Showing papers by "University of Medicine and Dentistry of New Jersey published in 2006"

Adenosine receptors: therapeutic aspects for inflammatory and immune diseases

Abstract: Adenosine is a key endogenous molecule that regulates tissue function by activating four G-protein-coupled adenosine receptors: A1, A2A, A2B and A3. Cells of the immune system express these receptors and are responsive to the modulatory effects of adenosine in an inflammatory environment. Animal models of asthma, ischaemia, arthritis, sepsis, inflammatory bowel disease and wound healing have helped to elucidate the regulatory roles of the various adenosine receptors in dictating the development and progression of disease. This recent heightened awareness of the role of adenosine in the control of immune and inflammatory systems has generated excitement regarding the potential use of adenosine-receptor-based therapies in the treatment of infection, autoimmunity, ischaemia and degenerative diseases.

Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol

Abstract: The prototypical xanthine oxidase (XO) inhibitor allopurinol, has been the cornerstone of the clinical management of gout and conditions associated with hyperuricemia for several decades. More recent data indicate that XO also plays an important role in various forms of ischemic and other types of tissue and vascular injuries, inflammatory diseases, and chronic heart failure. Allopurinol and its active metabolite oxypurinol showed considerable promise in the treatment of these conditions both in experimental animals and in small-scale human clinical trials. Although some of the beneficial effects of these compounds may be unrelated to the inhibition of the XO, the encouraging findings rekindled significant interest in the development of additional, novel series of XO inhibitors for various therapeutic indications. Here we present a critical overview of the effects of XO inhibitors in various pathophysiological conditions and also review the various emerging therapeutic strategies offered by this approach.

Locoregional Relapse and Distant Metastasis in Conservatively Managed Triple Negative Early-Stage Breast Cancer

Abstract: Purpose To determine the prognostic significance of triple negative breast cancers with respect to locoregional relapse and distant metastasis in conservatively managed breast cancer patients. Patients and Methods A database of conservative managed (conservative surgery followed by radiation) patients, in whom all three markers (estrogen receptor, progesterone receptor, and HER2/neu) were available, was reviewed. Patients were classified as triple negative if they tested negative for all three markers. Of 482 patients with all three markers available, 117 were classified as triple negative. Results As of September 2005, with a median follow-up time of 7.9 years, of the 482 patients in the study, there have been 53 in-breast relapses, 10 nodal relapses, 77 distant relapses, and 69 deaths. At 5 years, the triple negative cohort had a poorer distant metastasis-free rate compared with the other subtypes (67% v 82%, respectively; P .002). Triple negative subtype was an independent predictor of distant metastasis (hazard ratio 2.14; 95% CI, 1.31 to 3.53; P .002) and cause-specific survival (hazard ratio 1.79; 95% CI, 1.03 to 3.22; P .047). There was no significant difference in local control between the triple negative and other subtypes (83% v 83%, respectively). Of 99 BRCA-tested patients in this cohort, 10 had deleterious mutations in BRCA1, and seven had mutations in BRCA2 .O f 10BRCA1 patients, eight were triple negative, whereas only one of seven BRCA2 patients was triple negative (P .001). Conclusion Patients classified as triple negative have a poor prognosis. However, there was no evidence that these patients are at higher risk for local relapse after conservative surgery and radiation. Patients with BRCA1 mutations develop predominantly triple negative tumors.

The Regulation of Exosome Secretion: a Novel Function of the p53 Protein

Abstract: The p53 protein responds to stress signals by regulating the transcription of a variety of genes. Some of these genes encode secreted proteins that may be involved in the communication between adjacent cells. In this study, a proteomics approach was employed to identify proteins secreted by cells in a p53-dependent manner after DNA damage. In addition to the known transcriptional targets of p53, a set of proteins encoded by genes that are not transcriptional targets of p53 were found to increase in the culture medium after p53 activation. These proteins exit the cell via small, secreted vesicles called exosomes and exosome production by cells was found to be regulated by the p53 response. A p53-regulated gene product, TSAP6, was shown to enhance exosome production in cells undergoing a p53 response to stress. Thus, the p53 pathway regulates the production of exosomes into the medium and these vesicles can communicate with adjacent cells and even cells of the immune system.

