Showing papers by "University of California, San Francisco published in 2005"
TL;DR: Members of the Chamber Quantification Writing Group are: Roberto M. Lang, MD, Fase, Michelle Bierig, MPH, RDCS, FASE, Richard B. Devereux,MD, Frank A. Flachskampf, MD and Elyse Foster, MD.
Abstract: Members of the Chamber Quantification Writing Group are: Roberto M. Lang, MD, FASE, Michelle Bierig, MPH, RDCS, FASE, Richard B. Devereux, MD, Frank A. Flachskampf, MD, Elyse Foster, MD, Patricia A. Pellikka, MD, Michael H. Picard, MD, Mary J. Roman, MD, James Seward, MD, Jack S. Shanewise, MD, FASE, Scott D. Solomon, MD, Kirk T. Spencer, MD, FASE, Martin St John Sutton, MD, FASE, and William J. Stewart, MD
10,834 citations
TL;DR: A strong scoring system and NAS for NAFLD and NASH with reasonable inter‐rater reproducibility that should be useful for studies of both adults and children with any degree ofNAFLD are presented.
8,253 citations
27 Oct 2005
TL;DR: A public database of common variation in the human genome: more than one million single nucleotide polymorphisms for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted.
Abstract: Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.
5,479 citations
TL;DR: This paper has prepared a library of 727,842 molecules, each with 3D structure, using catalogs of compounds from vendors, and hopes that this database will bring virtual screening libraries to a wide community of structural biologists and medicinal chemists.
Abstract: A critical barrier to entry into structure-based virtual screening is the lack of a suitable, easy to access database of purchasable compounds. We have therefore prepared a library of 727,842 molecules, each with 3D structure, using catalogs of compounds from vendors (the size of this library continues to grow). The molecules have been assigned biologically relevant protonation states and are annotated with properties such as molecular weight, calculated LogP, and number of rotatable bonds. Each molecule in the library contains vendor and purchasing information and is ready for docking using a number of popular docking programs. Within certain limits, the molecules are prepared in multiple protonation states and multiple tautomeric forms. In one format, multiple conformations are available for the molecules. This database is available for free download (http://zinc.docking.org) in several common file formats including SMILES, mol2, 3D SDF, and DOCK flexibase format. A Web-based query tool incorporating a molecular drawing interface enables the database to be searched and browsed and subsets to be created. Users can process their own molecules by uploading them to a server. Our hope is that this database will bring virtual screening libraries to a wide community of structural biologists and medicinal chemists.
3,354 citations
TL;DR: Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit beyond that afforded by treatment with 10 mg of least-in- LDL cholesterol levels per day, with a greater incidence of elevated aminotransferase levels.
Abstract: background Previous trials have demonstrated that lowering low-density lipoprotein (LDL) cholesterol levels below currently recommended levels is beneficial in patients with acute coronary syndromes. We prospectively assessed the efficacy and safety of lowering LDL cholesterol levels below 100 mg per deciliter (2.6 mmol per liter) in patients with stable coronary heart disease (CHD). methods A total of 10,001 patients with clinically evident CHD and LDL cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) were randomly assigned to double-blind therapy and received either 10 mg or 80 mg of atorvastatin per day. Patients were followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event, defined as death from CHD, nonfatal non–procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. results The mean LDL cholesterol levels were 77 mg per deciliter (2.0 mmol per liter) during treatment with 80 mg of atorvastatin and 101 mg per deciliter (2.6 mmol per liter) during treatment with 10 mg of atorvastatin. The incidence of persistent elevations in liver aminotransferase levels was 0.2 percent in the group given 10 mg of atorvastatin and 1.2 percent in the group given 80 mg of atorvastatin (P<0.001). A primary event occurred in 434 patients (8.7 percent) receiving 80 mg of atorvastatin, as compared with 548 patients (10.9 percent) receiving 10 mg of atorvastatin, representing an absolute reduction in the rate of major cardiovascular events of 2.2 percent and a 22 percent relative reduction in risk (hazard ratio, 0.78; 95 percent confidence interval, 0.69 to 0.89; P<0.001). There was no difference between the two treatment groups in overall mortality. conclusions Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit beyond that afforded by treatment with 10 mg of atorvastatin per day. This occurred with a greater incidence of elevated aminotransferase levels.
