Catharine Smith

Catharine Smith, PhD, focuses on epigenetic mechanisms of gene expression, particularly their regulation through signaling pathways and their modulation by anti-cancer drugs. Epigenetic mechanisms play a very important role in transcriptional regulation of genes but the specifics of these mechanisms require ongoing study. A very exciting new area of research focuses on how these mechanisms are disrupted during tumorigenesis but may also be harnessed to treat cancer.   Signaling pathways control the expression of key genes in non-cancerous cells but are often misregulated during the process of oncogenesis. Chromatin proteins and transcription factors that interact with chromatin are often targets of these pathways. Two projects in the lab are directed at the interface of signaling pathways and chromatin. First, Dr. Smith is interested in the mechanism by which the female reproductive steroid, progesterone, regulates target genes in the physiological context of chromatin. Chronic progestin exposure has been linked to increased incidence of breast cancer in post-menopausal women on hormone-replacement therapy. However, the function of the progesterone receptor in mammary tissue and its role in oncogenesis are not well understood. Current studies in this area are directed at the role of chaperone proteins in determining how the progesterone receptor functions at target genes in chromatin and how it is impacted by other signaling pathways.
Second, her lab has discovered a novel cAMP signaling pathway that regulates cell cycle progression and are focused on identifying specific components and targets of this pathway.
Third, histone deacetylases (HDACs) are key transcriptional regulatory proteins. Inhibitors that target these enzymes have shown great promise as anti-cancer drugs and are currently in clinical trials. However, a lack of knowledge of HDAC biology has made it difficult to predict which tumors will respond to these drugs. HDACs are known to participate in gene repression, but recent work indicates that they are also transcriptional coactivators. Further studies on the mechanism of gene repression through HDAC inhibitors will provide insight into the role of these enzymes as coactivators.
Communicable And Non Communicable Diseases Among Recent Immigrants With Implications For Primary Care; A Comprehensive Immigrant Health Approach. Source: Journal Of Immigrant And Minority Health / Center For Minority Public Health
October 31st, 2011 PMID: 21573748 Catharine Smith
Data on health status of immigrants and practice recommendations for providers are scarce. We evaluated 99 recent immigrants from developing nations in an immigrant clinic in New York City to assess epidemiology of diseases and to recommend potential screening. Providers received ongoing training. Majority patient was from West Africa and Central America with a mean of 2.1 years in the US. Two thirds were uninsured. Half had positive PPD. Half had prior hepatitis B infection, which was higher in Africans. One quarter had intestinal parasites. Two thirds were overweight; 33% had hypercholesterolemia, 26% were hypertensive, and 25% of women had a Pap smear previously. Eosinophila was higher in African and males (P < 0.05) but didn't predict stool O&P. Recent immigrants were at risk for chronic non-communicable diseases, similar to the US population. Providers should balance their focus on communicable and non-communicable diseases. We recommend practice-based training and on-site comprehensive health services.<br><br>
Determinants Of Nucleosome Organization In Primary Human Cells. Source: Nature
May 22nd, 2011 PMID: 21602827 Catharine Smith
Nucleosomes are the basic packaging units of chromatin, modulating accessibility of regulatory proteins to DNA and thus influencing eukaryotic gene regulation. Elaborate chromatin remodelling mechanisms have evolved that govern nucleosome organization at promoters, regulatory elements, and other functional regions in the genome. Analyses of chromatin landscape have uncovered a variety of mechanisms, including DNA sequence preferences, that can influence nucleosome positions. To identify major determinants of nucleosome organization in the human genome, we used deep sequencing to map nucleosome positions in three primary human cell types and in vitro. A majority of the genome showed substantial flexibility of nucleosome positions, whereas a small fraction showed reproducibly positioned nucleosomes. Certain sites that position in vitro can anchor the formation of nucleosomal arrays that have cell type-specific spacing in vivo. Our results unveil an interplay of sequence-based nucleosome preferences and non-nucleosomal factors in determining nucleosome organization within mammalian cells.<br><br>
Naturally High Plasma Glucose Levels In Mourning Doves (Zenaida Macroura) Do Not Lead To High Levels Of Reactive Oxygen Species In The Vasculature. Source: Zoology (Jena, Germany)
May 19th, 2011 PMID: 21600747 Catharine Smith
Plasma glucose (P(Glu)) concentrations in birds are 1.5-2 times higher than those of mammals of similar body mass. In mammals, sustained elevations of P(Glu) lead to oxidative stress and free radical-mediated scavenging of endogenous vasodilators (e.g., nitric oxide), contributing to elevated blood pressure. Despite the relatively high P(Glu) levels in birds, they appear resistant to the development of oxidative stress in tissues such as the heart, brain and kidneys. To our knowledge no information exists on oxidative stress susceptibility in the resistance vasculature of birds. Therefore, we compared endogenous antioxidant mechanisms in the resistance vasculature of mourning doves (MODO; Zenaida macroura) and rats (Rattus norvegicus). Reactive oxygen species (ROS) were assessed with the fluorescent indicator 7'-dichlorodihydrofluorescein diacetate, acetyl ester in mesenteric arteries from rats and wild-caught MODO. Despite having significantly higher P(Glu) than rats, there were no significant differences in ROS levels between mesenteric arteries from rats or doves. Although superoxide dismutase and catalase activities were lower in the plasma, total antioxidant capacity, uric acid, vitamin E (α-tocopherol), and carotenoids (lutein and zeaxanthin) were significantly higher in MODO than in rats. Thus, compared to rats, MODO have multiple circulating antioxidants that may prevent the development of oxidative stress in the vasculature.<br><br>
