Faculty Bibliography

Even with the most meticulous planning, and utilizing the most experienced fossil-hunters, fossil prospecting in remote and/or extensive areas can be time-consuming, expensive, logistically challenging, and often hit or miss. While nothing can predict or guarantee with 100% assurance that fossils will be found in any particular location, any procedures or techniques that might increase the odds of success would be a major benefit to the field. Here we describe, and test, one such technique that we feel has great potential for increasing the probability of finding fossiliferous sediments - a relatively simple spectral signature model using the spatial analysis and image classification functions of ArcGIS((R))10 that creates interactive thematic land cover maps that can be used for "remote" fossil prospecting. Our test case is the extensive Eocene sediments of the Uinta Basin, Utah - a fossil prospecting area encompassing approximately 1200 square kilometers. Using Landsat 7 ETM+ satellite imagery, we "trained" the spatial analysis and image classification algorithms using the spectral signatures of known fossil localities discovered in the Uinta Basin prior to 2005 and then created interactive probability models highlighting other regions in the Basin having a high probability of containing fossiliferous sediments based on their spectral signatures. A fortuitous "post-hoc" validation of our model presented itself. Our model identified several paleontological "hotspots", regions that, while not producing any fossil localities prior to 2005, had high probabilities of being fossiliferous based on the similarities of their spectral signatures to those of previously known fossil localities. Subsequent fieldwork found fossils in all the regions predicted by the model.

BACKGROUND: Desmosomes and adherens junctions provide mechanical continuity between cardiac cells, whereas gap junctions allow for cell-cell electrical/metabolic coupling. These structures reside at the cardiac intercalated disc (ID). Also at the ID is the voltage-gated sodium channel (VGSC) complex. Functional interactions between desmosomes, gap junctions, and VGSC have been demonstrated. Separate studies show, under various conditions, reduced presence of gap junctions at the ID and redistribution of connexin43 (Cx43) to plaques oriented parallel to fiber direction (gap junction "lateralization"). OBJECTIVE: To determine the mechanisms of Cx43 lateralization, and the fate of desmosomal and sodium channel molecules in the setting of Cx43 remodeling. METHODS: Adult sheep were subjected to right ventricular pressure overload (pulmonary hypertension). Tissue was analyzed by quantitative confocal microscopy and by transmission electron microscopy. Ionic currents were measured using conventional patch clamp. RESULT: Quantitative confocal microscopy demonstrated lateralization of immunoreactive junctional molecules. Desmosomes and gap junctions in lateral membranes were demonstrable by electron microscopy. Cx43/desmosomal remodeling was accompanied by lateralization of 2 microtubule-associated proteins relevant for Cx43 trafficking: EB1 and kinesin protein Kif5b. In contrast, molecules of the VGSC failed to reorganize in plaques discernable by confocal microscopy. Patch-clamp studies demonstrated change in amplitude and kinetics of sodium current and a small reduction in electrical coupling between cells. CONCLUSIONS: Cx43 lateralization is part of a complex remodeling that includes mechanical and gap junctions but may exclude components of the VGSC. We speculate that lateralization results from redirectionality of microtubule-mediated forward trafficking. Remodeling of junctional complexes may preserve electrical synchrony under conditions that disrupt ID integrity.

Gap junctions are essential to the function of multicellular animals, which require a high degree of coordination between cells. In vertebrates, gap junctions comprise connexins and currently 21 connexins are known in humans. The functions of gap junctions are highly diverse and include exchange of metabolites and electrical signals between cells, as well as functions, which are apparently unrelated to intercellular communication. Given the diversity of gap junction physiology, regulation of gap junction activity is complex. The structure of the various connexins is known to some extent; and structural rearrangements and intramolecular interactions are important for regulation of channel function. Intercellular coupling is further regulated by the number and activity of channels present in gap junctional plaques. The number of connexins in cell-cell channels is regulated by controlling transcription, translation, trafficking, and degradation; and all of these processes are under strict control. Once in the membrane, channel activity is determined by the conductive properties of the connexin involved, which can be regulated by voltage and chemical gating, as well as a large number of posttranslational modifications. The aim of the present article is to review our current knowledge on the structure, regulation, function, and pharmacology of gap junctions. This will be supported by examples of how different connexins and their regulation act in concert to achieve appropriate physiological control, and how disturbances of connexin function can lead to disease.

This report outlines a goal-directed scientific agenda for a national initiative to overcome the Alzheimer's disease (AD) crisis. The statement; which reflects the collective views and recommendations of leaders in AD research; is intended to aid the implementation of the National Alzheimer's Project Act (NAPA)'s National Plan to defeat AD. The primary public policy aims of this 10-year scientific agenda are to discover; validate; and develop: (1) a broad range of technologies; tools and algorithms for early detection of people with symptomatic AD; and asymptomatic individuals at elevated risk for AD and other dementias; and (2) a wide range of interventions to preserve and/or restore health and normal neural function; aiming to maintain independent functioning for as long as possible. The long-term scientific public health objectives of this comprehensive plan are to: (1) reduce the number of people with chronic disabling symptoms who will require prolonged care and; eventually; reduce the number of asymptomatic people at elevated risk for AD/dementia; (2) delay the onset of chronic disability for people with AD and other degenerative brain disorders; and (3) lower the cost and burden of care. The plan calls for significant expansion of research programs to identify and validate the cause(s) and pathogenesis of AD; genetic and epigenetic factors that contribute to AD risk; therapeutic targets that affect disease progression; surrogate biomarkers of AD pathobiology; and technologies for early detection of AD.