3,141 citations
TL;DR: Modest changes in SCr were significantly associated with mortality, LOS, and costs, even after adjustment for age, gender, admission International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis, severity of illness (diagnosis-related group weight), and chronic kidney disease.
Abstract: The marginal effects of acute kidney injury on in-hospital mortality, length of stay (LOS), and costs have not been well described. A consecutive sample of 19,982 adults who were admitted to an urban academic medical center, including 9210 who had two or more serum creatinine (SCr) determinations, was evaluated. The presence and degree of acute kidney injury were assessed using absolute and relative increases from baseline to peak SCr concentration during hospitalization. Large increases in SCr concentration were relatively rare (e.g., >or=2.0 mg/dl in 105 [1%] patients), whereas more modest increases in SCr were common (e.g., >or=0.5 mg/dl in 1237 [13%] patients). Modest changes in SCr were significantly associated with mortality, LOS, and costs, even after adjustment for age, gender, admission International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis, severity of illness (diagnosis-related group weight), and chronic kidney disease. For example, an increase in SCr >or=0.5 mg/dl was associated with a 6.5-fold (95% confidence interval 5.0 to 8.5) increase in the odds of death, a 3.5-d increase in LOS, and nearly 7500 dollars in excess hospital costs. Acute kidney injury is associated with significantly increased mortality, LOS, and costs across a broad spectrum of conditions. Moreover, outcomes are related directly to the severity of acute kidney injury, whether characterized by nominal or percentage changes in serum creatinine.
2,963 citations
TL;DR: From an analysis of the effect of obesity on longevity, it is concluded that the steady rise in life expectancy during the past two centuries may soon come to an end.
Abstract: Forecasts of life expectancy are an important component of public policy that influence age-based entitlement programs such as Social Security and Medicare. Although the Social Security Administration recently raised its estimates of how long Americans are going to live in the 21st century, current trends in obesity in the United States suggest that these estimates may not be accurate. From our analysis of the effect of obesity on longevity, we conclude that the steady rise in life expectancy during the past two centuries may soon come to an end.
2,798 citations
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TL;DR: The structure, function, and ligand specificity of the receptors responsible for NK cell recognition are reviewed and the role of EMT inNK cell recognition is reviewed.
Abstract: The integrated processing of signals transduced by activating and inhibitory cell surface receptors regulates NK cell effector functions. Here, I review the structure, function, and ligand specificity of the receptors responsible for NK cell recognition.
2,724 citations
TL;DR: The Alzheimer's Disease Neuroimaging Initiative will help identify clinical, neuroimaging, and biomarker outcome measures that provide the highest power for measurement of longitudinal changes and for prediction of transitions.
2,665 citations
Indiana University1, University Health Network2, University Hospital Bonn3, Radboud University Nijmegen4, Cleveland Clinic5, New York University6, Jean Monnet University7, University of Chicago8, University of Queensland9, Erasmus University Rotterdam10, University of California, San Francisco11, Aichi Medical University12, University Hospital of Wales13, Cambridge University Hospitals NHS Foundation Trust14, Baylor College of Medicine15, Wayne State University16, Medical College of Wisconsin17
TL;DR: This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France, where topics brought to consensus included approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns.
Abstract: Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging-targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed.
2,636 citations
TL;DR: The genetic alterations identified in melanoma at different sites and with different levels of sun exposure indicate that there are distinct genetic pathways in the development of melanoma and implicate CDK4 and CCND1 as independent oncogenes in melanomas without mutations in BRAF or N-RAS.
Abstract: Background Exposure to ultraviolet light is a major causative factor in melanoma, although the relationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of melanoma with different susceptibility to ultraviolet light. Methods We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and N-RAS in 126 melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal melanomas. Results We found significant differences in the frequencies of regional changes in the number of copies of DNA and mutation frequencies in BRAF among the four groups of melanomas. Samples could be correctly classified into the four groups with 70 percent accuracy on the basis of the changes in the number of copies of...
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23 Mar 2005TL;DR: In this paper, the authors discuss the need to regrounded theory and symbolic interactionism as a theory/Methods package, pushing and being pulled around the Postmodern Turn Grounded Theory/Symbolic Interactionism, as a Theory/Methods Package, as always already around the postmodern Turn, as Recalcitrant Against the Post Modern Turn, Reflections and anticipations.