Real-time ultrasound-guided catheterisation of the internal jugular vein: a prospective comparison with the landmark technique in critical care patients.

Abstract: Central venous cannulation is crucial in the management of the critical care patient. This study was designed to evaluate whether real-time ultrasound-guided cannulation of the internal jugular vein is superior to the standard landmark method. In this randomised study, 450 critical care patients who underwent real-time ultrasound-guided cannulation of the internal jugular vein were prospectively compared with 450 critical care patients in whom the landmark technique was used. Randomisation was performed by means of a computer-generated random-numbers table, and patients were stratified with regard to age, gender, and body mass index. There were no significant differences in gender, age, body mass index, or side of cannulation (left or right) or in the presence of risk factors for difficult venous cannulation such as prior catheterisation, limited sites for access attempts, previous difficulties during catheterisation, previous mechanical complication, known vascular abnormality, untreated coagulopathy, skeletal deformity, and cannulation during cardiac arrest between the two groups of patients. Furthermore, the physicians who performed the procedures had comparable experience in the placement of central venous catheters (p = non-significant). Cannulation of the internal jugular vein was achieved in all patients by using ultrasound and in 425 of the patients (94.4%) by using the landmark technique (p < 0.001). Average access time (skin to vein) and number of attempts were significantly reduced in the ultrasound group of patients compared with the landmark group (p < 0.001). In the landmark group, puncture of the carotid artery occurred in 10.6% of patients, haematoma in 8.4%, haemothorax in 1.7%, pneumothorax in 2.4%, and central venous catheter-associated blood stream infection in 16%, which were all significantly increased compared with the ultrasound group (p < 0.001). The present data suggest that ultrasound-guided catheterisation of the internal jugular vein in critical care patients is superior to the landmark technique and therefore should be the method of choice in these patients.

Toward Understanding the Insight Paradox: Internalized Stigma Moderates the Association Between Insight and Social Functioning, Hope, and Self-esteem Among People with Schizophrenia Spectrum Disorders

Abstract: Research has paradoxically linked awareness of illness to both better function outcomes and lesser hope and self-esteem. One possible explanation for these findings is that acceptance of having schizophrenia may impact outcomes differently depending on the meanings the person attaches to this acceptance, particularly whether he or she accepts stigmatizing beliefs about mental illness. To explore this possibility we performed a cluster analysis of 75 persons with schizophrenia spectrum disorders based on single measures of insight using the Positive and Negative Syndrome Scale, internalized stigma using the Internalized Stigma of Mental Illness Scale, and compared groups on concurrent assessments of hope and self-esteem. Three groups were produced by the cluster analyses: low in sight/mild stigma (n = 23), high insight/minimal stigma (n = 25), and high insight/moderate stigma (n = 27). As predicted, analysis of variance-comparing groups revealed that the high insight/moderate stigma group had significantly the lowest levels of hope on the Beck Hopelessness Scale and self-esteem using the Multidimensional Self-esteem Inventory. As predicted, the high insight/minimal stigma group also had significantly less impaired social function than the other groups. Implications for assisting persons to come to cope with awareness of illness and stigma are discussed.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don't know

Abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important hematopoietic growth factor and immune modulator. GM-CSF also has profound effects on the functional activities of various circulating leukocytes. It is produced by a variety of cell types including T cells, macrophages, endothelial cells and fibroblasts upon receiving immune stimuli. Although GM-CSF is produced locally, it can act in a paracrine fashion to recruit circulating neutrophils, monocytes and lymphocytes to enhance their functions in host defense. Recent intensive investigations are centered on the application of GM-CSF as an immune adjuvant for its ability to increase dendritic cell (DC) maturation and function as well as macrophage activity. It is used clinically to treat neutropenia in cancer patients undergoing chemotherapy, in AIDS patients during therapy, and in patients after bone marrow transplantation. Interestingly, the hematopoietic system of GM-CSF-deficient mice appears to be normal; the most significant changes are in some specific T cell responses. Although molecular cloning of GM-CSF was carried out using cDNA library of T cells and it is well known that the T cells produce GM-CSF after activation, there is a lack of systematic investigation of this cytokine in production by T cells and its effect on T cell function. In this article, we will focus mainly on the immunobiology of GM-CSF in T cells.

Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study

Abstract: Insulin resistance and oxidative stress are associated with accelerated telomere attrition in leukocytes. Both are also implicated in the biology of aging and in aging-related disorders, including hypertension. We explored the relations of leukocyte telomere length, expressed by terminal restriction fragment (TRF) length, with insulin resistance, oxidative stress and hypertension. We measured leukocyte TRF length in 327 Caucasian men with a mean age of 62.2 years (range 40-89 years) from the Offspring cohort of the Framingham Heart Study. TRF length was inversely correlated with age (r = -0.41, P < 0.0001) and age-adjusted TRF length was inversely correlated with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (r =-0.16, P = 0.007) and urinary 8-epi-PGF(2alpha) (r = -0.16, P = 0.005) - an index of systemic oxidative stress. Compared with their normotensive peers, hypertensive subjects exhibited shorter age-adjusted TRF length (hypertensives = 5.93 +/- 0.042 kb, normotensives = 6.07 +/- 0.040 kb, P = 0.025). Collectively, these observations suggest that hypertension, increased insulin resistance and oxidative stress are associated with shorter leukocyte telomere length and that shorter leukocyte telomere length in hypertensives is largely due to insulin resistance.

Global Phylogeny of Mycobacterium tuberculosis Based on Single Nucleotide Polymorphism (SNP) Analysis: Insights into Tuberculosis Evolution, Phylogenetic Accuracy of Other DNA Fingerprinting Systems, and Recommendations for a Minimal Standard SNP Set

Abstract: We analyzed a global collection of Mycobacterium tuberculosis strains using 212 single nucleotide polymorphism (SNP) markers. SNP nucleotide diversity was high (average across all SNPs, 0.19), and 96% of the SNP locus pairs were in complete linkage disequilibrium. Cluster analyses identified six deeply branching, phylogenetically distinct SNP cluster groups (SCGs) and five subgroups. The SCGs were strongly associated with the geographical origin of the M. tuberculosis samples and the birthplace of the human hosts. The most ancestral cluster (SCG-1) predominated in patients from the Indian subcontinent, while SCG-1 and another ancestral cluster (SCG-2) predominated in patients from East Asia, suggesting that M. tuberculosis first arose in the Indian subcontinent and spread worldwide through East Asia. Restricted SCG diversity and the prevalence of less ancestral SCGs in indigenous populations in Uganda and Mexico suggested a more recent introduction of M. tuberculosis into these regions. The East African Indian and Beijing spoligotypes were concordant with SCG-1 and SCG-2, respectively; X and Central Asian spoligotypes were also associated with one SCG or subgroup combination. Other clades had less consistent associations with SCGs. Mycobacterial interspersed repetitive unit (MIRU) analysis provided less robust phylogenetic information, and only 6 of the 12 MIRU microsatellite loci were highly differentiated between SCGs as measured by GST. Finally, an algorithm was devised to identify two minimal sets of either 45 or 6 SNPs that could be used in future investigations to enable global collaborations for studies on evolution, strain differentiation, and biological differences of M. tuberculosis.

