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INTRODUCTION The health sciences and biotechnology arc booming research sectors. (2) Due to the highly technical nature of this research, universities arc in a unique position to aid private industry [...] more...

Angiotensin-converting enzyme 2 (ACE2) is a newly discovered homolog of ACE whose actions oppose those of angiotensin II (AngII). However, the underlying mechanisms by which ACE2 effectively suppresses early atherosclerotic lesions remain poorly understood. Here, we show, both in vitro and in vivo, that ACE2 inhibited the development of early atherosclerotic lesions by suppressing the growth of vascular smooth muscle cells (VSMCs) and improving endothelial function. In a relatively large cohort animal study (66 rabbits), aortic segments transfected by Ad-ACE2 showed significantly attenuated fatty streak formation, neointimal macrophage infiltration, and alleviation of impaired endothelial function. Segments also showed decreased expression of monocyte chemoattractant protein 1, lectin-like oxidized low-density lipoprotein receptor 1, and proliferating cell nuclear antigen, which led to the delayed onset of atherosclerotic lesions. At the cellular level, ACE2 significantly modulated Angll-induced growth and migration in human umbilical vein endothelial cells and VSMCs. The antiatherosclerotic effect of ACE2 involved down-regulation of the ERK-p38, JAK-STAT, and AngII-ROS-NF-[kappa]B signaling pathways and up-regulation of the PI3K-Akt pathway. These findings revealed the molecular mechanisms of the antiatherosclerotic activity of ACE2 and suggested that modulation of ACE2 could offer a therapeutic option for treating atherosclerosis. atherosclerosis | endothelial cell | gene therapy | smooth muscle cell | signaling pathway doi/ 10.1073/pnas.1001253107 more...

Neutrophil extracellular traps (NETs) are part of the innate immune response to infections. NETs are a meshwork of DNA fibers comprising histones and antimicrobial proteins. Microbes are immobilized in NETs and encounter a locally high and lethal concentration of effector proteins. Recent studies show that NETs are formed inside the vasculature in infections and noninfectious diseases. Here we report that NETs provide a heretofore unrecognized scaffold and stimulus for thrombus formation. NETs perfused with blood caused platelet adhesion, activation, and aggregation. DNase or the anticoagulant heparin dismantled the NET scaffold and prevented thrombus formation. Stimulation of platelets with purified histones was sufficient for aggregation. NETs recruited red blood cells, promoted fibrin deposition, and induced a red thrombus, such as that found in veins. Markers of extracellular DNA traps were detected in a thrombus and plasma of baboons subjected to deep vein thrombosis, an example of inflammation-enhanced thrombosis. Our observations indicate that NETs are a previously unrecognized link between inflammation and thrombosis and may further explain the epidemiological association of infection with thrombosis. neutrophils | platelets | histones | red blood cells | chromatin doi/ 10.1073/pnas.1005743107 more...

Chronic fatigue syndrome (CFS) is a serious systemic illness of unknown cause. A recent study identified DNA from a xenotropic murine leukemia virus-related virus (XMRV) in peripheral blood mononuclear cells (PBMCs) from 68 of 101 patients (67%) by nested PCR, as compared with 8 of 218 (3.7%) healthy controls. However, four subsequent reports failed to detect any murine leukemia virus (MLV)-related virus gene sequences in blood of CFS patients. We examined 41 PBMC-derived DNA samples from 37 patients meeting accepted diagnostic criteria for CFS and found MLV-like virus gag gene sequences in 32 of 37 (86.5%) compared with only 3 of 44 (6.8%) healthy volunteer blood donors. No evidence of mouse DNA contamination was detected in the PCR assay system or the clinical samples. Seven of 8 gag-positive patients tested again positive in a sample obtained nearly 15 y later. In contrast to the reported findings of near-genetic identity of all XMRVs, we identified a genetically diverse group of MLV-related viruses. The gag and env sequences from CFS patients were more closely related to those of polytropic mouse endogenous retroviruses than to those of XMRVs and were even less closely related to those of ecotropic MLVs. Further studies are needed to determine whether the same strong association with MLV-related viruses is found in other groups of patients with CFS, whether these viruses play a causative role in the development of CFS, and whether they represent a threat to the blood supply. xenotropic murine leukemia virus-related virus | murine leukemia virus-like virus | viral gag gene sequence | polytropic | mouse mitochondria DNA PCR doi/ 10.1073/pnas.1006901107 more...