Relations Of Temperament To Maladjustment And Ego Resiliency In At Risk Children. Source: Social Development (Oxford, England)
May 11th, 2011 PMID: 20567606 Catharine Smith
Advanced Paternal Age Is A Risk Factor For Schizophrenia In Iranians. Source: Annals Of General Psychiatry
April 24th, 2011 PMID: 21513574 Catharine Smith
BACKGROUND:<br>Since 1958 many, but not all studies have demonstrated that paternal age is a risk factor for schizophrenia. There may be many different explanations for differences between studies, including study design, sample size, collection criteria, heterogeneity and the confounding effects of environmental factors that can for example perturb epigenetic programming and lead to an increase in disease risk. The small number of children in Western families makes risk comparisons between siblings born at different paternal ages difficult. In contrast, more Eastern families have children both at early and later periods of life. In the present study, a cross-sectional population study in an Iranian population was performed to compare frequency of schizophrenia in younger offspring (that is, older paternal age) versus older offspring.<br><br>METHODS:<br>A total of 220 patients with the diagnosis of schizophrenia (cases) from both psychiatric hospitals and private clinics and 220 individuals from other hospital wards (controls), matched for sex and age were recruited for this study. Patients with neurological problem, substance abuse, mental retardation and mood disorder were excluded from both groups.<br><br>RESULTS:<br>Birth rank comparisons revealed that 35% vs 24% of the cases vs the controls were in the third or upper birth rank (P = 0.01). Also, the mean age of fathers at birth in case group (30 ± 6.26 years) was significantly more than the control group (26.45 ± 5.64 years; P = 0.0001). The age of 76 fathers at birth in case group was over 32 versus 33 fathers in control group. Individuals whose fathers' age was more than 32 (at birth) were at higher risk (2.77 times) for schizophrenia versus others (P < 0.0001, 95% CI 1.80 to 4.27). The maternal age at parturition of the case versus controls groups was 26.1 ± 5.41 vs 25.07 ± 4.47 (P = 0.02). Logistic regression analysis suggests that maternal age is less likely to be involved in the higher risk of schizophrenia than advanced parental age.<br><br>DISCUSSION:<br>This study demonstrates a relationship between paternal age and schizophrenia in large families of an Iranian population. Arguments have been put forth that DNA bases changes or epigenetic changes in sperm account for the increased risk associated with older fathers. However, it would not be surprising that both de novo germline mutations and epigenetic changes contribute to disease occurrence because DNA replication and DNA methylation are closely linked at both the macromolecular level (that is, methylation closely follows replication), and at the metabolic level (both processes require folate), and susceptible to modulation by the environment. Further research on samples such as those collected here are needed to sort out the contributions of de novo mutations versus epigenetic changes to schizophrenia.<br><br>
Epicardial Derived Cell Epithelial To Mesenchymal Transition And Fate Specification Require Pdgf Receptor Signaling. Source: Circulation Research
April 21st, 2011 PMID: 21512159 Catharine Smith
RATIONALE:<br>In early heart development, platelet-derived growth factor (PDGF) receptor expression in the heart ventricles is restricted to the epicardium. Previously, we showed that PDGFRβ is required for coronary vascular smooth muscle cell (cVSMC) development, but a role for PDGFRα has not been identified. Therefore, we investigated the combined and independent roles of these receptors in epicardial development.<br><br>OBJECTIVE:<br>To understand the contribution of PDGF receptors in epicardial development and epicardial-derived cell fate determination.<br><br>METHODS AND RESULTS:<br>By generating mice with epicardial-specific deletion of the PDGF receptors, we found that epicardial epithelial-to-mesenchymal transition (EMT) was defective. Sox9, an SRY-related transcription factor, was reduced in PDGF receptor-deficient epicardial cells, and overexpression of Sox9 restored epicardial migration, actin reorganization, and EMT gene expression profiles. The failure of epicardial EMT resulted in hearts that lacked epicardial-derived cardiac fibroblasts and cVSMC. Loss of PDGFRα resulted in a specific disruption of cardiac fibroblast development, whereas cVSMC development was unperturbed.<br><br>CONCLUSIONS:<br>Signaling through both PDGF receptors is necessary for epicardial EMT and formation of epicardial-mesenchymal derivatives. PDGF receptors also have independent functions in the development of specific epicardial-derived cell fates.<br><br>
Mapping The Protein Protein Interface Between A Toxin And Its Cognate Antitoxin From The Bacterial Pathogen Streptococcus Pyogenes. Source: Biochemistry
April 19th, 2011 PMID: 21466233 Catharine Smith