Abstract: List of Illustrations Acknowledgments Prologue: Regrounding Grounded Theory 1. Pushing and Being Pulled Around the Postmodern Turn Grounded Theory/Symbolic Interactionism as a Theory/Methods Package Grounded Theory/Symbolic Interactionism as Always Already Around the Postmodern Turn Grounded Theory as Recalcitrant Against the Postmodern Turn Pushing Grounded Theory Around the Postmodern Turn Reflections and Anticipations 2. From Chicago Ecologies to Situational Analysis Root Metaphors: From Chicago School Social Ecologies to Social Worlds/Arenas/Discourses New Roots I: Foucault and the Interactionist Project New Roots II: Taking the Nonhuman Explicitly Into Account New Roots III: From Social Worlds/Arenas to Situational Maps and Analysis Project Design, Data Gathering, and Accountability Temporary Closures 3. Doing Situational Maps and Analysis Doing Situational Maps Doing Social Worlds/Arenas Maps Doing Positional Maps Final Products: Project Maps Provisional Conclusions 4. Turning to Discourse(s) Introducing Discourse Analysis Multisite/Multiscape Research Issues in Situational Analysis of Discourse(s) Turnings 5. Mapping Narrative Discourses Designing a Narrative Project Doing Situational Maps of Narrative Discourse Doing Social Worlds/Arenas Maps of Narrative Discourse Doing Positional Maps of Narrative Discourse Final Comments: Situational Analysis of Narrative Discourse 6. Mapping Visual Discourses Entering Visual Discourse Doing Situational Analysis of Visual Discourse Visual Discourse Exemplars: Moore and Clarke's Anatomies Final Comments: Situational Analysis of Visual Discourse 7. Mapping Historical Discourses Designing Historical and Historicizing Projects Doing Situational Maps of Historical Discourse Doing Social Worlds/Arenas Maps of Historical Discourse Doing Positional Maps of Historical Discourse Project Map of Historical Discourse Final Comments: Situational Analysis of Historical Discourse Epilogue: FAQs and Conversations References Index About the Author
TL;DR: Experimental results show that a 2D point resolution of <50 nm is possible on sufficiently bright and photostable samples, and a recently proposed method in which the nonlinearity arises from saturation of the excited state is experimentally demonstrated.
Abstract: Contrary to the well known diffraction limit, the fluorescence microscope is in principle capable of unlimited resolution. The necessary elements are spatially structured illumination light and a nonlinear dependence of the fluorescence emission rate on the illumination intensity. As an example of this concept, this article experimentally demonstrates saturated structured-illumination microscopy, a recently proposed method in which the nonlinearity arisesfromsaturationoftheexcitedstate.Thismethodcanbeused in a simple, wide-field (nonscanning) microscope, uses only a single, inexpensive laser, and requires no unusual photophysical properties of the fluorophore. The practical resolving power is determined by the signal-to-noise ratio, which in turn is limited by photobleaching. Experimental results show that a 2D point resolution of <50 nm is possible on sufficiently bright and photostable samples.
TL;DR: It is shown that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier, which may represent the first example of a novel class of autoimmune channelopathy.
Abstract: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that selectively affects optic nerves and spinal cord. It is considered a severe variant of multiple sclerosis (MS), and frequently is misdiagnosed as MS, but prognosis and optimal treatments differ. A serum immunoglobulin G autoantibody (NMO-IgG) serves as a specific marker for NMO. Here we show that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier. NMO may represent the first example of a novel class of autoimmune channelopathy.
Veterans Health Administration1, University of Miami2, San Francisco General Hospital3, University of California, San Francisco4, University of Missouri5, University of California, Los Angeles6, Tufts University7, University of Washington8, University of Minnesota9, Stanford University10, Palo Alto Medical Foundation11, VA Palo Alto Healthcare System12, Medical College of Wisconsin13
TL;DR: It is the recommendation of this committee that patients with soft-tissue infection be distinguished by signs and symptoms of systemic toxicity (e.g., fever or hypothermia, tachycardia [heart rate,] and so on).
