Motor unit discharge rate is correlated within individuals: A case for multilevel model statistical analysis

Statistical analysis of motor unit discharge rate commonly uses the ordinary least squares based ANOVA and regression analyses or a repeated-measures ANOVA is used to account for within motor unit variance when the same motor unit is assessed multiple times. Both of these methods assume statistical independence of multiple motor units assessed within an individual. This investigation details two studies which quantify the statistical dependence of motor units within an individual. During a ramp contraction, motor unit initial discharge rate is mildly correlated within an individual (ICC: 0.11), though accounting for this effect significantly impacts regression analysis (p = 0.01). When a contraction is held at constant force and multiple observations are made on a motor unit, the motor unit discharges are more highly correlated (ICC: 0.41), even after accounting for the effects of multiple motor unit observations. A subject-level ICC of 0.01 can increase Type 1 error rate to 3.9–19.7%, depending on the number of motor units and study subjects. The increase in Type 1 error due to subject-level effects can be mitigated through the use of multilevel modeling techniques. This study details the use and benefit of multilevel models when statistically analyzing motor unit discharge data.     

Variability in patterns of growth and morphology of Posidonia oceanica exposed to urban and industrial wastes: contrasts with two reference locations

Urban and industrial wastes have been claimed to negatively affect Posidonia oceanica meadows, but few studies have addressed this issue by comparing disturbed locations with replicated reference locations. Here, we examined the general proposition that patterns of growth and morphology of P. oceanica exposed to urban and industrial effluents were different from those observed in reference meadows. Hypotheses were both on differences in mean values of response variables and on variation of these measures at a hierarchy of spatial scales (from centimetres to hundreds of metres). Results indicated a significant reduction in mean number of intermediate leaves at the outfall compared to reference locations, whereas the opposite pattern occurred for juvenile leaves. There were significant, though temporally variable differences in growth of rhizomes between disturbed and reference locations, with reduced growth at the outfall in 2 out of 3 years analysed. Measures of spatial variance in number of juvenile leaves and length of adult leaves at the scale of shoots were significantly larger at the outfall compared to reference locations. At the same scale, measures of spatial variance in length of juvenile and intermediate leaves were significantly lower at the putatively impacted location. Spatial variance in number of intermediate leaves was reduced at the outfall compared to reference locations at the scale of quadrats. Past values of spatial variance in number of leaves per shoot were lower at the outfall than at the two reference locations at the scale of shoots, whereas the opposite occurred at the scale of areas. None of the structural variables examined showed any difference between the putatively impacted location and the two reference locations, either in terms of mean response or as changes in spatial variance. These results indicated that integrating methods to examine present and past events of disturbance, including analyses to detect changes in spatial variance of response variables, may provide a powerful approach to the analysis of environmental impacts on P. oceanica.     

Design,synthesis, docking and anti-inflammatory evaluation of novel series of benzofuran based prodrugs

Several new benzofuran derivatives were synthesized, via appropriate synthetic route as anti-inflammatory agents. The anti-inflammatory activity of the prepared compounds was evaluated using carrageenan rat model. Among the synthesized compounds, some compounds showed comparable anti-inflammatory activity to nimesulide, the standard drug taken for anti-inflammatory studies. Docking study of the prepared compounds was performed for the study of interaction of molecules with the active site of COX-2. Preliminary biological studies and docking gave an interesting insight, into the validity of employing benzofuran analogues as good anti-inflammatory agent.     

Optimising Body Layout Design of Limbed Machines

This paper presents our efforts to explain why mammals have large thigh muscles while insects have small ones. After a discussion of this observation a definition of body foot ratio is defined which describes how animals stand and how their legs are arranged. To investigate the mechanics, we present a closed optimum solution of the body foot ratio for a 2D two-leg walking machine. A multi-walker is used as a case for 3D general analysis, and the numerical simulation is presented. Both 2D and 3D case studies can explain the above observations of mammals and insects. These findings can also be used as a guide for the design of man-made limbed machines.     