Protein--protein interactions are ubiquitous and essential for most biological processes. Although new proteomic technologies have generated large catalogs of interacting proteins, considerably less is known about these interactions at the molecular level, information that would aid in predicting protein interactions, designing therapeutics to alter these interactions, and understanding the effects of disease-producing mutations. Here we describe mapping the interacting surfaces of the bacterial toxin SPN (Streptococcus pyogenes NAD(+) hydrolase) in complex with its antitoxin IFS (immunity factor for SPN) by using hydrogen-deuterium amide exchange and electrospray ionization mass spectrometry. This approach affords data in a relatively short time for small amounts of protein, typically 5-7 pmol per analysis. The results show a good correspondence with a recently determined crystal structure of the IFS--SPN complex but additionally provide strong evidence for a folding transition of the IFS protein that accompanies its binding to SPN. The outcome shows that mass-based chemical footprinting of protein interaction surfaces can provide information about protein dynamics that is not easily obtained by other methods and can potentially be applied to large, multiprotein complexes that are out of range for most solution-based methods of biophysical analysis.<br><br>
Enhanced Transduction Of Photonic Crystal Dye Lasers For Gas Sensing Via Swelling Polymer Film. Source: Optics Letters
April 18th, 2011 PMID: 21499367 Catharine Smith
We present the enhanced transduction of a photonic crystal dye laser for gas sensing via deposition of an additional swelling polymer film. Device operation involves swelling of the polymer film during exposure to specific gases, leading to a change in total effective refractive index. Experimental results show an enhancement of 16.09 dB in sensing ethanol vapor after deposition of a polystyrene film. We verify different responses of the polystyrene film when exposed to either ethanol vapor or increased humidity, indicating selectivity. The concept is generic and, in principle, straightforward in its application to other intracavity-based detection schemes to enable gas sensing.<br><br>
Sequestration Of Ca Mkii In Dendritic Spines In Silico. Source: Journal Of Computational Neuroscience
April 14th, 2011 PMID: 21491127 Catharine Smith
Calcium calmodulin dependent kinase II (CaMKII) is sequestered in dendritic spines within seconds upon synaptic stimulation. The program Smoldyn was used to develop scenarios of single molecule CaMKII diffusion and binding in virtual dendritic spines. We first validated simulation of diffusion as a function of spine morphology. Additional cellular structures were then incorporated to simulate binding of CaMKII to the post-synaptic density (PSD); binding to cytoskeleton; or their self-aggregation. The distributions of GFP tagged native and mutant constructs in dissociated hippocampal neurons were measured to guide quantitative analysis. Intra-spine viscosity was estimated from fluorescence recovery after photo-bleach (FRAP) of red fluorescent protein. Intra-spine mobility of the GFP-CaMKIIα constructs was measured, with hundred-millisecond or better time resolution, from FRAP of distal spine tips in conjunction with fluorescence loss (FLIP) from proximal regions. Different FRAP \ FLIP profiles were predicted from our Scenarios and provided a means to differentiate binding to the PSDs from self-aggregation. The predictions were validated by experiments. Simulated fits of the Scenarios provided estimates of binding and rate constants. We utilized these values to assess the role of self-aggregation during the initial response of native CaMKII holoenzymes to stimulation. The computations revealed that self-aggregation could provide a concentration-dependent switch to amplify CaMKII sequestration and regulate its activity depending on its occupancy of the actin cytoskeleton.<br><br>
Genomic And Epigenomic Instability, Fragile Sites, Schizophrenia And Autism. Source: Current Genomics
March 1st, 2011 PMID: 21358990 Catharine Smith
Increasing evidence links genomic and epigenomic instability, including multiple fragile sites regions to neuropsychiatric diseases including schizophrenia and autism. Cancer is the only other disease associated with multiple fragile site regions, and genome and epigenomic instability is a characteristic of cancer. Research on cancer is far more advanced than research on neuropsychiatric disease; hence, insight into neuropsychiatric disease may be derived from cancer research results. Towards this end, this article will review the evidence linking schizophrenia and other neuropsychiatric diseases (especially autism) to genomic and epigenomic instability, and fragile sites. The results of studies on genetic, epigenetic and environmental components of schizophrenia and autism point to the importance of the folate-methionine-transulfuration metabolic hub that is diseases also perturbed in cancer. The idea that the folate-methionine-transulfuration hub is important in neuropsychiatric is exciting because this hub present novel targets for drug development, suggests some drugs used in cancer may be useful in neuropsychiatric disease, and raises the possibility that nutrition interventions may influence the severity, presentation, or dynamics of disease.<br><br>
Structural Basis Of Streptococcus Pyogenes Immunity To Its Nad+ Glycohydrolase Toxin. Source: Structure (London, England : 1993)
February 8th, 2011 PMID: 21300288 Catharine Smith
The virulence of Gram-positive bacteria is enhanced by toxins like the Streptococcus pyogenes β-NAD(+) glycohydrolase known as SPN. SPN-producing strains of S. pyogenes additionally express the protein immunity factor for SPN (IFS), which forms an inhibitory complex with SPN. We have determined crystal structures of the SPN-IFS complex and IFS alone, revealing that SPN is structurally related to ADP-ribosyl transferases but lacks the canonical binding site for protein substrates. SPN is instead a highly efficient glycohydrolase with the potential to deplete cellular levels of β-NAD(+). The protective effect of IFS involves an extensive interaction with the SPN active site that blocks access to β-NAD(+). The conformation of IFS changes upon binding to SPN, with repacking of an extended C-terminal α helix into a compact shape. IFS is an attractive target for the development of novel bacteriocidal compounds functioning by blocking the bacterium's self-immunity to the SPN toxin.<br><br>
