Structure-activity relationship and mechanism of action studies of manzamine analogues for the control of neuroinflammation and cerebral infections

Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinal isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g., Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3beta (GSK-3beta), which is a putative target of manzamines. On the basis of the results presented here, it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases.

Factor Structure of the Neck Disability Index

BACKGROUND CONTEXT: The Neck Disability Index frequently is used to measure outcomes of the neck. The statistical rigor of the Neck Disability Index has been assessed with conflicting outcomes. To date, Confirmatory Factor Analysis of the Neck Disability Index has not been reported for a suitably large population study. Because the Neck Disability Index is not a condition-specific measure of neck function, initial Confirmatory Factor Analysis should consider problematic neck patients as a homogenous group. PURPOSE: We sought to analyze the factor structure of the Neck Disability Index through Confirmatory Factor Analysis in a symptomatic, homogeneous, neck population, with respect to pooled populations and gender subgroups. STUDY DESIGN: This was a secondary analysis of pooled data. PATIENT SAMPLE: A total of 1,278 symptomatic neck patients (67.5% female, median age 41 years), 803 nonspecific and 475 with whiplash-associated disorder. OUTCOME MEASURES: The Neck Disability Index was used to measure outcomes. METHODS: We analyzed pooled baseline data from six independent studies of patients with neck problems who completed Neck Disability Index questionnaires at baseline. The Confirmatory Factor Analysis was considered in three scenarios: the full sample and separate sexes. Models were compared empirically for best fit. RESULTS: Two-factor models have good psychometric properties across both the pooled and sex subgroups. However, according to these analyses, the one-factor solution is preferable from both a statistical perspective and parsimony. The two-factor model was close to significant for the male subgroup (p<.07) where questions separated into constructs of mental function (pain, reading headaches and concentration) and physical function (personal care, lifting, work, driving, sleep, and recreation). CONCLUSIONS: The Neck Disability Index demonstrated a one-factor structure when analyzed by Confirmatory Factor Analysis in a pooled, homogenous sample of neck problem patients. However, a two-factor model did approach significance for male subjects where questions separated into constructs of mental and physical function. Further investigations in different conditions, subgroup and sex-specific populations are warranted.

A Semiempirical Transition State Structure for the First Step in the Alkaline Hydrolysis of Cocaine. Comparison between the Transition State Structure, the Phosphonate Monoester Transition State Analog, and a Newly Designed Thiophosphonate Transition State Analog

Semiempirical molecular orbital calculations have been performed for the first step in the alkaline hydrolysis of the neutral benzoylester of cocaine. Successes, failures, and limitations of these calculations are reviewed. A PM3 calculated transition state structure is compared with the PM3 calculated structure for the hapten used to induce catalytic antibodies for the hydrolysis of cocaine. Implications of these calculations for the computer–aided design of transition state analogs for the induction of catalytic antibodies are discussed.

Computational Design and Experimental Discovery of an Anti-estrogenic Peptide Derived from Alpha-Fetoprotein

Breast cancer is the most common cancer among women, and tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment. Many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Consequently, there is an ongoing need for breast cancer drugs that have different molecular targets. Previous work has shown that 8-mer and cyclic 9-mer peptides inhibit breast cancer in mouse and rat models, interacting with an unsolved receptor, while peptides smaller than eight amino acids did not. We show that the use of replica exchange molecular dynamics predicts the structure and dynamics of active peptides, leading to the discovery of smaller peptides with full biological activity. Simulations identified smaller peptide analogues with the same conserved reverse turn demonstrated in the larger peptides. These analogues were synthesized and shown to inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition.

Computational approaches for the design of peptides with anti-breast cancer properties

Background: Breast cancer is the most common cancer among women. Tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment, yet many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Therefore, scientists are searching for breast cancer drugs that have different molecular targets. Methodology: Recently, a computational approach was used to successfully design peptides that are new lead compounds against breast cancer. We used replica exchange molecular dynamics to predict the structure and dynamics of active peptides, leading to the discovery of smaller bioactive peptides. Conclusions: These analogs inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition. We outline the computational methods that were tried and used along with the experimental information that led to the successful completion of this research.

