintaining cattle health and welfare.     

Fiber Strength After Grain Growth in Nextel™ 610 Alumina Fiber

Nextel^? 610 alumina fiber tows were heat‐treated at 1100°C–1500°C for 1 to 100 h in air. Tensile strengths and Weibull moduli were measured for 30 filaments after each heat‐treatment. 3‐D grain size and orientation distributions were described using oblate ellipsoids. The number of grains in a 1 inch gauge length and grains with the largest major and minor ellipsoid‐axes were determined from these distributions. The grain with the largest K_EFF for mixed‐mode fracture was also determined, using the maximum energy release rate criteria from grain‐size and orientation distributions. Grain‐size dependence of tensile strength and Weibull modulus was evaluated. Strength had no obvious dependence on grain size for fibers with average major‐axes smaller than 0.25 μm. For fibers with larger grains, grain‐size dependence may involve flaws originating from clumps of grains, rather than a single grain. Possible relationships between strength and grain‐size and other causes of strength degradation after heat‐treatment are discussed.     

Static fatigue of Hi-Nicalon™-S fiber at elevated temperature in air,steam, and silicic acid-saturated steam

A facility for testing SiC fiber tows in static fatigue and creep at elevated temperatures in air and steam was developed. Static fatigue of Hi-Nicalon™-S fibers was investigated at 800°C-1100°C at applied stresses between 115 and 1250 MPa in air, in Si(OH)₄(g)-saturated steam, and in unsaturated steam. Fibers tested in Si(OH)₄(g)-saturated steam and in air had silica scales throughout the test sections, but those tested in unsaturated steam did not develop scales near the steam injection point. Fiber lifetimes in static fatigue were shortest in unsaturated steam, intermediate in Si(OH)₄(g)-saturated steam, and longest in air. Failure strains did not exceed 0.3%. Steady-state strain rates and static fatigue lifetimes are modelled empirically by the Monkman-Grant relationship. Failure mechanisms are discussed.     

Computer-based engineering of thermostabilized antibody fragments

We used the molecular modeling program Rosetta to identify clusters of amino acid substitutions in antibody fragments (scFvs and scAbs) that improve global protein stability and resistance to thermal deactivation. Using this methodology, we increased the melting temperature (T_m) and resistance to heat treatment of an antibody fragment that binds to the Clostridium botulinum hemagglutinin protein (anti-HA33). Two designed antibody fragment variants with two amino acid replacement clusters, designed to stabilize local regions, were shown to have both higher T_m compared to the parental scFv and importantly to retain full antigen binding activity after 2 hr of incubation at 70°C. The crystal structure of one thermostabilized scFv variants was solved at 1.6 Å and shown to be in close agreement with the RosettaAntibody model prediction.     

Relationship between persistent organic pollutants (POPs) and ranging patterns in common bottlenose dolphins (Tursiops truncatus) from coastal Georgia, USA

Bottlenose dolphins (Tursiops truncatus) are apex predators in coastal southeastern U.S. waters; as such they are indicators of persistent organic pollutants (POPs) in coastal ecosystems. POP concentrations measured in a dolphin's blubber are influenced by a number of factors, including the animal's sex and ranging pattern in relation to POP point sources. This study examined POP concentrations measured in bottlenose dolphin blubber samples (n = 102) from the Georgia, USA coast in relation to individual ranging patterns and specifically, distance of sightings from a polychlorinated biphenyl (PCB) point source near Brunswick, Georgia. Dolphin ranging patterns were determined based upon 5 years of photo-identification data from two field sites approximately 40 km apart: (1) the Brunswick field site, which included the Turtle/Brunswick River Estuary (TBRE), and (2) the Sapelo field site, which included the Sapelo Island National Estuarine Research Reserve (SINERR). Dolphins were categorized into one of three ranging patterns from photo-identification data. Individuals with sighting histories exclusively within one of the defined field sites were considered to have either Brunswick or Sapelo ranging patterns. Individuals sighted in both field sites were classified as having a Mixed ranging pattern. Brunswick males had the highest concentrations of PCBs reported for any marine mammal. The pattern of PCB congeners was consistent with Aroclor 1268, a highly chlorinated PCB mixture associated with a Superfund site in Brunswick. PCB levels in Sapelo males were lower than in Brunswick males, but comparable to the highest levels measured in other dolphin populations along the southeastern U.S. Female dolphins had higher Aroclor 1268 proportions than males, suggesting that the highly chlorinated congeners associated with Aroclor 1268 may not be offloaded through parturition and lactation, as easily as less halogenated POPs. Individuals sighted farther from the Superfund point source had lower Aroclor 1268 proportions.     

Does migration function to reduce earnings differentials by race and gender?

Traditionally, studies of migration have focused on two functions of migration: first, as a means to redistribute society's labor force to its most efficient use and, second, at the level of the individual, as a human capital investment. This study investigates the role of migration in the determination of earnings differentials by race and gender. Microdata from the United Status Census are used to estimate earnings functions by race, gender, and migration status. Strong evidence is provided suggesting that unexplained portions of earnings differentials, reflecting wage discrimination and other unobserved heterogeneity, are substantially reduced for both race and gender through the process of interstate migration.I am grateful to Michael J. Greenwood, Janet M. Rives, and an anonymous referee for insightful comments.     

Advanced Monte Carlo simulations of the adsorption of chiral alcohols in a homochiral metal‐organic framework

Grand canonical Monte Carlo (GCMC) simulations with configurational biasing were used to study the enantioselective adsorption of four alkanols in a homochiral metal‐organic framework, known as hybrid organic‐inorganic zeolite analogue HOIZA‐1. Conventional GCMC simulations are not able to converge satisfactorily for this system due to the tight fit of the chiral alcohols in the narrow pores. However, parallel tempering and parallel mole‐fraction GCMC simulations overcome this problem. The simulations show that the enantioselective adsorption of the different (R,S)‐alkanols is due to the specific geometry of the chiral molecules relative to the pore size and shape. © 2014 American Institute of Chemical Engineers AIChE J, 60: 2324–2334, 2014