Abstract: EXECUTIVE SUMMARYSoft-tissue infections are common, generally of mild tomodest severity, and are easily treated with a variety ofagents. An etiologic diagnosis of simple cellulitis is fre-quently difficult and generally unnecessary for patientswith mild signs and symptoms of illness. Clinical as-sessment of the severity of infection is crucial, and sev-eral classification schemes and algorithms have beenproposed to guide the clinician [1]. However, mostclinical assessments have been developed from eitherretrospective studies or from an author’s own “clinicalexperience,” illustrating the need for prospectivestudieswith defined measurements of severity coupled to man-agement issues and outcomes.Until then, it is the recommendation of this com-mittee that patients with soft-tissue infection accom-panied by signs and symptoms of systemic toxicity (e.g.,fever or hypothermia, tachycardia [heart rate,
TL;DR: Evidence shows that conclusions about nonsocioeconomic causes of racial/ethnic differences in health may depend on the measure-eg, income, wealth, education, occupation, neighborhood socioeconomic characteristics, or past socioeconomic experiences used to "control for SES," suggesting that findings from studies that have measured limited aspects of SES should be reassessed.
Abstract: Problems with measuring socioeconomic status (SES)—frequently included in clinical and public health studies as a control variable and less frequently as the variable(s) of main interest—could affect research findings and conclusions, with implications for practice and policy.Wecritically examine standard SES measurement approaches, illustrating problems with examples from new analyses and the literature. For example, marked racial/ethnic differences in income at a given educational level and in wealth at a given income level raise questions about the socioeconomic comparability of individuals who are similar on education or income alone. Evidence also shows that conclusions about nonsocioeconomic causes of racial/ethnic differences in health may depend on the measure—eg, income, wealth, education, occupation, neighborhood socioeconomic characteristics, or past socioeconomic experiences—used to “control for SES,” suggesting that findings from studies that have measured limited aspects of SES should be reassessed. We recommend an outcome- and social group–specific approach to SES measurement that involves (1) considering plausible explanatory pathways and mechanisms, (2) measuring as much relevant socioeconomic information as possible, (3) specifying the particular socioeconomic factors measured (rather than SES overall), and (4) systematically considering how potentially important unmeasured socioeconomic factors may affect conclusions. Better SES measures are needed in data sources, but improvements could be made by using existing information more thoughtfully and acknowledging its limitations.
TL;DR: Advances in understanding of the role of molecular weight and architecture on the in vivo behavior of dendrimers, together with recent progress in the design of biodegradable chemistries, has enabled the application of these branched polymers as anti-viral drugs, tissue repair scaffolds, targeted carriers of chemotherapeutics and optical oxygen sensors.
Abstract: Dendrimers are branched, synthetic polymers with layered architectures that show promise in several biomedical applications. By regulating dendrimer synthesis, it is possible to precisely manipulate both their molecular weight and chemical composition, thereby allowing predictable tuning of their biocompatibility and pharmacokinetics. Advances in our understanding of the role of molecular weight and architecture on the in vivo behavior of dendrimers, together with recent progress in the design of biodegradable chemistries, has enabled the application of these branched polymers as anti-viral drugs, tissue repair scaffolds, targeted carriers of chemotherapeutics and optical oxygen sensors. Before such products can reach the market, however, the field must not only address the cost of manufacture and quality control of pharmaceutical-grade materials, but also assess the long-term human and environmental health consequences of dendrimer exposure in vivo.
TL;DR: The results suggest that SPR scattering imaging or SPR absorption spectroscopy generated from antibody conjugated gold nanoparticles can be useful in molecular biosensor techniques for the diagnosis and investigation of oral epithelial living cancer cells in vivo and in vitro.
Abstract: Gold nanoparticles with unique optical properties may be useful as biosensors in living whole cells. Using a simple and inexpensive technique, we recorded surface plasmon resonance (SPR) scattering images and SPR absorption spectra from both colloidal gold nanoparticles and from gold nanoparticles conjugated to monoclonal anti-epidermal growth factor receptor (anti-EGFR) antibodies after incubation in cell cultures with a nonmalignant epithelial cell line (HaCaT) and two malignant oral epithelial cell lines (HOC 313 clone 8 and HSC 3). Colloidal gold nanoparticles are found in dispersed and aggregated forms within the cell cytoplasm and provide anatomic labeling information, but their uptake is nonspecific for malignant cells. The anti-EGFR antibody conjugated nanoparticles specifically and homogeneously bind to the surface of the cancer type cells with 600% greater affinity than to the noncancerous cells. This specific and homogeneous binding is found to give a relatively sharper SPR absorption band with...