Processing-structure-property relationships in solid-state shear pulverization: Parametric study of specific energy

Solid-state shear pulverization (SSSP) is a unique processing technique for mechanochemical modification of polymers, compatibilization of polymer blends, and exfoliation and dispersion of fillers in polymer nanocomposites. A systematic parametric study of the SSSP technique is conducted to elucidate the detailed mechanism of the process and establish the basis for a range of current and future operation scenarios. Using neat, single component polypropylene (PP) as the model material, we varied machine type, screw design, and feed rate to achieve a range of shear and compression applied to the material, which can be quantified through specific energy input (Ep). As a universal processing variable, Ep reflects the level of chain scission occurring in the material, which correlates well to the extent of the physical property changes of the processed PP. Additionally, we compared the operating cost estimates of SSSP and conventional twin screw extrusion to determine the practical viability of SSSP.

Processing-Structure-Property Relationships in Solid-State Shear Pulverization: Parametric Study of specific energy

Solid-state shear pulverization (SSSP) is a unique processing technique for mechanochemical modification of polymers, compatibilization of polymer blends, and exfoliation and dispersion of fillers in polymer nanocomposites. A systematic parametric study of the SSSP technique is conducted to elucidate the detailed mechanism of the process and establish the basis for a range of current and future operation scenarios. Using neat, single component polypropylene (PP) as the model material, we varied machine type, screw design, and feed rate to achieve a range of shear and compression applied to the material, which can be quantified through specific energy input (Ep). As a universal processing variable, Ep reflects the level of chain scission occurring in the material, which correlates well to the extent of the physical property changes of the processed PP. Additionally, we compared the operating cost estimates of SSSP and conventional twin screw extrusion to determine the practical viability of SSSP.

Broadband Fourier transform rotational spectroscopy for structure determination: The water heptamer

Over the recent years chirped-pulse, Fourier-transform microwave (CP-FTMW) spectrometers have chan- ged the scope of rotational spectroscopy. The broad frequency and large dynamic range make possible structural determinations in molecular systems of increasingly larger size from measurements of heavy atom (13C, 15N, 18O) isotopes recorded in natural abundance in the same spectrum as that of the parent isotopic species. The design of a broadband spectrometer operating in the 2–8 GHz frequency range with further improvements in sensitivity is presented. The current CP-FTMW spectrometer performance is benchmarked in the analyses of the rotational spectrum of the water heptamer, (H2O)7, in both 2– 8 GHz and 6–18 GHz frequency ranges. Two isomers of the water heptamer have been observed in a pulsed supersonic molecular expansion. High level ab initio structural searches were performed to pro- vide plausible low-energy candidates which were directly compared with accurate structures provided from broadband rotational spectra. The full substitution structure of the most stable species has been obtained through the analysis of all possible singly-substituted isotopologues (H218O and HDO), and a least-squares rm(1) geometry of the oxygen framework determined from 16 different isotopic species compares with the calculated O–O equilibrium distances at the 0.01 Å level.

Broadband Fourier transform rotational spectroscopy for structure determination: The water heptamer

Over the recent years chirped-pulse, Fourier-transform microwave (CP-FTMW) spectrometers have changed the scope of rotational spectroscopy. The broad frequency and large dynamic range make possible structural determinations in molecular systems of increasingly larger size from measurements of heavy atom (C-13, N-15, O-18) isotopes recorded in natural abundance in the same spectrum as that of the parent isotopic species. The design of a broadband spectrometer operating in the 2-8 GHz frequency range with further improvements in sensitivity is presented. The current CP-FTMW spectrometer performance is benchmarked in the analyses of the rotational spectrum of the water heptamer, (H2O)(7), in both 2-8 GHz and 6-18 GHz frequency ranges. Two isomers of the water heptamer have been observed in a pulsed supersonic molecular expansion. High level ab initio structural searches were performed to provide plausible low-energy candidates which were directly compared with accurate structures provided from broadband rotational spectra. The full substitution structure of the most stable species has been obtained through the analysis of all possible singly-substituted isotopologues ((H2O)-O-18 and HDO), and a least-squares r(m)((1)) geometry of the oxygen framework determined from 16 different isotopic species compares with the calculated O-O equilibrium distances at the 0.01 angstrom level. (C) 2013 Elsevier B.V. All rights reserved.

