401 research outputs found
Water Level Observations in Mangrove Swamps During Two Hurricanes in Florida
Little is known about the effectiveness of mangroves in suppressing water level heights during landfall of tropical storms and hurricanes. Recent hurricane strikes along the Gulf Coast of the United States have impacted wetland integrity in some areas and hastened the need to understand how and to what degree coastal forested wetlands confer protection by reducing the height of peak water level. In recent years, U.S. Geological Survey Gulf Coast research projects in Florida have instrumented mangrove sites with continuous water level recorders. Our ad hoc network of water level recorders documented the rise, peak, and fall of water levels (6 0.5 hr) from two hurricane events in 2004 and 2005. Reduction of peak water level heights from relatively in-line gages associated with one storm surge event indicated that mangrove wetlands can reduce water level height by as much as 9.4 cm/km inland over intact, relatively unchannelized expanses. During the other event, reductions were slightly less for mangroves along a river corridor. Estimates of water level attenuation were within the range reported in the literature but erred on the conservative side. These synoptic data from single storm events indicate that intact mangroves may support a protective role in reducing maximum water level height associated with surge
A Membrane Defect in the Pathogenesis of the Smith-Lemli-Opitz Syndrome
The Smith-Lemli-Opitz syndrome (SLOS) is an often lethal birth defect resulting from mutations in the gene responsible for the synthesis of the enzyme 3beta-hydroxy-steroid-Delta7-reductase, which catalyzes the reduction of the double bond at carbon 7 on 7-dehydrocholesterol (7-DHC) to form unesterified cholesterol. We hypothesize that the deficiency in cholesterol biosynthesis and subsequent accumulation of 7-DHC in the cell membrane leads to defective composition, organization, dynamics, and function of the cell membrane. Using skin fibroblasts obtained from SLOS patients, we demonstrate that the SLOS membrane has increased 7-DHC and reduced cholesterol content and abnormal membrane fluidity. X-ray diffraction analyses of synthetic membranes prepared to mimic SLOS membranes revealed atypical membrane organization. In addition, calcium permeability is markedly augmented, whereas membrane-bound Na+/K+ATPase activity, folate uptake, inositol-1,4,5-trisphosphate signaling, and cell proliferation rates are markedly suppressed. These data indicate that the disturbance in membrane sterol content in SLOS, likely at the level of membrane caveolae, directly contributes to the widespread tissue abnormalities in this disease
mTOR Inhibitors Synergize on Regression, Reversal of Gene Expression, and Autophagy in Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) affects more than half a million people worldwide and is the third most common cause of cancer deaths. Because mammalian target of rapamycin (mTOR) signaling is up-regulated in 50% of HCCs, we compared the effects of the U.S. Food and Drug Administration-approved mTOR-allosteric inhibitor, RAD001, with a new-generation phosphatidylinositol 3-kinase/mTOR adenosine triphosphate-site competitive inhibitor, BEZ235. Unexpectedly, the two drugs acted synergistically in inhibiting the proliferation of cultured HCC cells. The synergistic effect closely paralleled eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) dephosphorylation, which is implicated in the suppression of tumor cell proliferation. In a mouse model approximating human HCC, the drugs in combination, but not singly, induced a marked regression in tumor burden. However, in the tumor, BEZ235 alone was as effective as the combination in inhibiting 4E-BP1 phosphorylation, which suggests that additional target(s) may also be involved. Microarray analyses revealed a large number of genes that reverted to normal liver tissue expression in mice treated with both drugs, but not either drug alone. These analyses also revealed the down-regulation of autophagy genes in tumors compared to normal liver. Moreover, in HCC patients, altered expression of autophagy genes was associated with poor prognosis. Consistent with these findings, the drug combination had a profound effect on UNC51-like kinase 1 (ULK1) dephosphorylation and autophagy in culture, independent of 4E-BP1, and in parallel induced tumor mitophagy, a tumor suppressor process in liver. These observations have led to an investigator-initiated phase 1B-2 dose escalation trial with RAD001 combined with BEZ235 in patients with HCC and other advance
Decreased Expression Of apM1 in Omental and Subcutaneous Adipose Tissue of Humans With Type 2 Diabetes
We have screened a subtracted cDNA library in
order to identify differentially expressed genes in
omental adipose tissue of human patients with
Type 2 diabetes. One clone (#1738) showed a marked
reduction in omental adipose tissue from patients
with Type 2 diabetes. Sequencing and BLAST analysis
revealed clone #1738 was the adipocyte-specific
secreted protein gene apM1 (synonyms ACRP30,
AdipoQ, GBP28). Consistent with the murine orthologue,
apM1 mRNA was expressed in cultured
human adipocytes and not in preadipocytes.
