Spectral analysis methods for the robust measurement of the flexural rigidity of biopolymers

The mechanical properties of biopolymers can be determined from a statistical analysis of the ensemble of shapes they exhibit when subjected to thermal forces. In practice, extracting information from fluorescence microscopy images can be challenging due to low signal/noise ratios and other artifacts. To address these issues, we develop a suite of tools for image processing and spectral data analysis that is based on a biopolymer contour representation expressed in a spectral basis of orthogonal polynomials. We determine biopolymer shape and stiffness using global fitting routines that optimize a utility function measuring the amount of fluorescence intensity overlapped by such contours. This approach allows for filtering of high-frequency noise and interpolation over sporadic gaps in fluorescence. We use benchmarking to demonstrate the validity of our methods, by analyzing an ensemble of simulated images generated using a simulated biopolymer with known stiffness and subjected to various types of image noise. We then use these methods to determine the persistence lengths of taxol-stabilized microtubules. We find that single microtubules are well described by the wormlike chain polymer model, and that ensembles of chemically identical microtubules show significant heterogeneity in bending stiffness, which cannot be attributed to sampling or fitting errors. We expect these approaches to be useful in the study of biopolymer mechanics and the effects of associated regulatory molecules.     

Reduced pulmonary surfactant interaction of daptomycin analogs via tryptophan replacement with alternative amino acids

Daptomycin was shown to interact in vitro with pulmonary surfactant leading to reduction of its antibacterial activity. We report herein the preparation and anti-staphylococcal activity of a series of daptomycin analogs with reduced pulmonary surfactant interaction by replacing tryptophan with various amino acids.     

Systems analysis of eleven rodent disease models reveals an inflammatome signature and key drivers

Common inflammatome gene signatures as well as disease‐specific signatures were identified by analyzing 12 expression profiling data sets derived from 9 different tissues isolated from 11 rodent inflammatory disease models. The inflammatome signature significantly overlaps with known drug targets and co‐expressed gene modules linked to metabolic disorders and cancer. A large proportion of genes in this signature are tightly connected in tissue‐specific Bayesian networks (BNs) built from multiple independent mouse and human cohorts. Both the inflammatome signature and the corresponding consensus BNs are highly enriched for immune response‐related genes supported as causal for adiposity, adipokine, diabetes, aortic lesion, bone, muscle, and cholesterol traits, suggesting the causal nature of the inflammatome for a variety of diseases. Integration of this inflammatome signature with the BNs uncovered 151 key drivers that appeared to be more biologically important than the non‐drivers in terms of their impact on disease phenotypes. The identification of this inflammatome signature, its network architecture, and key drivers not only highlights the shared etiology but also pinpoints potential targets for intervention of various common diseases.     

Insights into the pathogenicity of Penicillium marneffei.

Penicillium marneffei is a significant pathogen of AIDS patients in Southeast Asia. This fungus is unique in that it is the only dimorphic member of the genus. Pathogenesis of P. marneffei requires the saprobic mold form to undergo a morphological change upon tissue invasion. The in vivo form of this fungus reproduces as a fission yeast that capably evades the host immune system. The processes that control these morphological changes, better termed as phase transition, can be replicated in vitro by incubation of the mold form at 37 degrees C. The unidentified molecular mechanisms regulating phase transition in this fungus are now being uncovered using modern methodologies and novel strategies. A better comprehension of these underlying regulatory pathways will provide insight into eukaryotic cellular development as well as the potential factors responsible for infections caused by P. marneffei and other fungi. Such knowledge may lead to better chemotherapeutic interventions of fungal diseases.     

Greater sensitivity of the vestibulosympathetic reflex in the upright posture in humans.

Otolith organs have been shown to activate the sympathetic nervous system in the prone position by head-down rotation (HDR) in humans. To date, otolithic stimulation by HDR has not been comprehensively studied in the upright posture. The purpose of the present study was to determine whether otolithic stimulation increases muscle sympathetic nerve activity (MSNA) in the upright posture. It was hypothesized that stimulation of the otolith organs would increase MSNA in the upright posture, despite increased baseline sympathetic activation due to unloading of the baroreceptors. MSNA, arterial blood pressure, heart rate, and degree of head rotation were measured during HDR in 18 volunteers (23 +/- 1 yr) in different postures. Study 1 (n = 11) examined HDR in the prone and sitting positions and study 2 (n = 7) examined HDR in the prone and 60 degrees head-up tilt positions. Baseline MSNA was 8 +/- 4, 15 +/- 4, and 33 +/- 2 bursts/min for prone, sitting, and head-up tilt, respectively. HDR significantly increased MSNA in the prone (Delta4 +/- 1 and Delta105 +/- 37% for burst frequency and total activity, respectively), sitting (Delta5 +/- 1 and Delta43 +/- 12%), and head-up tilt (Delta7 +/- 1 and Delta110 +/- 41%; P < 0.05). Sensitivity of the vestibulosympathetic reflex (%DeltaMSNA/DeltaHDR; degree of head rotation) was significantly greater in the sitting and head-up tilt than prone position (prone = 74 +/- 22; sitting = 109 +/- 30; head-up tilt = 276 +/- 103; P < 0.05). These data indicate that stimulation of the otolith organs can mediate increases in MSNA in the upright posture and suggest a greater sensitivity of the vestibulosympathetic reflex in the upright posture in humans.