It is generally assumed that white adipocytes arise from resident adipose tissue mesenchymal progenitor cells. We challenge this paradigm by defining a hematopoietic origin for both the de novo development of a subset of white adipocytes in adults and a previously uncharacterized adipose tissue resident mesenchymal progenitor population. Lineage and cytogenetic analysis revealed that bone marrow progenitor (BMP)-derived adipocytes and adipocyte progenitors arise from hematopoietic cells via the myeloid lineage in the absence of cell fusion. Global gene expression analysis indicated that the BMP-derived fat cells are bona fide adipocytes but differ from conventional white or brown adipocytes in decreased expression of genes involved in mitochondrial biogenesis and lipid oxidation, and increased inflammatory gene expression. The BMP-derived adipocytes accumulate with age, occur in higher numbers in visceral than in subcutaneous fat, and in female versus male mice. BMP-derived adipocytes may, therefore, account in part for adipose depot heterogeneity and detrimental changes in adipose metabolism and inflammation with aging and adiposity. bone marrow | hematopoietic | stem cell doi/ 10.1073/pnas.1003512107 more...

Gallbladder cancer is a highly aggressive disease with poor prognosis that is two to six times more frequent in women than men. The development of gallbladder cancer occurs over a long time (more than 15 y) and evolves from chronic inflammation to dysplasia/metaplasia, carcinoma in situ, and invasive carcinoma. In the present study we found that, in female mice in which the oxysterol receptor liver X receptor--[beta] (LXR[beta]) has been inactivated, preneoplastic lesions of the gallbladder developed and evolved to cancer in old animals. LXR[beta] is a nuclear receptor involved in the control of lipid homeostasis, glucose metabolism, inflammation, proliferation, and CNS development. LXR[[beta].sup.-/-] female gallbladders were severely inflamed, with regions of dysplasia and high cell density, hyperchromasia, metaplasia, and adenomas. No abnormalities were evident in male mice, nor in LXR[[alpha.sup.-/-] or LXR[[alpha.sup.-/-][[beta].sup.-/-] animals of either sex. Interestingly, the elimination of estrogens with ovariectomy prevented development of preneoplastic lesions in LXR[[beta].sup.-/-] mice. The etiopathological mechanism seems to involve TGF-[beta] signaling, as the precancerous lesions were characterized by strong nuclear reactivity of phospho-SMAD-2 and SMAD-4 and loss of E-cadherin expression. Upon ovariectomy, E-cadherin was reexpressed on the cell membranes and immunoreactivity of pSMAD-2 in the nuclei was reduced. These findings suggest that LXR[beta] in a complex interplay with estrogens and TGF-[beta] could play a crucial role in the malignant transformation of the gallbladder epithelium. cancer | hormone | oxysterols | SMAD | E-cadherin doi/ 10.1073/pnas.1009483107 more...

8:15 PRELIMINARY DATA ON THE LONG-TERM SURVIVAL AND FUNCTION OF EMBRYONIC CHICK HEARTS MAINTAINED IN VITRO **, Lindsey Parks *, Terry Archer-Liefde-Chance and Army Lester, Kennesaw State University, Kennesaw, GA [...] more...

The Lempel-Ziv (LZ) complexity and its variants are popular metrics for characterizing biological signals. Proper interpretation of such analyses, however, has not been thoroughly addressed. In this letter, we study the effect of finite data size. We derive analytic expressions for the LZ complexity for regular and random sequences, and employ them to develop a normalization scheme. To gain further understanding, we compare the LZ complexity with the correlation entropy from chaos theory in the context of epileptic seizure detection from EEG data, and discuss advantages of the normalized LZ complexity over the correlation entropy. Index Terms--Biomedical signal analysis, epileptic seizure detection, Lempel-Ziv complexity. more...

Triggered by an encounter with survivors of the studies on twins conducted in Auschwitz by Joseph Mengele, who held both MD and PhD degrees, I offer thoughts on the extraordinary [...]

Adult T cell leukemia/lymphoma (ATLL) has been characterized as one of the most aggressive human neoplasias and its incidence is thought to be caused by both genetic and epigenetic alterations to the host cellular genes of T cells infected with human T cell leukemia virus type I (HTLV-I). A multilobulated nuclear appearance is an important diagnostic marker of ATLL, and we have now identified that the molecular mechanisms underlying these formations occur through microtubule rearrangement via phosphatidylinositol 3-kinase (PI3-kinase) activation by AILIM/ICOS signaling. We also show that PTEN and/or SHIP-1, which are PIP3 inositol phosphatases that inhibit the activation of downstream effectors of the PI3-kinase cascade, are disrupted in both ATLL neoplasias and in multilobulated nuclei-forming Jurkat cells. This down-regulation of PTEN was found to be essential for the formation of ATLL-type nuclear lobules. Furthermore, PI3-kinase and PTEN activities were observed to be closely associated with cellular proliferation. Thus, our results suggest that alteration of PI3-kinase signaling cascades, as a result of the down-regulation of inositol phosphatases, induces ATLL-type multilobulated nuclear formation and is also associated with the cellular proliferation of malignant T cell leukemias/lymphomas. activation-inducible lymphocyte immunomediatory molecule/inducible costimulator | human T cell leukemia virus type | multilobulated nuclei | PTEN | SHIP more...