Using RT-PCR we confirmed that apM1 mRNA
levels were significantly reduced in omental adipose
tissue of obese patients with Type 2 diabetes compared
with lean and obese normoglycemic subjects.
Although less pronounced, apM1 mRNA levels
were reduced in subcutaneous adipose tissue of
Type 2 diabetic patients. Whereas the biological
function of apM1 is presently unknown, the tissue
specific expression, structural similarities to TNFα
and the dysregulated expression observed in obese
Type 2 diabetic patients suggest that this factor
may play a role in the pathogenesis of insulin resistance
and Type 2 diabetes
Systematic techniques for assisting recruitment to trials (START): study protocol for embedded, randomized controlled trials
BACKGROUND: Randomized controlled trials play a central role in evidence-based practice, but recruitment of participants, and retention of them once in the trial, is challenging. Moreover, there is a dearth of evidence that research teams can use to inform the development of their recruitment and retention strategies. As with other healthcare initiatives, the fairest test of the effectiveness of a recruitment strategy is a trial comparing alternatives, which for recruitment would mean embedding a recruitment trial within an ongoing host trial. Systematic reviews indicate that such studies are rare. Embedded trials are largely delivered in an ad hoc way, with interventions almost always developed in isolation and tested in the context of a single host trial, limiting their ability to contribute to a body of evidence with regard to a single recruitment intervention and to researchers working in different contexts. METHODS/DESIGN: The Systematic Techniques for Assisting Recruitment to Trials (START) program is funded by the United Kingdom Medical Research Council (MRC) Methodology Research Programme to support the routine adoption of embedded trials to test standardized recruitment interventions across ongoing host trials. To achieve this aim, the program involves three interrelated work packages: (1) methodology - to develop guidelines for the design, analysis and reporting of embedded recruitment studies; (2) interventions - to develop effective and useful recruitment interventions; and (3) implementation - to recruit host trials and test interventions through embedded studies. DISCUSSION: Successful completion of the START program will provide a model for a platform for the wider trials community to use to evaluate recruitment interventions or, potentially, other types of intervention linked to trial conduct. It will also increase the evidence base for two types of recruitment intervention. TRIAL REGISTRATION: The START protocol covers the methodology for embedded trials. Each embedded trial is registered separately or as a substudy of the host trial
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CST does not evict elongating telomerase but prevents initiation by ssDNA binding
The CST complex (CTC1-STN1-TEN1) has been shown to inhibit telomerase extension of the G-strand of telomeres and facilitate the switch to C-strand synthesis by DNA polymerase alpha-primase (pol α-primase). Recently the structure of human CST was solved by cryo-EM, allowing the design of mutant proteins defective in telomeric ssDNA binding and prompting the reexamination of CST inhibition of telomerase. The previous proposal that human CST inhibits telomerase by sequestration of the DNA primer was tested with a series of DNA-binding mutants of CST and modeled by a competitive binding simulation. The DNA-binding mutants had substantially reduced ability to inhibit telomerase, as predicted from their reduced affinity for telomeric DNA. These results provide strong support for the previous primer sequestration model. We then tested whether addition of CST to an ongoing processive telomerase reaction would terminate DNA extension. Pulse-chase telomerase reactions with addition of either wild-type CST or DNA-binding mutants showed that CST has no detectable ability to terminate ongoing telomerase extension in vitro. The same lack of inhibition was observed with or without pol α-primase bound to CST. These results suggest how the switch from telomerase extension to C-strand synthesis may occur
Sentinel-based Surveillance of Coyotes to Detect Bovine Tuberculosis, Michigan
Coyotes could be used as sentinels to detect Mycobacterium bovis in the wild
Human Resources and the Resource Based View of the Firm
The resource-based view (RBV) of the firm has influenced the field of strategic human resource management (SHRM) in a number of ways. This paper explores the impact of the RBV on the theoretical and empirical development of SHRM. It explores how the fields of strategy and SHRM are beginning to converge around a number of issues, and proposes a number of implications of this convergence
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