Continuation Electroconvulsive Therapy vs Pharmacotherapy for Relapse Prevention in Major Depression: A Multisite Study From the Consortium for Research in Electroconvulsive Therapy (CORE)

Abstract: Background Although electroconvulsive therapy (ECT) has been shown to be extremely effective for the acute treatment of major depression, it has never been systematically assessed as a strategy for relapse prevention. Objective To evaluate the comparative efficacy of continuation ECT (C-ECT) and the combination of lithium carbonate plus nortriptyline hydrochloride (C-Pharm) in the prevention of depressive relapse. Design Multisite, randomized, parallel design, 6-month trial performed from 1997 to 2004. Setting Five academic medical centers and their outpatient psychiatry clinics. Patients Two hundred one patients with Structured Clinical Interview for DSM-IV– diagnosed unipolar depression who had remitted with a course of bilateral ECT. Interventions Random assignment to 2 treatment groups receiving either C-ECT (10 treatments) or C-Pharm for 6 months. Main Outcome Measure Relapse of depression, compared between the C-ECT and C-Pharm groups. Results In the C-ECT group, 37.1% experienced disease relapse, 46.1% continued to have disease remission at the study end, and 16.8% dropped out of the study. In the C-Pharm group, 31.6% experienced disease relapse, 46.3% continued to have disease remission, and 22.1% dropped out of the study. Both Kaplan-Meier and Cox proportional hazards regression analyses indicated no statistically significant differences in overall survival curves and time to relapse for the groups. Mean ± SD time to relapse for the C-ECT group was 9.1 ± 7.0 weeks compared with 6.7 ± 4.6 weeks for the C-Pharm group ( P = .13). Both groups had relapse proportions significantly lower than a historical placebo control from a similarly designed study. Conclusions Both C-ECT and C-Pharm were shown to be superior to a historical placebo control, but both had limited efficacy, with more than half of patients either experiencing disease relapse or dropping out of the study. Even more effective strategies for relapse prevention in mood disorders are urgently needed.

Epidemiology of preterm birth and its clinical subtypes.

Abstract: Preterm birth (<37 weeks) complicates 12.5% of all deliveries in the USA, and remains the leading cause of perinatal mortality and morbidity, accounting for as many as 75% of perinatal deaths. Desp...

Hypoactive sexual desire disorder in postmenopausal women: US results from the Women's International Study of Health and Sexuality (WISHeS).

Abstract: Objective To determine the prevalence of hypoactive sexual desire disorder (HSDD) among US women by reproductive status and age and to explore the correlates of sexually related distress. Design The Women's International Study on Health and Sexuality questionnaire was mailed to a national sample of US women in 2000. The survey included validated questionnaires: the Short Form-36, which measures overall health status; the Profile of Female Sexual Function, which assesses sexual desire; and the Personal Distress Scale, which measures distress caused by low desire. Four groups of women were studied: surgically postmenopausal, aged 20 to 49 years and 50 to 70 years; premenopausal, aged 20 to 49 years; and naturally postmenopausal, aged 50 to 70 years. Clinically derived cutoff Profile of Female Sexual Function and Personal Distress Scale scores were used to classify women with HSDD and determine its prevalence. The relations between sexual desire and frequency of sexual activity or relationship satisfaction were assessed. Overall health status of HSDD women and women with normal desire were compared. Results The prevalence of HSDD ranged from 9% in naturally postmenopausal women to 26% in younger surgically postmenopausal women. The prevalence of HSDD was significantly greater among surgically postmenopausal women, aged 20 to 49 years, than premenopausal women of similar age, whereas there were no significant differences in the prevalence between surgically postmenopausal women, aged 50 to 70 years, and naturally postmenopausal women. For many women, HSDD was associated with emotional and psychological distress as well as significantly lower sexual and partner satisfaction. HSDD was also associated with significant decrements in general health status, including aspects of mental and physical health. Conclusions HSDD is prevalent among women at all reproductive stages, with younger surgically postmenopausal women at greater risk, and is associated with a less active sex life and decreased sexual and relationship satisfaction.