Hdac Activity Is Required For Efficient Core Promoter Function At The Mouse Mammary Tumor Virus Promoter. Source: Journal Of Biomedicine & Biotechnology
December 26th, 2010 PMID: 21253530 Catharine Smith
Histone deacetylases (HDACs) have been shown to be required for basal or inducible transcription at a variety of genes by poorly understood mechanisms. We demonstrated previously that HDAC inhibition rapidly repressed transcription from the mouse mammary tumor virus (MMTV) promoter by a mechanism that does not require the binding of upstream transcription factors. In the current study, we find that HDACs work through the core promoter sequences of MMTV as well as those of several cellular genes to facilitate transcriptional initiation through deacetylation of nonhistone proteins.<br><br>
Distinctive Functions Of P160 Steroid Receptor Coactivators In Proliferation Of An Estrogen Independent, Tamoxifen Resistant Breast Cancer Cell Line. Source: Endocrine Related Cancer
December 21st, 2010 PMID: 21059860 Catharine Smith
Elevated expression of steroid receptor coactivator-3 (SRC-3), a member of the p160 family of nuclear receptor coactivators, has been implicated in tamoxifen resistance of breast tumors while the involvement of the two other members of this family, SRC-1 and SRC-2, is less well characterized. In this study, using small interfering RNA-based silencing, the role of each SRC coactivator in the growth of the LCC2 estrogen-independent and tamoxifen-resistant breast cancer cell line was evaluated. The loss of SRC-1, SRC-2, or SRC-3 did not significantly alter LCC2 proliferation or cell cycle distribution of 4-hydroxytamoxifen- versus vehicle-treated cells. However, depletion of SRC-2 and SRC-3, but not SRC-1, decreased basal cell proliferation and increased apoptosis. Cell cycle analyses further illustrated the divergent contributions of SRC-2 and SRC-3 with depletion of the former increasing the percentage of cells in the G(0)G(1) and sub-G(0)G(1) phases of cell cycle yet maintaining sensitivity to estradiol and ICI 182 780 antiestrogen, while SRC-3 depletion increased cells in the sub-G(0)G(1) phase and ablated response to estrogen receptor α (ERα) ligands. Surprisingly, the effects of SRC coactivator depletion on ERα transcriptional activity, as measured by luciferase reporter gene, did not correspond to the observed effects on proliferation (e.g. SRC-1 knockdown increases ERα activity). Collectively, these data indicate that SRC control of basal and hormone-regulated proliferations is not solely mediated by ERα, and suggest that targeting growth inhibition by disrupting SRC-2 and SRC-3 function may be an effective approach to inhibit the growth of tamoxifen-resistant breast cancer.<br><br>
Long Term Follow Up Of Patients Undergoing Auto Sct For Advanced Germ Cell Tumour: A Multicentre Cohort Study. Source: Bone Marrow Transplantation
November 1st, 2010 PMID: 21042312 Catharine Smith
Failure of cisplatin-based chemotherapy in advanced germ cell tumour (GCT) is associated with a poor outcome. High-dose chemotherapy and auto-SCT is one therapeutic option, although the long-term outcome after this procedure is unclear. We conducted a multicentre cohort study of consecutive patients undergoing a single auto-SCT for GCT between January 1986 and December 2004. Of 71 subjects, median follow-up is 10.1 years. OS at 5 years is 44.7% (95% confidence interval (CI) 32.9-56.5%) and EFS is 43.5% (95% CI 31.4-55.1%). There were seven (10%) treatment-related deaths within 100 days of auto-SCT. Three (4.2%) patients developed secondary malignancies. Of 33 relapses, 31 occurred within 2 years of auto-SCT. Two very late relapses were noted 13 and 11 years after auto-SCT. In multivariate analysis, favourable outcome was associated with IGCCC (International Germ Cell Consensus Classification) good prognosis disease at diagnosis, primary gonadal disease and response to salvage chemotherapy. We conclude that auto-SCT results in successful outcome for a relatively large subgroup of patients with high-risk GCT. Late relapses may occur, a finding not previously reported.<br><br>
The Degree Of Bandemia In Septic Ed Patients Does Not Predict Inpatient Mortality. Source: The American Journal Of Emergency Medicine
October 20th, 2010 PMID: 20970296 Catharine Smith
BACKGROUND:<br>A delay in diagnosis of sepsis and appropriate treatment increases subsequent mortality. An association with the degree of bandemia, or the presence of immature neutrophils in the white blood cell count, has not been explored in septic patients presenting to the emergency department (ED). We hypothesized that the presenting band levels would be higher in septic patients who die in hospital compared with survivors.<br><br>METHODS:<br>This study reviewed charts of ED patients presenting with sepsis to a single urban, academic, tertiary care ED with an annual census of 80,000 visits. Patients were included if they had bandemia assessed and were eligible for early goal-directed therapy. Reviewers blinded to the study purpose abstracted data using predetermined definitions. The band level was compared between patients who died and those who survived to discharge using the Mann-Whitney U test. Logistic regression was used to estimate the effect of bandemia levels on the odds of death.<br><br>RESULTS:<br>Ninety-six patients meeting inclusion criteria were enrolled; 2 were excluded with incomplete data. Mean age was 59 years, 53% were white, and 51% were male. Thirty-two patients (34%) died during admission. The median band levels in patients who died was 17% (range, 0%-67%); and in patients surviving to discharge, the median band level was 9% (range, 0%-77%) (difference in medians, 8%; CI(95), -27.04 to 11.04; P = .222).<br><br>CONCLUSIONS:<br>The band level on presentation was not found to be associated with inpatient mortality in ED patients with sepsis who are eligible for early goal-directed therapy.<br><br>
