Antisense Approaches to the Function of Glial Cell Proteins a

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71598/1/j.1749-6632.1992.tb21074.x.pd

Cystic Fibrosis Airway Epithelia Fail to Kill Bacteria Because of Abnormal Airway Surface Fluid

AbstractDespite an increased understanding of the cellular and molecular biology of the CFTR Cl− channel, it is not known how defective Cl− transport across airway epithelia causes chronic bacterial infections in cystic fibrosis (CF) airways. Here, we show that common CF pathogens were killed when added to the apical surface of normal airway epithelia. In contrast, these bacteria multiplied on CF epithelia. We found that bactericidal activity was present in airway surface fluid of both normal and CF epithelia. However, because bacterial killing required a low NaCl concentration and because CF surface fluid has a high NaCl concentration, CF epithelia failed to kill bacteria. This defect was corrected by reducing the NaCl concentration on CF epithelia. These data explain how the loss of CFTR Cl− channels may lead to lung disease and suggest new approaches to therapy

The Mechanism of Sertoli-Germ Cell Interaction a

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73914/1/j.1749-6632.1987.tb25056.x.pd

The effect of 2-methoxyethanol and methoxyacetic acid on sertoli cell lactate production and protein synthesis in vitro

Exposure to 2-methoxyethanol (ME) or its major metabolite, methoxyacetic acid (MA), results in spermatocyte depletion and testicular atrophy in experimental animals. The site of spermatogenesis is within the seminiferous tubule. Sertoli cells support spermatogenesis, synthesizing and secreting proteins, and metabolic substrates for utilization by differentiating germ cells in the seminiferous tubule lumen. One of these substrates, lactate, is preferentially metabolized by spermatocytes. Therefore, because germ cells are dependent upon the metabolic products of Sertoli cells, the effect of ME and MA on production of lactate and protein synthesis was measured in cultured rat Sertoli cells. Cell cultures were incubated with ME or MA at 0, 3, or 10 m for up to 12 hr. No significant difference was seen in total protein synthesis as measured by [3H]leucine incorporation. ME and MA had no apparent effect on cell viability. However, lactate concentrations and rates of lactate accumulation were significantly decreased by MA, but not ME, at both 3 and 10 m following incubation for 6, 9, and 12 hr. The results suggest that inhibition of Sertoli cell lactate production resulting from ME or MA exposure could account for the inhibitory action of these compounds on spermatogenesis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24672/1/0000091.pd

Carbohydrate-derived amphiphilic macromolecules: a biophysical structural characterization and analysis of binding behaviors to model membranes.

The design and synthesis of enhanced membrane-intercalating biomaterials for drug delivery or vascular membrane targeting is currently challenged by the lack of screening and prediction tools. The present work demonstrates the generation of a Quantitative Structural Activity Relationship model (QSAR) to make a priori predictions. Amphiphilic macromolecules (AMs) "stealth lipids" built on aldaric and uronic acids frameworks attached to poly(ethylene glycol) (PEG) polymer tails were developed to form self-assembling micelles. In the present study, a defined set of novel AM structures were investigated in terms of their binding to lipid membrane bilayers using Quartz Crystal Microbalance with Dissipation (QCM-D) experiments coupled with computational coarse-grained molecular dynamics (CG MD) and all-atom MD (AA MD) simulations. The CG MD simulations capture the insertion dynamics of the AM lipophilic backbones into the lipid bilayer with the PEGylated tail directed into bulk water. QCM-D measurements with Voigt viscoelastic model analysis enabled the quantitation of the mass gain and rate of interaction between the AM and the lipid bilayer surface. Thus, this study yielded insights about variations in the functional activity of AM materials with minute compositional or stereochemical differences based on membrane binding, which has translational potential for transplanting these materials in vivo. More broadly, it demonstrates an integrated computational-experimental approach, which can offer a promising strategy for the in silico design and screening of therapeutic candidate materials

Abnormal small heat shock protein interactions involving neuropathy-associated HSP22 (HSPB8) mutants

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154632/1/fsb2fj065911fje.pd

The role of the circadian clock in animal models of mood disorders.

An association between circadian clock function and mood regulation is well established and has been proposed as a factor in the development of mood disorders. Patients with depression or mania suffer disturbed sleep-wake cycles and altered rhythms in daily activities. Environmentally disrupted circadian rhythms increase the risk of mood disorders in the general population. However, proof that a disturbance of circadian rhythms is causally involved in the development of psychiatric disorders remains elusive. Using clock gene mutants, manipulations of sleep-wake and light-dark cycles, and brain lesions affecting clock function, animal models have been developed to investigate whether circadian rhythm disruptions alter mood. In this review, selected animal models are examined to address the issue of causality between circadian rhythms and affective behavior