Ozone's Impact on Public Health: Contributions from Indoor Exposures to Ozone and Products of Ozone-Initiated Chemistry

Abstract: Many studies have reported associations between outdoor ozone concentrations and morbidity and mortality. Hubbell et al. (2005) systematically summarized this literature, including associations between ozone and respiratory-related hospital admissions, lost school days, restricted activity days, asthma-related emergency department visits, and premature mortality. Additionally, ozone has been associated with respiratory symptoms and the use of asthma medication for asthmatic school children using maintenance medication (Gent et al. 2003), and long-term exposure to ozone has been tentatively associated with the development of asthma in adult males (McDonnell et al. 1999). Since the submission of Hubbell et al. (2005), three independent meta-analyses have been published, indicating an increase of 0.87% in mortality per 10-ppb increase in daily ozone (Bell et al. 2005), an increase of 0.39% in mortality per 10-ppb increase in 1-hr daily maximum ozone (Ito et al. 2005), and an increase of 0.41% in mortality per 10-ppb increase in 1-hr daily maximum ozone (Levy et al. 2005); in most of the studies included in the meta analyses, same-day effects were larger than lagged effects. A study of 23 European cities found an increase of 0.66% in mortality per 10 ppb increase in 1-hr maximum ozone during the summer (Gryparis et al. 2004); a study in Genoa, Italy, found an increase of 4.0% in mortality per 25-ppb increase in ozone (Parodi et al. 2005); and a study in Shanghai found an increase of 0.45% in mortality per 5-ppb increase in 2-day average ozone (Zhang et al. 2006). Significantly, even when Bell et al. (2006) used data that included only days with average ozone levels lower than 15 ppb, outdoor ozone was significantly associated with premature mortality. For a more extended review of these and other studies, see the U.S. Environmental Protection Agency ozone criteria document (U.S. EPA 2006). An increase in the concentration of outdoor ozone concomitantly produces an increase in the indoor concentrations of ozone and its reaction products (Weschler 2000). Thus, some of the associations between outdoor ozone and both morbidity and mortality are likely due to outdoor ozone transported into various indoor environments (e.g., residences, workplaces, schools, hospitals, motor vehicles) where subsequent exposures occur. Although indoor ozone concentrations tend to be smaller than corresponding outdoor concentrations, this is somewhat counterbalanced by the much larger fraction of time that most people spend indoors. Moreover, excepting nitrogen dioxide, total concentrations of ozone reaction products are anticipated to be larger indoors than outdoors (see “Products of ozone-initiated indoor chemistry”). My aim in this article is to present evidence supporting the hypothesis that indoor exposures to ozone and its oxidation products contribute to ozone’s overall impact on public health. Apportioning ozone’s health impact among indoor and outdoor ozone, as well as indoor and outdoor oxidation products, is more than an academic exercise. If indoor ozone and the products of its chemistry are adversely affecting the public’s health, relatively simple strategies can mitigate these effects.

The Developmental Neurobiology of Autism Spectrum Disorder

Abstract: Editor’s Note: Two reviews in this week’s issue examine the rapidly expanding interest in autism research in the neuroscience community. Moldin et al. provide a brief prospective on the overall state of research in autism. DiCicco-Bloom and colleagues summarize their presentations at the

Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer.

Abstract: Most malignancies have increased glycolysis for energy requirement of rapid cell proliferation, which is the basis for tumor imaging through glucose analog FDG (2-deoxy-2-fluoro-D-glucose) with positron emission tomography. One of significant characteristics of prostate cancer is slow glycolysis and low FDG avidity. Recent studies showed that prostate cancer is associated with changes of fatty acid metabolism. Several enzymes involved in the metabolism of fatty acids have been determined to be altered in prostate cancer relative to normal prostate, which is indicative of an enhanced beta-oxidation pathway in prostate cancer. Increased fatty acid utilization in prostate cancer provides both ATP and acetyl-coenzyme A (CoA); subsequently, increased availability of acetyl-CoA makes acceleration of citrate oxidation possible, which is an important energy source as well. Dominant fatty acid metabolism rather than glycolysis has the potential to be the basis for imaging diagnosis and targeted treatment of prostate cancer.

Current insights into the regulation of programmed cell death by NF-kappaB.