Coupling Of Receptor Conformation And Ligand Orientation Determine Graded Activity. Source: Nature Chemical Biology
October 10th, 2010 PMID: 20924370 Catharine Smith
Small molecules stabilize specific protein conformations from a larger ensemble, enabling molecular switches that control diverse cellular functions. We show here that the converse also holds true: the conformational state of the estrogen receptor can direct distinct orientations of the bound ligand. 'Gain-of-allostery' mutations that mimic the effects of ligand in driving protein conformation allowed crystallization of the partial agonist ligand WAY-169916 with both the canonical active and inactive conformations of the estrogen receptor. The intermediate transcriptional activity induced by WAY-169916 is associated with the ligand binding differently to the active and inactive conformations of the receptor. Analyses of a series of chemical derivatives demonstrated that altering the ensemble of ligand binding orientations changes signaling output. The coupling of different ligand binding orientations to distinct active and inactive protein conformations defines a new mechanism for titrating allosteric signaling activity.<br><br>
Intravascular Large B Cell Lymphoma: An Elusive Cause Of Pyrexia Of Unknown Origin Diagnosed Postmortem. Source: Clinical Infectious Diseases : An Official Publication Of The Infectious Diseases Society Of America
October 7th, 2010 PMID: 20868278 Catharine Smith
Intravascular large B cell lymphoma (IVLBCL) is a rare cause of pyrexia of unknown origin. Because of its protean clinical manifestations, diagnosis is elusive and is often made postmortem. We report here a case of IVLBCL that evaded diagnosis despite multiple investigations in vivo for pyrexia of unknown origin over a 5&#x2010;month period.<br><br>
Amniotic Fluid Lamellar Body Concentration As A Marker Of Fetal Lung Maturity At Term Elective Caesarean Delivery. Source: The Australian & New Zealand Journal Of Obstetrics & Gynaecology
August 18th, 2010 PMID: 20716264 Catharine Smith
BACKGROUND:<br>Caesarean birth, without prior labour, is associated with an increased risk of neonatal respiratory morbidity among term infants. The concentration of lamellar bodies in amniotic fluid reflects pulmonary surfactant production and release, and is thus used in preterm populations as a marker of fetal lung maturity. Whether amniotic fluid lamellar body concentration (AFLBC) may correlate with risk factors for term respiratory distress has not previously been evaluated.<br><br>AIMS:<br>To determine the relationship between AFLBC and risk factors for respiratory distress following term caesarean birth.<br><br>METHODS:<br>The AFLBC of 249 women at the time of term caesarean birth was examined for an association with gestational age, gender, presentation and neonatal respiratory distress requiring special care nursery (SCN) admission.<br><br>RESULTS:<br>There was a significant increase in AFLBC with gestation. When compared with caesarean deliveries performed during the 37th week of gestation, there was a 50%, 54% and 56% increase in lamellar body concentrations (LBCs) taken during the 38th, 39th and 40th week of gestation respectively (P < 0.05 for all). Female fetuses had a 16% higher LBC than males (P < 0.05). An LBC <100 x 10(9) mL(-1) was associated with increased risk of admission to the SCN with respiratory distress (RR = 5.6; 1.2-26.5, P < 0.05).<br><br>CONCLUSION:<br>Known risk factors for term respiratory distress are reflected in the AFLBC. A significant relationship exists between AFLBC and respiratory morbidity following term caesarean birth. However, the low prevalence of this condition limits the clinical role of AFLBC as a predictive test for term respiratory morbidity.<br><br>
Systematic Review Of Self Ligating Brackets. Source: American Journal Of Orthodontics And Dentofacial Orthopedics : Official Publication Of The American Association Of Orthodontists, Its Constituent Societies, And The American Board Of Orthodontics
August 5th, 2010 PMID: 20685517 Catharine Smith
INTRODUCTION:<br>Self-ligating brackets have been gaining popularity over the past several decades. Various advantages for these systems have been claimed. The purposes of this systematic review were to identify and review the orthodontic literature with regard to the efficiency, effectiveness, and stability of treatment with self-ligating brackets compared with conventional brackets.<br><br>METHODS:<br>An electronic search in 4 data bases was performed from 1966 to 2009, with supplemental hand searching of the references of retrieved articles. Quality assessment of the included articles was performed. Data were extracted by using custom forms, and weighted mean differences were calculated.<br><br>RESULTS:<br>Sixteen studies met the inclusion criteria, including 2 randomized controlled trials with low risk of bias, 10 cohort studies with moderate risk of bias, and 4 cross-sectional studies with moderate to high risk of bias. Self-ligation appears to have a significant advantage with regard to chair time, based on several cross-sectional studies. Analyses also showed a small, but statistically significant, difference in mandibular incisor proclination (1.5 degrees less in self-ligating systems). No other differences in treatment time and occlusal characteristics after treatment were found between the 2 systems. No studies on long-term stability of treatment were identified.<br><br>CONCLUSIONS:<br>Despite claims about the advantages of self-ligating brackets, evidence is generally lacking. Shortened chair time and slightly less incisor proclination appear to be the only significant advantages of self-ligating systems over conventional systems that are supported by the current evidence.<br><br>