Investigation of the Design of a Bistable Micro-Chemical-Mechanical Device Utilizing Lateral Buckling

The Gracias Laboratory at Johns Hopkins University has developed microgrippers which utilize chemically-actuated joints to be used in micro-surgery. These grippers, however, take up to thirty minutes to close fully when activated biochemicals in the human body. This is very problematic and could limit the use of the devices in surgery. It is the goal of this research to develop a gripper that uses theGracias Laboratory's existing joints in conjunction with mechanical components to decrease the closing time. The purpose of including the mechanical components is to induce a state of instability at which time a small perturbation would cause the joint to close fully.The main concept of the research was to use the lateral buckling of a triangular gripper geometry and use a toggle mechanism to decrease the closure time of the device. This would create a snap-action device mimicking the quick closure of a Venus flytrap. All developed geometries were tested using finite element analysis to determine ifloading conditions produced the desired buckled shape. This research examines lateral buckling on the micro-scale and the possibility ofusing this phenomenon in a micro-gripper. Although a final geometry with the required deformed shaped was not found, this document contains suggestions for future geometries that may produce the correct deformed shape. It was determined through this work that in order to obtain the desired deformed shape, polymeric sections need to be added to the geometry. This simplifies the analysis and allows the triangular structure to buckle in the appropriate way due to the added joints. Future work for this project will be completed by undergraduate students at Bucknell University. Fabrication and testing of devices will be done at Johns Hopkins University in the Gracias Laboratory.

Investigating the Effects of Various Crowd Characteristics on the Dynamic Properties of an Occupied Structure

One of the challenges for structural engineers during design is considering how the structure will respond to crowd-induced dynamic loading. It has been shown that human occupants of a structure do not simply add mass to the system when considering the overall dynamic response of the system, but interact with it and may induce changes of the dynamic properties from those of the empty structure. This study presents an investigation into the human-structure interaction based on several crowd characteristics and their effect on the dynamic properties of an empty structure. The dynamic properties including frequency, damping, and mode shapes were estimated for a single test structure by means of experimental modal analysis techniques. The same techniques were utilized to estimate the dynamic properties when the test structure was occupied by a crowd with different combinations of size, posture, and distribution. The goal of this study is to isolate the occupant characteristics in order to determine the significance of each to be considered when designing new structures to avoid crowd serviceability issues. The results are presented and summarized based on the level of influence of each characteristic. The posture that produces the most significant effects based on the scope of this research is standing with bent knees with a maximum decrease in frequency of the first mode of the empty structure by 32 percent atthe highest mass ratio. The associated damping also increased 36 times the damping of the empty structure. In addition to the analysis of the experimental data, finite element models and a two degree-of-freedom model were created. These models were used to gain an understanding of the test structure, model a crowd as an equivalent mass, and also to develop a single degree-of-freedom (SDOF) model to best represent a crowd of occupants based on the experimental results. The SDOF models created had an averagefrequency of 5.0 Hz, within the range presented in existing biomechanics research, and combined SDOF systems of the test structure and crowd were able to reproduce the frequency and damping ratios associated with experimental tests. Results of this study confirmed the existence of human-structure interaction andthe inability to simply model a crowd as only additional mass. The two degree-offreedom model determined was able to predict the change in natural frequency and damping ratio for a structure occupied by multiple group sizes in a single posture. These results and model are the preliminary steps in the development of an appropriate methodfor modeling a crowd in combination with a more complex FE model of the empty structure.

Using the Natural Period of a Structure as an Indicator of the Significance of Second-Order Effects

This study investigates the feasibility of predicting the momentamplification in beam-column elements of steel moment-resisting frames using the structure's natural period. Unlike previous methods, which perform moment-amplification on a story-by-story basis, this study develops and tests two models that aim to predict a global amplification factor indicative of the largest relevant instance of local moment amplification in the structure. To thisend, a variety of two-dimensional frames is investigated using first and secondorder finite element analysis. The observed moment amplification is then compared with the predicted amplification based on the structure's natural period, which is calculated by first-order finite element analysis. As a benchmark, design moment amplification factors are calculated for each story using the story stiffness approach, and serve to demonstrate the relativeconservatism and accuracy of the proposed models with respect to current practice in design. The study finds that the observed moment amplification factors may vastly exceed expectations when internal member stresses are initially very small. Where the internal stresses are small relative to the member capacities, thesecases are inconsequential for design. To qualify the significance of the observed amplification factors, two parameters are used: the second-order moment normalized to the plastic moment capacity, and the combined flexural and axial stress interaction equations developed by AISC