Abstract: The nuclear factor-kappaB (NF-kappaB) transcription factors have emerged as major regulators of programmed cell death (PCD) whether via apoptosis or necrosis. In this context, NF-kappaB's activity has important ramifications for normal tissue development, homoeostasis and the physiological functions of various cell systems including the immune, hepatic, epidermal and nervous systems. However, improper regulation of PCD by NF-kappaB can have severe pathologic consequences, ranging from neurodegeneration to cancer, where its activity often precludes effective therapy. Although NF-kappaB generally protects cells by inducing the expression genes encoding antiapoptotic and antioxidizing proteins, its role in apoptosis and necrosis can vary markedly in different cell contexts, and NF-kappaB can sensitize cells to death-inducing stimuli in some instances. This article describes our current knowledge of the role of NF-kappaB in apoptosis and necrosis, and focuses on the many advances since we last reviewed this rapidly evolving topic in Oncogene 3 years ago. There has been substantial progress in understanding NF-kappaB's mode of action in apoptosis and necrosis and the mechanisms that regulate its anti- vs proapoptotic activities. These recent developments shed new light on the role of NF-kappaB in many disease conditions including tumor development, tumor progression and anticancer treatment.

Population Genetics Study of Isoniazid Resistance Mutations and Evolution of Multidrug-Resistant Mycobacterium tuberculosis

Abstract: The molecular basis for isoniazid resistance in Mycobacterium tuberculosis is complex. Putative isoniazid resistance mutations have been identified in katG, ahpC, inhA, kasA, and ndh. However, small sample sizes and related potential biases in sample selection have precluded the development of statistically valid and significant population genetic analyses of clinical isoniazid resistance. We present the first large-scale analysis of 240 alleles previously associated with isoniazid resistance in a diverse set of 608 isoniazid-susceptible and 403 isoniazid-resistant clinical M. tuberculosis isolates. We detected 12 mutant alleles in isoniazid-susceptible isolates, suggesting that these alleles are not involved in isoniazid resistance. However, mutations in katG, ahpC, and inhA were strongly associated with isoniazid resistance, while kasA mutations were associated with isoniazid susceptibility. Remarkably, the distribution of isoniazid resistance-associated mutations was different in isoniazid-monoresistant isolates from that in multidrug-resistant isolates, with significantly fewer isoniazid resistance mutations in the isoniazid-monoresistant group. Mutations in katG315 were significantly more common in the multidrug-resistant isolates. Conversely, mutations in the inhA promoter were significantly more common in isoniazid-monoresistant isolates. We tested for interactions among mutations and resistance to different drugs. Mutations in katG, ahpC, and inhA were associated with rifampin resistance, but only katG315 mutations were associated with ethambutol resistance. There was also a significant inverse association between katG315 mutations and mutations in ahpC or inhA and between mutations in kasA and mutations in ahpC. Our results suggest that isoniazid resistance and the evolution of multidrug-resistant strains are complex dynamic processes that may be influenced by interactions between genes and drug-resistant phenotypes.

An essential role for β-actin mRNA localization and translation in Ca2+-dependent growth cone guidance

Abstract: Axon pathfinding requires directional responses of growth cones to extracellular cues, which have been shown to involve local synthesis of protein. The identity and functions of the locally produced proteins remain, however, unclear. Here we report that Ca2+-dependent bidirectional turning of Xenopus laevis growth cones requires localized distribution and translation of β-actin messenger RNA. Both β-actin mRNA and its zipcode-binding protein, ZBP1, are localized at the growth cone and become asymmetrically distributed upon local exposure to brain-derived neurotrophic factor (BDNF). Inhibition of protein synthesis or antisense interference with β-actin mRNA–ZBP1 binding abolishes both Ca2+-mediated attraction and repulsion. In addition, attraction involves a local increase in β-actin, whereas repulsion is accompanied by a local decrease in β-actin; thus, both produce a synthesis- and ZBP1 binding–dependent β-actin asymmetry but with opposite polarities. Together with a similar asymmetry in Src activity during bidirectional responses, our findings indicate that Ca2+-dependent spatial regulation of β-actin synthesis through Src contributes to the directional motility of growth cones during guidance.