Pulmonary Function Measurements Immediately After Exercise Are Correlated With Neutrophil Percentage In Tracheal Aspirates In Horses With Poor Racing Performance. Source: Research In Veterinary Science
August 1st, 2010 PMID: 20678784 Catharine Smith
Inflammatory airway disease (IAD) is common in racehorses, and is a cause of wastage in the industry. IAD has been diagnosed by measurement of percent neutrophils (N%) in tracheal aspirates (TA). The aim of this study was to investigate whether spirometric indices of pulmonary function were correlated with N% in TAs. Limits to breathing were measured by analyses of relationships between relative times and relative respiratory gas flows during inspiration and expiration in individual breaths recorded after exercise. Horses with higher N% had significantly lower relative gas flows at the same relative times during inspiration and expiration, suggesting a limit to breathing. These findings confirm a physiological basis for the measurement of N% in TA after exercise for diagnosis of IAD. Spirometric pulmonary function testing using analyses of individual breaths after exercise has application for assessment of pulmonary function and poor exercise performance.<br><br>
Restoration Of Growth Phenotypes Of Escherichia Coli Dh5alpha In Minimal Media Through Reversal Of A Point Mutation In Pur B. Source: Applied And Environmental Microbiology
July 30th, 2010 PMID: 20675450 Catharine Smith
A point mutation (E115K) resulting in slower growth of Escherichia coli DH5alpha and XL1-Blue in minimal media was identified in the purB gene, coding for adenylosuccinate lyase (ASL), through complementation with an E. coli K-12 genomic library and serial subcultures. Chromosomal modification reversing the mutation to the wild type restored growth phenotypes in minimal media.<br><br>
The Complement Of Research And Theory In Practice: Contact Theory At Work In Nonfamilial Intergenerational Programs. Source: The Gerontologist
July 25th, 2010 PMID: 20660474 Catharine Smith
PURPOSE OF THE STUDY:<br>We assessed whether a shared site intergenerational care program informed by contact theory contributed to more desirable social behaviors of elders and children during intergenerational programming than a center with a more traditional programming approach that lacks some or all of the contact theory tenets.<br><br>DESIGN AND METHODS:<br>We observed 59 elder and child participants from the two sites during intergenerational activities. Using the Intergenerational Observation Scale, we coded participants' predominant behavior in 15-s intervals through each activity's duration. We then calculated for each individual the percentage of time frames each behavior code was predominant.<br><br>RESULTS:<br>Participants at the theory-based program demonstrated higher rates of intergenerational interaction, higher rates of solitary behavior, and lower rates of watching than at the traditional program.<br><br>IMPLICATIONS:<br>Contact theory tenets were optimized when coupled with evidence-based practices. Intergenerational programs with stakeholder support that promotes equal group status, cooperation toward a common goal, and mechanisms of friendship among participants can achieve important objectives for elder and child participants in care settings.<br><br>
Epicardial Spindle Orientation Controls Cell Entry Into The Myocardium. Source: Developmental Cell
July 20th, 2010 PMID: 20643355 Catharine Smith
During heart morphogenesis, epicardial cells undergo an epithelial-to-mesenchymal transition (EMT) and migrate into the subepicardium. The cellular signals controlling this process are poorly understood. Here, we show that epicardial cells exhibit two distinct mitotic spindle orientations, directed either parallel or perpendicular to the basement membrane. Cells undergoing perpendicular cell division subsequently enter the myocardium. We found that loss of beta-catenin led to a disruption of adherens junctions and a randomization of mitotic spindle orientation. Loss of adherens junctions also disrupted Numb localization within epicardial cells, and disruption of Numb and Numblike expression in the epicardium led to randomized mitotic spindle orientations. Taken together, these data suggest that directed mitotic spindle orientation contributes to epicardial EMT and implicate a junctional complex of beta-catenin and Numb in the regulation of spindle orientation.<br><br>
Relations Among Maternal Socialization, Effortful Control, And Maladjustment In Early Childhood. Source: Development And Psychopathology
June 25th, 2010 PMID: 20576175 Catharine Smith
In a sample of 18-, 30-, and 42-month-olds, the relations among parenting, effortful control (EC), and maladjustment were examined. Parenting was assessed with mothers' reports and observations; EC was measured with mothers' and caregivers' reports, as well as a behavioral task; and externalizing and internalizing symptoms were assessed with parents' and caregivers' reports. Although 18-month unsupportive (vs. supportive) parenting negatively predicted EC at 30 months, when the stability of these variables was taken into account, there was no evidence of additional potentially causal relations between these two constructs. Although EC was negatively related to both internalizing and externalizing problems within all three ages as well as across 1 year, EC did not predict maladjustment once the stability of the constructs and within time covariation between the constructs were taken into account. In addition, externalizing problems at 30 months negatively predicted EC at 42 months, and internalizing problems at 30 months positively predicted EC at 42 months, but only when the effects of externalizing on EC were controlled. The findings are discussed in terms of the reasons for the lack of causal relations over time.<br><br>