Process design for enzymatic peptide synthesis in near-anhydrous organic media

This work is a case study on a process design for enzymatic peptide synthesis, which is based on and inspired by previously established data about the Alcalase-catalyzed coupling of an amino acid amide and a chemically synthesized activated N-protected amino acid carbamoylmethyl ester in near-anhydrous tetrahydrofuran. The choices with regard to Alcalase formulation, the type of reactor, method of controlling the water content, and whether or not to recycle the enzyme, are discussed. In addition, an estimate is given for the reactor size, volumes of solvent, amount of substrate, enzyme and molecular sieves, needed in order to meet a specific demand for peptides. We believe that this case study gives a good indication of the various choices that have to be made when designing a process for enzymatic peptide synthesis and the implications of these choices.     

Ligand based design and synthesis of pyrazole based derivatives as selective COX-2 inhibitors

The design and synthesis of novel pyrazole based derivatives has been carried out using the ligand based approach like pharmacophore and QSAR modelling of reported pyrazoles from the available literature to investigate the chemical features that are essential for the design of selective and potent COX-2 inhibitors. Both pharmacophore and QSAR models with good statistical parameters were selected for the design of the lead molecule. Also by exploiting the chemical structures of selective and marketed COX-2 inhibitors, celecoxib and SC-558 were used in designing the molecules which are used in the treatment of inflammation and related disorders. The therapeutic action of the Non-Steroidal Anti-inflammatory Agents (NSAIDs) is based primarily on the COX-2 inhibition. With this background we have synthesized some azomethine derivatives of 3-methyl-1-substituted-4-phenyl-6-[{(1E)-phenylmethylene}amino]-1,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile 6(a-o) and were characterized by ¹HNMR, ¹³CNMR and Mass spectral techniques. All the synthesized pyrazole derivatives were tested for in vitro membrane stability property in both COX-1 & COX-2 inhibition studies and in vivo anti-inflammatory activity by carrageenan induced rat paw edema model. Among them, compound 6k showed very good activity by in vivo anti-inflammatory activity with 0.8575 mmol/kg as ED₅₀. Similarly compounds 6m, 6o, 6i and 6h exhibited comparable anti-inflammatory activity to standard drugs. Also the active compounds were further screened for ulcerogenic activity and were found be safer with less ulcer index compared to the marketed drugs like aspirin, ibuprofen and celecoxib.     

New A2A adenosine receptor antagonists: a structure-based upside-down interaction in the receptor cavity

Adenosine receptor antagonists are generally based on heterocyclic core structures presenting substituents of various volumes and chemical-physical profiles. Adenine and purine-based adenosine receptor antagonists have been reported in literature. In this work we combined various substituents in the 2, 6, and 8-positions of 9-ethylpurine to depict a structure-affinity relationship analysis at the human adenosine receptors. Compounds were rationally designed trough molecular modeling analysis and then synthesized and evaluated at radioligand binding studies at human adenosine receptors. The new compounds showed affinity for the human adenosine receptors, with some derivatives endowed with low nanomolar K_i data, in particular at the A_2AAR subtype. The purine core proves to be a versatile core structure for the development of novel adenosine receptor antagonists with nanomolar affinity for these membrane proteins.     

Discovery of hybrid Hsp90 inhibitors and their anti-neoplastic effects against gefitinib-resistant non-small cell lung cancer (NSCLC)

Heat shock protein 90 (Hsp90) represents an attractive cancer therapeutic target due to its role in the stabilization and maturation of many oncogenic proteins. We have designed a series of hybrid Hsp90 inhibitors by connecting the resorcinol ring of VER-49009 (2) and the trimethoxyphenyl ring of PU3 (3) using structure-based approach. Subsequent testing established that compound 1f inhibited gefitinib-resistant H1975 cell proliferation, brought about the degradation of Hsp90 client proteins including EGFR, Met, Her2 and Akt and induced the expression of Hsp70. The design, synthesis, and evaluation of 1f are described herein.     

Evaluating Chessboard MANOVA Designs Using Predictive and Matching Configural Frequency Analysis

This paper concerns the nonparametric evaluation of chessboard MANOVA designs. For this purpose, a matching procedure based on rook methodology is suggested as a complement to predictive coafigural frequency analysis. Using this procedure, a multivariate hypothesis can be tested in a single test. It is also possible to design a significance test to fit a specific composite hypothesis. The procedure is illustrated by results from a multivariate psychopharmacological experiment in which the effects of alcohol and caffeine were studied on test performance and volatility.