Rapidly inducible changes in phosphatidylinositol 4,5-bisphosphate levels influence multiple regulatory functions of the lipid in intact living cells

Abstract: Rapamycin (rapa)-induced heterodimerization of the FRB domain of the mammalian target of rapa and FKBP12 was used to translocate a phosphoinositide 5-phosphatase (5-ptase) enzyme to the plasma membrane (PM) to evoke rapid changes in phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) levels. Rapa-induced PM recruitment of a truncated type IV 5-ptase containing only the 5-ptase domain fused to FKBP12 rapidly decreased PM PtdIns(4,5)P2 as monitored by the PLCδ1PH-GFP fusion construct. This decrease was paralleled by rapid termination of the ATP-induced Ca2+ signal and the prompt inactivation of menthol-activated transient receptor potential melastatin 8 (TRPM8) channels. Depletion of PM PtdIns(4,5)P2 was associated with a complete blockade of transferrin uptake and inhibition of epidermal growth factor internalization. None of these changes were observed upon rapa-induced translocation of an mRFP-FKBP12 fusion protein that was used as a control. These data demonstrate that rapid inducible depletion of PM PtdIns(4,5)P2 is a powerful tool to study the multiple regulatory roles of this phospholipid and to study differential sensitivities of various processes to PtdIns(4,5)P2 depletion.

The molecular basis for calcium-dependent axon pathfinding

Abstract: 2+ signalling influences a broad range of biological events in most, if not all cells, beginning with fertilization and continuing through development, into adulthood and concluding with cell death (for reviews, see REFS 1,2). That this simple ion can mediate such a vast spectrum of physiological events is remarkable. One particularly well-studied, yet highly confounding cellular location where Ca 2+ has been reported to have many unique effects is in the terminal growth cones of extending axons and developing dendrites. Although Ca 2+

TRPM7, a novel regulator of actomyosin contractility and cell adhesion

Abstract: Actomyosin contractility regulates various cell biological processes including cytokinesis, adhesion and migration. While in lower eukaryotes, alpha-kinases control actomyosin relaxation, a similar role for mammalian alpha-kinases has yet to be established. Here, we examined whether TRPM7, a cation channel fused to an alpha-kinase, can affect actomyosin function. We demonstrate that activation of TRPM7 by bradykinin leads to a Ca(2+)- and kinase-dependent interaction with the actomyosin cytoskeleton. Moreover, TRPM7 phosphorylates the myosin IIA heavy chain. Accordingly, low overexpression of TRPM7 increases intracellular Ca2+ levels accompanied by cell spreading, adhesion and the formation of focal adhesions. Activation of TRPM7 induces the transformation of these focal adhesions into podosomes by a kinase-dependent mechanism, an effect that can be mimicked by pharmacological inhibition of myosin II. Collectively, our results demonstrate that regulation of cell adhesion by TRPM7 is the combined effect of kinase-dependent and -independent pathways on actomyosin contractility.

The effects of social status on biological aging as measured by white-blood-cell telomere length

Abstract: Low socio-economic status (SES) is associated with a shortened life expectancy, but its effect on aging is unknown. The rate of white-blood-cell (WBC) telomere attrition may be a biological indicator of human aging. We tested the hypothesis that SES is associated with telomere attrition independent of known risk factors influencing the aging process. We studied 1552 female twins. A venous blood sample was taken from each twin and isolated WBCs used for extraction of DNA. Terminal restriction fragment length (TRFL) was measured. Questionnaire data were collected on occupation, education, income, smoking, exercise, height and weight. Standard multiple linear regression and multivariate analyses of variance tested for associations between SES and TRFL, adjusting for covariates. A discordant twin analysis was conducted on a subset to verify findings. WBC telomere length was highly variable but significantly shorter in lower SES groups. The mean difference in TRFL between nonmanual and manual SES groups was 163.2 base pairs (bp) of which 22.9 bp (approximately 14%) was accounted for by body mass index, smoking and exercise. Comparison of TRFL in the 17 most discordant SES twin pairs confirmed this difference. Low SES, in addition to the harmful effects of smoking, obesity and lack of exercise, appears to have an impact on telomere length.