TL;DR: Induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, but it could safely improve survival without severe neurodevelopmental disability in infants with less severe aEEG changes.
TL;DR: Noise terminology is summarized and comment on recent investigations into the sources, consequences, and control of noise in gene expression are commented on.
Abstract: Genetically identical cells and organisms exhibit remarkable diversity even when they have identical histories of environmental exposure. Noise, or variation, in the process of gene expression may contribute to this phenotypic variability. Recent studies suggest that this noise has multiple sources, including the stochastic or inherently random nature of the biochemical reactions of gene expression. In this review, we summarize noise terminology and comment on recent investigations into the sources, consequences, and control of noise in gene expression.
TL;DR: This work reviews the molecular basis for the specificity and versatility of signaling by the many ligands through this conceptually simple signal transduction mechanism of the TGF-β family.
Abstract: The TGF-β family comprises many structurally related differentiation factors that act through a heteromeric receptor complex at the cell surface and an intracellular signal transducing Smad complex. The receptor complex consists of two type II and two type I transmembrane serine/threonine kinases. Upon phosphorylation by the receptors, Smad complexes translocate into the nucleus, where they cooperate with sequence-specific transcription factors to regulate gene expression. The vertebrate genome encodes many ligands, fewer type II and type I receptors, and only a few Smads. In contrast to the perceived simplicity of the signal transduction mechanism with few Smads, the cellular responses to TGF-β ligands are complex and context dependent. This raises the question of how the specificity of the ligand-induced signaling is achieved. We review the molecular basis for the specificity and versatility of signaling by the many ligands through this conceptually simple signal transduction mechanism.
TL;DR: In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States, and education of patients, physicians, and pharmacies to limit high‐risk use settings is recommended.
TL;DR: It is found that the miR-1 genes are direct transcriptional targets of muscle differentiation regulators including serum response factor, MyoD and Mef2, and a new algorithm for microRNA target identification that incorporates features of RNA structure and target accessibility is used.
Abstract: Gradients of signalling and transcription factors govern many aspects of embryogenesis, highlighting the need for spatiotemporal control of regulatory protein levels. MicroRNAs are phylogenetically conserved small RNAs that regulate the translation of target messenger RNAs, providing a mechanism for protein dose regulation. Here we show that microRNA-1-1 (miR-1-1) and miR-1-2 are specifically expressed in cardiac and skeletal muscle precursor cells. We found that the miR-1 genes are direct transcriptional targets of muscle differentiation regulators including serum response factor, MyoD and Mef2. Correspondingly, excess miR-1 in the developing heart leads to a decreased pool of proliferating ventricular cardiomyocytes. Using a new algorithm for microRNA target identification that incorporates features of RNA structure and target accessibility, we show that Hand2, a transcription factor that promotes ventricular cardiomyocyte expansion, is a target of miR-1. This work suggests that miR-1 genes titrate the effects of critical cardiac regulatory proteins to control the balance between differentiation and proliferation during cardiogenesis.
TL;DR: Function-blocking antibodies to VEGF receptors R1 and R2 were used to probe their roles in controlling angiogenesis in a mouse model of pancreatic islet carcinogenesis, finding phenotypic resistance to V EGFR2 blockade emerged.
TL;DR: These studies identify TSPs as CNS synaptogenic proteins, provide evidence that astrocytes are important contributors to synaptogenesis within the developing CNS, and suggest that TSP-1 and -2 act as a permissive switch that times CNSsynaptogenesis by enabling neuronal molecules to assemble into synapses within a specific window of CNS development.
TL;DR: Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors, and effects of the molecular abnormalities in vitro are identified.
Abstract: Background The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. Methods We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro. Results Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rap...
TL;DR: Current knowledge about the metabolism and disposition kinetics of nicotine, some other naturally occurring tobacco alkaloids, and nicotine analogs that are under development as potential therapeutic agents are reviewed.