The MYC protooncogene is frequently deregulated in human cancers. Here, by screening a kinase-directed library of small inhibitory RNAs, we identify glycogen synthase kinase 3 [beta] (GSK3 [BETA]) as a gene whose inactivation potentiates TNF-related apoptosis-inducing ligand death receptor-mediated apoptosis specifically in MYC-overexpressing cells. Small inhibitory RNA-induced silencing of GSK3[BETA] prevents phosphorylation of MYC on T58, thereby inhibiting recognition of MYC by the E3 ubiquitin ligase component FBW7. Attenuating the GSK3/[BETA]-FBW7 axis results in stabilization of MYC, up-regulation of surface levels of the TNF-related apoptosis-inducing ligand death receptor 5, and potentiation of death receptor 5-induced apoptosis in vitro and in vivo. These results identify GSK3[BETA] and FBW7 as potential cancer therapeutic targets and MYC as a critical substrate in the GSK3[BETA] survival-signaling pathway. The results also demonstrate paradoxically that MYC-expressing tumors might be treatable by drug combinations that increase rather than decrease MYC oncoprotein function. FBW7 | MYC | TNF-related apoptosis-inducing ligand more...

OCCUPATIONAL STRESS AND QUALITY OF CARE: NURSES PERSEPTIONS IN THE NEUROLOGICAL INTENSIVE CARE AND STEP-DOWN UNITS. Elizabeth Mosley, Dept. of Nursing, Uni. of Ala., Birmingham, AL 35294. There is no [...] more...

Theories of health and disease which oppose evaluative and descriptive claims or opt for one or the other in defining fundamental concepts err, it is argued, due to an oversimplified conception of both the science of medicine and the art of clinical judgment. The work of Georges Canguilhem on the biological dimensions of value and subjectivity is explored. I conclude that he avoids the falsehoods of (a) neutral, pure fact-based medical science, and (b) cultural, arbitrary notions of value. Keywords: biology, creativity, health, subjectivity, value more...

Twenty-sixth Annual Albert L. Tester Memorial Symposium, 11-12 April 2001 (1) The Albert L. Tester Memorial Symposium is held in honor of Professor Albert Tester, who, at the time of [...]

In the last two decades, scientists, government officials, and science policy experts have expressed concerns about the increasing role of financial interests in research. Many believe that these interests are undermining research by causing bias and error, suppression of results, and even outright fraud. This paper seeks to shed some light on this view by (2) explicating the concept research bias, (2) describing some ways that financial interests can cause research biases, and (3) discussing some strategies for mitigating or managing the influence of financial interests. These strategies include (a) using government funds to counter-balance privately funded research, (b) increasing public input into government funding decisions, (c) disclosing and managing conflicts of interest in research, (d) auditing data, (e) expanding access to data. Since it is neither possible nor desirable to eliminate financial interests from research, the wisest policy is to manage and counter-balance these interests for the good of science and society., Introduction The influence of financial interests on research and development (R & D) has grown steadily since the 1970s. Prior to World War II, research funding (public or private) was [...] more...

During the past four decades, biomedical scientists have slowly begun to recognize the unique opportunities for studying biomedical processes, disease etiology, and mechanisms of pathogenesis in populations with unusual genetic structures, physiological characteristics, focal endemic disease, or special circumstances. Such populations greatly extend our research capabilities and provide a natural laboratory for studying relationships among biobehavioral, genetic, and ecological processes that are involved in the development of disease. The models presented illustrate three different types of natural experiments: those occurring in traditionally living, modernizing, and modern populations. The examples are drawn from current research that involves population mechanisms of adaptation among East African Turkana pastoralists; a search for etiology and mechanisms of pathogenesis of an emerging disease among the Yakut people of Siberia; and psychosocial stress, hypertension, and cardiovascular disease in women working outside the home in New York City and among subpopulations in Hawaii. The models in general, and the examples in specific, represent natural laboratories in which relatively small intrapopulation differences and large interpopulation differences can be used to evaluate health and disease outcomes. more...

This autobiographical account of the life and achievements in the field of physiology of one of its outstanding and now august members tells about research and about a more rewarding role in developing three departments of physiology and fostering careers of others. Observations on the nature of department building/hiring and career-fostering are made. Research on muscle spindles is discussed. more...

Several reviews have been conducted in the development and application of three-dimensional (3-D) cell culture systems particularly in biomedical research. Some studies have involved new techniques in immunotherapy, description of multicellular-mediated drug resistance and ways in quantifying hypoxia. Several 3-D cultures have been used in researches on molecular mechanisms involved in metastasis and invasion in tumor spheroids. Likewise, these cultures were also used in exploring tumor angiogenesis and the importance of vascular endothelial growth factor. more...

Knowledge on cellular physiology is vital in understanding the mechanisms are functions of different forms of cellular membrane transport. The principles of cellular physiology are essential in understanding the pathogenesis or progression of diseases that are caused by disruptions in normal membrane transport of metabolites. Furthermore, the basic principles of cellular physiology such as the mass balance principle, flow-force relationship, capacitance and thermodynamic equilibrium is important in understanding the mechanisms of cellular metabolism and life cycle. more...