Pentraxins and atherosclerosis: the role of PTX3

Pentraxins are a family of evolutionarily conserved multifunctional pattern-recognition proteins characterized by a cyclic multimeric structure. Based on the primary structure of the subunit, the pentraxins are divided into two groups: short pentraxins and long pentraxins. C-reactive protein (CRP) and serum amyloid P-component (SAP) are the two short pentraxins. The prototype protein of the long pentraxin group is pentraxin 3 (PTX3). CRP and SAP are produced primarily in the liver in response to IL-6, while PTX3 is produced by a variety of tissues and cells and in particular by innate immunity cells in response to proinflammatory signals and Toll-like receptor (TLR) engagement. PTX3 interacts with several ligands, including growth factors, extracellular matrix components and selected pathogens, playing a role in complement activation and facilitating pathogen recognition by phagocytes, acting as a predecessor of antibodies. In addition, PTX3 is essential in female fertility by acting as a nodal point for the assembly of the cumulus oophorus hyaluronan-rich extracellular matrix. Here we will concisely review the general properties of PTX3 in the context of the pentraxin superfamily and discuss recent data suggesting that PTX3 plays a cardiovascular protective effect. PTX3 may represent a new marker in vascular pathology which correlates with the risk of developing vascular events.

Misleading Population Estimates: Biases and Consistency of Visual Surveys and Matrix Modelling in the Endangered Bearded Vulture

Conservation strategies for long-lived vertebrates require accurate estimates of parameters relative to the populations' size, numbers of non-breeding individuals (the “cryptic” fraction of the population) and the age structure. Frequently, visual survey techniques are used to make these estimates but the accuracy of these approaches is questionable, mainly because of the existence of numerous potential biases. Here we compare data on population trends and age structure in a bearded vulture (Gypaetus barbatus) population from visual surveys performed at supplementary feeding stations with data derived from population matrix-modelling approximations. Our results suggest that visual surveys overestimate the number of immature (<2 years old) birds, whereas subadults (3–5 y.o.) and adults (>6 y.o.) were underestimated in comparison with the predictions of a population model using a stable-age distribution. In addition, we found that visual surveys did not provide conclusive information on true variations in the size of the focal population. Our results suggest that although long-term studies (i.e. population matrix modelling based on capture-recapture procedures) are a more time-consuming method, they provide more reliable and robust estimates of population parameters needed in designing and applying conservation strategies. The findings shown here are likely transferable to the management and conservation of other long-lived vertebrate populations that share similar life-history traits and ecological requirements.

Assessment Of Dynamic Properties Of A Crowd Model For Human-Structure Interaction Modeling

As lightweight and slender structural elements are more frequently used in the design, large scale structures become more flexible and susceptible to excessive vibrations. To ensure the functionality of the structure, dynamic properties of the occupied structure need to be estimated during the design phase. Traditional analysis method models occupants simply as an additional mass; however, research has shown that human occupants could be better modeled as an additional degree-of- freedom. In the United Kingdom, active and passive crowd models are proposed by the Joint Working Group as a result of a series of analytical and experimental research. It is expected that the crowd models would yield a more accurate estimation to the dynamic response of the occupied structure. However, experimental testing recently conducted through a graduate student project at Bucknell University indicated that the proposed passive crowd model might be inaccurate in representing the impact on the structure from the occupants. The objective of this study is to provide an assessment of the validity of the crowd models proposed by JWG through comparing the dynamic properties obtained from experimental testing data and analytical modeling results. The experimental data used in this study was collected by Firman in 2010. The analytical results were obtained by performing a time-history analysis on a finite element model of the occupied structure. The crowd models were created based on the recommendations from the JWG combined with the physical properties of the occupants during the experimental study. During this study, SAP2000 was used to create the finite element models and to implement the analysis; Matlab and ME¿scope were used to obtain the dynamic properties of the structure through processing the time-history analysis results from SAP2000. The result of this study indicates that the active crowd model could quite accurately represent the impact on the structure from occupants standing with bent knees while the passive crowd model could not properly simulate the dynamic response of the structure when occupants were standing straight or sitting on the structure. Future work related to this study involves improving the passive crowd model and evaluating the crowd models with full-scale structure models and operating data.