Frequent Multidrug Resistant Acinetobacter Baumannii Contamination Of Gloves, Gowns, And Hands Of Healthcare Workers. Source: Infection Control And Hospital Epidemiology : The Official Journal Of The Society Of Hospital Epidemiologists Of America
June 4th, 2010 PMID: 20486855 Catharine Smith
BACKGROUND:<br>Multidrug-resistant (MDR) gram-negative bacilli are important nosocomial pathogens.<br><br>OBJECTIVE:<br>To determine the incidence of transmission of MDR Acinetobacter baumannii and Pseudomonas aeruginosa from patients to healthcare workers (HCWs) during routine patient care.<br><br>DESIGN:<br>Prospective cohort study.<br><br>SETTING:<br>Medical and surgical intensive care units. Methods. We observed HCWs who entered the rooms of patients colonized with MDR A. baumannii or colonized with both MDR A. baumannii and MDR P. aeruginosa. We examined their hands before room entry, their disposable gloves and/or gowns upon completion of patient care, and their hands after removal of gloves and/or gowns and before hand hygiene.<br><br>RESULTS:<br>Sixty-five interactions occurred with patients colonized with MDR A. baumannii and 134 with patients colonized with both MDR A. baumannii and MDR P. aeruginosa. Of 199 interactions between HCWs and patients colonized with MDR A. baumannii, 77 (38.7% [95% confidence interval {CI}, 31.9%-45.5%]) resulted in HCW contamination of gloves and/or gowns, and 9 (4.5% [95% CI, 1.6%-7.4%]) resulted in contamination of HCW hands after glove removal before hand hygiene. Of 134 interactions with patients colonized with MDR P. aeruginosa, 11 (8.2% [95% CI, 3.6%-12.9%]) resulted in HCW contamination of gloves and/or gowns, and 1 resulted in HCW contamination of hands. Independent risk factors for contamination with MDR A. baumannii were manipulation of wound dressing (adjusted odds ratio [aOR], 25.9 [95% CI, 3.1-208.8]), manipulation of artificial airway (aOR, 2.1 [95% CI, 1.1-4.0]), time in room longer than 5 minutes (aOR, 4.3 [95% CI, 2.0-9.1]), being a physician or nurse practitioner (aOR, 7.4 [95% CI, 1.6-35.2]), and being a nurse (aOR, 2.3 [95% CI, 1.1-4.8]).<br><br>CONCLUSIONS:<br>Gowns, gloves, and unwashed hands of HCWs were frequently contaminated with MDR A. baumannii. MDR A. baumannii appears to be more easily transmitted than MDR P. aeruginosa and perhaps more easily transmitted than previously studied methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus. This ease of transmission may help explain the emergence of MDR A. baumannii.<br><br>
Hodgkin Lymphoma And Fulminant Hepatic Failure. Source: Leukemia & Lymphoma
April 28th, 2010 PMID: 20367133 Catharine Smith
Photonic Based Multi Wavelength Sensor For Object Identification. Source: Optics Express
April 14th, 2010 PMID: 20389388 Catharine Smith
A Photonic-based multi-wavelength sensor capable of discriminating objects is proposed and demonstrated for intruder detection and identification. The sensor uses a laser combination module for input wavelength signal multiplexing and beam overlapping, a custom-made curved optical cavity for multi-beam spot generation through internal beam reflection and transmission and a high-speed imager for scattered reflectance spectral measurements. Experimental results show that five different wavelengths, namely 473 nm, 532 nm, 635 nm, 670 nm and 785 nm, are necessary for discriminating various intruding objects of interest through spectral reflectance and slope measurements. Objects selected for experiments were brick, cement sheet, cotton, leather and roof tile.<br><br>
Cooperative Activation Of Cyclin D1 And Progesterone Receptor Gene Expression By The Src 3 Coactivator And Smrt Corepressor. Source: Molecular Endocrinology (Baltimore, Md.)
April 14th, 2010 PMID: 20392877 Catharine Smith
Although the ability of coactivators to enhance the expression of estrogen receptor-alpha (ERalpha) target genes is well established, the role of corepressors in regulating 17beta-estradiol (E2)-induced gene expression is poorly understood. Previous studies revealed that the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressor is required for full ERalpha transcriptional activity in MCF-7 breast cancer cells, and we report herein the E2-dependent recruitment of SMRT to the regulatory regions of the progesterone receptor (PR) and cyclin D1 genes. Individual depletion of SMRT or steroid receptor coactivator (SRC)-3 modestly decreased E2-induced PR and cyclin D1 expression; however, simultaneous depletion revealed a cooperative effect of this coactivator and corepressor on the expression of these genes. SMRT and SRC-3 bind directly in an ERalpha-independent manner, and this interaction promotes E2-dependent SRC-3 binding to ERalpha measured by co-IP and SRC-3 recruitment to the cyclin D1 gene as measured by chromatin IP assays. Moreover, SMRT stimulates the intrinsic transcriptional activity of all of the SRC family (p160) coactivators. Our data link the SMRT corepressor directly with SRC family coactivators in positive regulation of ERalpha-dependent gene expression and, taken with the positive correlation found for SMRT and SRC-3 in human breast tumors, suggest that SMRT can promote ERalpha- and SRC-3-dependent gene expression in breast cancer.<br><br>
Stability In Infant Frontal Asymmetry As A Predictor Of Toddlerhood Internalizing And Externalizing Behaviors. Source: Developmental Psychobiology
February 26th, 2010 PMID: 20175143 Catharine Smith
