Three Dimensional Quantitative Structure-Activity Relationships of Sulfonamides Binding Monoclonal Antibody by Comparative Molecular Field Analysis

The three-dimensional quantitative structure-activity relationship (3D-QSAR) model of sulfonamide analogs binding a monoclonal antibody (MabSMR) produced against sulfamerazine, was carried out by comparative molecular field analysis (CoMFA). The affinities of MabSMR, expressed as Log10IC50, for 17 sulfonamide analogs were determined by competitive fluorescence polarization immunoassay (FPIA). Removal of two outliers from the initial set of 17 sulfonamide analogs improved the predictability of the models. The 3D-QSAR model of 15 sulfonamides resulted in q2cv values of 0.600, and r2 values of 0.995, respectively. This novel study combining FPIA with CoMFA demonstrates that multidisciplinary research can be used as a useful tool to investigate antigen-antibody interactions and provide information required for design of novel haptens, which may result in new antibodies with properties already optimized by an antibody-based immunoassay

Investigation of Antigen-Antibody Interactions of Sulfonamides with a Monoclonal Antibody in a Fluorescence Polarization Immunoassay Using 3D-QSAR Models

A three-dimensional quantitative structure-activity relationship (3D-QSAR) model of sulfonamide analogs binding a monoclonal antibody (MAbSMR) produced against sulfamerazine was carried out by Distance Comparison (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA). The affinities of the MAbSMR, expressed as Log10IC50, for 17 sulfonamide analogs were determined by competitive fluorescence polarization immunoassay (FPIA). The results demonstrated that the proposed pharmacophore model containing two hydrogen-bond acceptors, two hydrogen-bond donors and two hydrophobic centers characterized the structural features of the sulfonamides necessary for MAbSMR binding. Removal of two outliers from the initial set of 17 sulfonamide analogs improved the predictability of the models. The 3D-QSAR models of 15 sulfonamides based on CoMFA and CoMSIA resulted in q2 cv values of 0.600 and 0.523, and r2 values of 0.995 and 0.994, respectively, which indicates that both methods have significant predictive capability. Connolly surface analysis, which mainly focused on steric force fields, was performed to complement the results from CoMFA and CoMSIA. This novel study combining FPIA with pharmacophore modeling demonstrates that multidisciplinary research is useful for investigating antigen-antibody interactions and also may provide information required for the design of new haptens

Pharmacologic inhibition of JAK-STAT signaling promotes hair growth

Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth. We show that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. Our findings open new avenues for exploration of JAK-STAT inhibition for promotion of hair growth and highlight the role of this pathway in regulating the activation of hair follicle stem cells

Intense duskside lower band chorus waves observed by Van Allen Probes: Generation and potential acceleration effect on radiation belt electrons

Abstract Local acceleration driven by whistler mode chorus waves largely accounts for the enhancement of radiation belt relativistic electron fluxes, whose favored region is usually considered to be the plasmatrough with magnetic local time approximately from midnight through dawn to noon. On 2 October 2013, the Van Allen Probes recorded a rarely reported event of intense duskside lower band chorus waves (with power spectral density up to 10-3nT 2/Hz) in the low-latitude region outside of L=5. Such chorus waves are found to be generated by the substorm-injected anisotropic suprathermal electrons and have a potentially strong acceleration effect on the radiation belt energetic electrons. This event study demonstrates the possibility of broader spatial regions with effective electron acceleration by chorus waves than previously expected. For such intense duskside chorus waves, the occurrence probability, the preferential excitation conditions, the time duration, and the accurate contribution to the long-term evolution of radiation belt electron fluxes may need further investigations in future

Plasmatrough exohiss waves observed by Van Allen Probes: Evidence for leakage from plasmasphere and resonant scattering of radiation belt electrons

Abstract Exohiss waves are whistler mode hiss observed in the plasmatrough region. We present a case study of exohiss waves and the corresponding background plasma distributions observed by the Van Allen Probes in the dayside low-latitude region. The analysis of wave Poynting fluxes, suprathermal electron fluxes, and cold electron densities supports the scenario that exohiss leaks from the plasmasphere into the plasmatrough. Quasilinear calculations further reveal that exohiss can potentially cause the resonant scattering loss of radiation belt electrons

Nonstorm time dynamics of electron radiation belts observed by the Van Allen Probes

Abstract Storm time electron radiation belt dynamics have been widely investigated for many years. Here we present a rarely reported nonstorm time event of electron radiation belt evolution observed by the Van Allen Probes during 21-24 February 2013. Within 2 days, a new belt centering around L=5.8 formed and gradually merged with the original outer belt, with the enhancement of relativistic electron fluxes by a factor of up to 50. Strong chorus waves (with power spectral density up to 10-4nT2/Hz) occurred in the region L\u3e5. Taking into account the local acceleration driven by these chorus waves, the two-dimensional STEERB can approximately reproduce the observed energy spectrums at the center of the new belt. These results clearly illustrate the complexity of electron radiation belt behaviors and the importance of chorus-driven local acceleration even during the nonstorm times

Disappearance of plasmaspheric hiss following interplanetary shock

Abstract Plasmaspheric hiss is one of the important plasma waves controlling radiation belt dynamics. Its spatiotemporal distribution and generation mechanism are presently the object of active research. We here give the first report on the shock-induced disappearance of plasmaspheric hiss observed by the Van Allen Probes on 8 October 2013. This special event exhibits the dramatic variability of plasmaspheric hiss and provides a good opportunity to test its generation mechanisms. The origination of plasmaspheric hiss from plasmatrough chorus is suggested to be an appropriate prerequisite to explain this event. The shock increased the suprathermal electron fluxes, and then the enhanced Landau damping promptly prevented chorus waves from entering the plasmasphere. Subsequently, the shrinking magnetopause removed the source electrons for chorus, contributing significantly to the several-hours-long disappearance of plasmaspheric hiss

A genetic variation map for chicken with 2.8 million single-nucleotide polymorphisms

We describe a genetic variation map for the chicken genome containing 2.8 million single-nucleotide polymorphisms ( SNPs). This map is based on a comparison of the sequences of three domestic chicken breeds ( a broiler, a layer and a Chinese silkie) with that of their wild ancestor, red jungle fowl. Subsequent experiments indicate that at least 90% of the variant sites are true SNPs, and at least 70% are common SNPs that segregate in many domestic breeds. Mean nucleotide diversity is about five SNPs per kilobase for almost every possible comparison between red jungle fowl and domestic lines, between two different domestic lines, and within domestic lines - in contrast to the notion that domestic animals are highly inbred relative to their wild ancestors. In fact, most of the SNPs originated before domestication, and there is little evidence of selective sweeps for adaptive alleles on length scales greater than 100 kilobases