Peripherin, a neuronal intermediate filament protein implicated in neurodegenerative disease, coexists with the neurofilament triplet proteins [neurofilament light (NFL), medium (NFM), and heavy (NFH) chain] but has an unknown function. The earlier peak expression of peripherin than the triplet during brain development and its ability to form homopolymers, unlike the triplet, which are obligate heteropolymers, have supported a widely held view that peripherin and neurofilament triplets form separate filament systems. However, here, we demonstrate that, despite a postnatal decline in expression, peripherin is as abundant as the triplet in the adult PNS and exists in a relatively fixed stoichiometry with these subunits. Peripherin exhibits a distribution pattern identical to those of triplet proteins in sciatic axons and colocalizes with NFL on single neurofilaments by immunogold electron microscopy. Peripherin also coassembles into a single network of filaments containing NFL, NFM, and NFH with and without alpha-internexin in quadruple- or quintuple-transfected SW13vim(-) cells. Genetically deleting NFL in mice dramatically reduces peripherin content in sciatic axons. Moreover, peripherin mutations has been shown to disrupt the neurofilament network in transfected SW13vim(-) cells. These data show that peripherin and the neurofilament proteins are functionally interdependent. The results strongly support the view that, rather than forming an independent structure, peripherin is a subunit of neurofilaments in the adult PNS. Our findings provide a basis for its close relationship with neurofilaments in PNS diseases associated with neurofilament accumulation.

BACKGROUND: Stem cells are located in specific regulatory environments termed niches, which modulate the survival and proliferation of the cells through a variety of both mitogenic and inhibitory cytokines. In the murine prostate, stem cells are located in the proximal region of prostatic ducts. We examined the regulation of murine prostate cells in the stem cell niche by transforming growth factor beta (TGF-beta) and stem cell factor (SCF). METHODS: Prostate cells from the proximal and distal regions of prostatic ducts were cultured in the presence and absence of TGF-beta and SCF, both on collagen-coated wells and in collagen gels. Cell growth on collagen was assessed by determining cell number. Cell growth in collagen gels was quantified by determining the number, size and complexity of prostatic ducts. The basal and luminal phenotype of the cells was determined by immunohistochemistry. RESULTS: Endogenous TGF-beta inhibited proliferation and promoted differentiation of proximal cells towards a luminal phenotype. It also inhibited duct-forming capacity and promoted differentiation of prostatic ducts towards a luminal phenotype. Addition of SCF enhanced proximal cell proliferation on collagen-coated wells and duct formation in collagen gels. Proliferation was further increased by ablation of endogenous TGF-beta. CONCLUSION: Proliferation and the basal/luminal cell composition of cells isolated from the proximal region of prostatic ducts, the stem cell niche, is regulated in part by opposing effects of SCF and endogenous TGF-beta. Prostate 72:998-1005, 2012. (c) 2011 Wiley Periodicals, Inc.

Ag receptor diversity involves the introduction of DNA double-stranded breaks during lymphocyte development. To ensure fidelity, cleavage is confined to the G(0)-G(1) phase of the cell cycle. One established mechanism of regulation is through periodic degradation of the RAG2 recombinase protein. However, there are additional levels of protection. In this paper, we show that cyclical changes in the IL-7R signaling pathway functionally segregate pro-B cells according to cell cycle status. In consequence, the level of a downstream effector of IL-7 signaling, phospho-STAT5, is inversely correlated with cell cycle expression of Rag, a key gene involved in recombination. Higher levels of phopho-STAT5 in S-G(2) correlate with decreased Rag expression and Rag relocalization to pericentromeric heterochromatin. These cyclical changes in transcription and locus repositioning are ablated upon transformation with v-Abl, which renders STAT5 constitutively active across the cell cycle. We propose that this activity of the IL-7R/STAT5 pathway plays a critical protective role in development, complementing regulation of RAG2 at the protein level, to ensure that recombination does not occur during replication. Our data, suggesting that pro-B cells are not a single homogeneous population, explain inconsistencies in the role of IL-7 signaling in regulating Igh recombination.

Germline stem cells are key to genome transmission to future generations. Over recent years, there have been numerous insights into the regulatory mechanisms that govern both germ cell specification and the maintenance of the germline in adults. Complex regulatory interactions with both the niche and the environment modulate germline stem cell function. This perspective highlights some examples of this regulation to illustrate the diversity and complexity of the mechanisms involved.