Abstract: Nicotine is of importance as the addictive chemical in tobacco, pharmacotherapy for smoking cessation, a potential medication for several diseases, and a useful probe drug for phenotyping cytochrome P450 2A6 (CYP2A6). We review current knowledge about the metabolism and disposition kinetics of nicotine, some other naturally occurring tobacco alkaloids, and nicotine analogs that are under development as potential therapeutic agents. The focus is on studies in humans, but animal data are mentioned when relevant to the interpretation of human data. The pathways of nicotine metabolism are described in detail. Absorption, distribution, metabolism, and excretion of nicotine and related compounds are reviewed. Enzymes involved in nicotine metabolism including cytochrome P450 enzymes, aldehyde oxidase, flavin-containing monooxygenase 3, amine N-methyltransferase, and UDP-glucuronosyltransferases are represented, as well as factors affecting metabolism, such as genetic variations in metabolic enzymes, effects of diet, age, gender, pregnancy, liver and kidney diseases, and racial and ethnic differences. Also effects of smoking and various inhibitors and inducers, including oral contraceptives, on nicotine metabolism are discussed. Due to the significance of the CYP2A6 enzyme in nicotine clearance, special emphasis is given to the effects and population distributions of CYP2A6 alleles and the regulation of CYP2A6 enzyme.
TL;DR: It is shown that mutations in the signalling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in non-syndromic autosomal-dominant human pedigrees.
Abstract: Calcification of the aortic valve is the third leading cause of heart disease in adults. The incidence increases with age, and it is often associated with a bicuspid aortic valve present in 1-2% of the population. Despite the frequency, neither the mechanisms of valve calcification nor the developmental origin of a two, rather than three, leaflet aortic valve is known. Here, we show that mutations in the signalling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in non-syndromic autosomal-dominant human pedigrees. Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2, a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors (Hrt), which are activated by Notch1 signalling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independent of histone deacetylase activity. These results suggest that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later de-repression of calcium deposition that causes progressive aortic valve disease.
TL;DR: This review article describes the current knowledge about the nature of pericytes and their functions during vessel growth, vessel maintenance, and pathological angiogenesis.
Abstract: Blood vessels are composed of two interacting cell types. Endothelial cells form the inner lining of the vessel wall, and perivascular cells—referred to as pericytes, vascular smooth muscle cells or mural cells—envelop the surface of the vascular tube. Over the last decades, studies of blood vessels have concentrated mainly on the endothelial cell component, especially when the first angiogenic factors were discovered, while the interest in pericytes has lagged behind. Pericytes are, however, functionally significant; when vessels lose pericytes, they become hemorrhagic and hyperdilated, which leads to conditions such as edema, diabetic retinopathy, and even embryonic lethality. Recently, pericytes have gained new attention as functional and critical contributors to tumor angiogenesis and therefore as potential new targets for antiangiogenic therapies. Pericytes are complex. Their ontogeny is not completely understood, and they perform various functions throughout the body. This review article describes the current knowledge about the nature of pericytes and their functions during vessel growth, vessel maintenance, and pathological angiogenesis.
TL;DR: It is shown that mammalian Smoothened (Smo), a seven-transmembrane protein essential for Hh signalling, is expressed on the primary cilium, and Hh-dependent translocation to cilia is essential for Smo activity, suggesting that Smo acts at thePrimary cilia.
Abstract: The unanticipated involvement of several intraflagellar transport proteins in the mammalian Hedgehog (Hh) pathway has hinted at a functional connection between cilia and Hh signal transduction. Here we show that mammalian Smoothened (Smo), a seven-transmembrane protein essential for Hh signalling, is expressed on the primary cilium. This ciliary expression is regulated by Hh pathway activity; Sonic hedgehog or activating mutations in Smo promote ciliary localization, whereas the Smo antagonist cyclopamine inhibits ciliary localization. The translocation of Smo to primary cilia depends upon a conserved hydrophobic and basic residue sequence homologous to a domain previously shown to be required for the ciliary localization of seven-transmembrane proteins in Caenorhabditis elegans. Mutation of this domain not only prevents ciliary localization but also eliminates Smo activity both in cultured cells and in zebrafish embryos. Thus, Hh-dependent translocation to cilia is essential for Smo activity, suggesting that Smo acts at the primary cilium.