Stability in frontal brain electrical activity (i.e., electroencephalographic or EEG) asymmetry at 10 and 24 months was examined with respect to maternal ratings of internalizing and externalizing behaviors at 30 months in a sample of 48 children. Children with stable left frontal EEG asymmetry during infancy were rated higher in externalizing behaviors by their mothers, whereas children with stable right frontal EEG asymmetry were rated higher in internalizing behaviors. These findings highlight the need to focus on the early stability in physiological measures that may be implicated later in developing behavioral problems.<br><br>
The Path To Fusion Power. Source: Philosophical Transactions. Series A, Mathematical, Physical, And Engineering Sciences
February 3rd, 2010 PMID: 20123748 Catharine Smith
The promise, status and challenges of developing fusion power are outlined. The key physics and engineering principles are described and recent progress quantified. As the successful demonstration of 16 MW of fusion in 1997 in the Joint European Torus showed, fusion works. The central issue is therefore to make it work reliably and economically on the scale of a power station. We argue that to meet this challenge in 30 years we must follow the aggressive programme known as the 'Fast Track to Fusion'. This programme is described in some detail.<br><br>
3' End Sequencing For Expression Quantification (3 Seq) From Archival Tumor Samples. Source: Plo S One
January 19th, 2010 PMID: 20098735 Catharine Smith
Gene expression microarrays are the most widely used technique for genome-wide expression profiling. However, microarrays do not perform well on formalin fixed paraffin embedded tissue (FFPET). Consequently, microarrays cannot be effectively utilized to perform gene expression profiling on the vast majority of archival tumor samples. To address this limitation of gene expression microarrays, we designed a novel procedure (3'-end sequencing for expression quantification (3SEQ)) for gene expression profiling from FFPET using next-generation sequencing. We performed gene expression profiling by 3SEQ and microarray on both frozen tissue and FFPET from two soft tissue tumors (desmoid type fibromatosis (DTF) and solitary fibrous tumor (SFT)) (total n = 23 samples, which were each profiled by at least one of the four platform-tissue preparation combinations). Analysis of 3SEQ data revealed many genes differentially expressed between the tumor types (FDR<0.01) on both the frozen tissue (approximately 9.6K genes) and FFPET (approximately 8.1K genes). Analysis of microarray data from frozen tissue revealed fewer differentially expressed genes (approximately 4.64K), and analysis of microarray data on FFPET revealed very few (69) differentially expressed genes. Functional gene set analysis of 3SEQ data from both frozen tissue and FFPET identified biological pathways known to be important in DTF and SFT pathogenesis and suggested several additional candidate oncogenic pathways in these tumors. These findings demonstrate that 3SEQ is an effective technique for gene expression profiling from archival tumor samples and may facilitate significant advances in translational cancer research.<br><br>
Integrating Phenotype Ontologies Across Multiple Species. Source: Genome Biology
January 8th, 2010 PMID: 20064205 Catharine Smith
Phenotype ontologies are typically constructed to serve the needs of a particular community, such as annotation of genotype-phenotype associations in mouse or human. Here we demonstrate how these ontologies can be improved through assignment of logical definitions using a core ontology of phenotypic qualities and multiple additional ontologies from the Open Biological Ontologies library. We also show how these logical definitions can be used for data integration when combined with a unified multi-species anatomy ontology.<br><br>
Identification Of Four Novel Phosphorylation Sites In Estrogen Receptor Alpha: Impact On Receptor Dependent Gene Expression And Phosphorylation By Protein Kinase Ck2. Source: Bmc Biochemistry
December 31st, 2009 PMID: 20043841 Catharine Smith
BACKGROUND:<br>Estrogen receptor alpha (ERalpha) phosphorylation is important for estrogen-dependent transcription of ER-dependent genes, ligand-independent receptor activation and endocrine therapy response in breast cancer. However ERalpha phosphorylation at the previously identified sites does not fully account for these receptor functions. To determine if additional ERalpha phosphorylation sites exist, COS-1 cells expressing human ERalpha were labeled with [32P]H3PO4 in vivo and ERalpha tryptic phosphopeptides were isolated to identify phosphorylation sites.<br><br>RESULTS:<br>Previously uncharacterized phosphorylation sites at serines 46/47, 282, 294, and 559 were identified by manual Edman degradation and phosphoamino acid analysis and confirmed by mutagenesis and phospho-specific antibodies. Antibodies detected phosphorylation of endogenous ERalpha in MCF-7, MCF-7-LCC2, and Ishikawa cancer cell lines by immunoblot. Mutation of Ser-282 and Ser-559 to alanine (S282A, S559A) resulted in ligand independent activation of ERalpha as determined by both ERE-driven reporter gene assays and endogenous pS2 gene expression in transiently transfected HeLa cells. Mutation of Ser-46/47 or Ser-294 to alanine markedly reduced estradiol dependent reporter activation. Additionally protein kinase CK2 was identified as a kinase that phosphorylated ERalpha at S282 and S559 using motif analysis, in vitro kinase assays, and incubation of cells with CK2 kinase inhibitor.<br><br>CONCLUSION:<br>These novel ERalpha phosphorylation sites represent new means for modulation of ERalpha activity. S559 represents the first phosphorylation site identified in the extreme C-terminus (F domain) of a steroid receptor.<br><br>
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