The project should lead to large-scale models of molecular and cellular processes involved in neuronal signaling. A prerequisite is the proper storage of knowledge coming from the literature.DopaNet DopaNet Molecular Pages are highly structured descriptions of quantitative parameters related to a specific molecular complex involved in neuronal signal processing. A Molecular Page is built by maintainers who are experts in the field, and responsible for the quality of the page content. Each piece of data is identified by a specific ontology code, annotated  and linked to the relevant bibliography. The Molecular Pages are stored as XML files, and processed through the DopaNet Web Service, which provides functionalities to edit the Molecular Pages, to cross-link the Pages and generate the public display, and to search them.DopaNet Molecular Pages are one of the core resources of the DopaNet project but should be of widespread utility in the field of Systems Neurobiology. Genes to Cognition consortium . Anot. AnotGen Gilman ,4), whic, whicGenSimilarly, we started at the end of 2001 the mesotelencephalic dopamine consortium . The inA first step, prior to the design of large-scale dedicated experiments, consists in data mining the current literature in molecular and cellular neurobiology for existing quantitative knowledge. The resulting data has to be properly stored and annotated.α and βγ subunits. The information collected deals with the structure of the complex, its anatomical distribution within DopaNet target cells, and its functional properties. Each page is under the responsibility of its maintainer(s), who decide which data is to be included or not, and acknowledge the input of the various contributors. All the data included in a Molecular Page is annotated , and linked to bibliographic references. In addition, each single data stored in the databases of DopaNet is attached to one or several terms of the DopaNet Neuronal Ontology. This ontology will therefore act as a glue, relating the various pieces of data one to the other.A DopaNet Molecular Page is a collection of annotated numerical data relative to a "molecular complex" present in one or several DopaNet target cells. The "molecular complex" is taken here in the sense of the DopaNet Neuronal Ontology (see below), as a "stable assembly of molecules", a "molecule" being described as a "set of atoms linked together by covalent bounds". As a consequence, we can have a Molecular Page storing data relative to a molecular complex made up of components, that are themselves described in other Molecular Pages. An anticipated example is an heterotrimeric G protein and its 2(beta2)3 nAChR. Each term can be the child of several others. Therefore the complete picture is not a genealogical tree, but rather a network or relationships.An ontology is defined here in its information science meaning, as a hierarchical structuring of knowledge. In our case, it is a relational vocabulary, that is a set of terms linked together, aiming to describe a neuron. Each term has a definition and a unique identifier. Terms are related by "is a" inheritances, which represent sub-classing, and "part of" inheritances which represent deepening knowledge. For instance, the nicotinic receptor subunit alpha6 "is a" nicotinic receptor subunit, and is "part of" the There are several biological ontologies, the most famous (and complete) being Gene Ontology ,10). Num. Num10])A Molecular Page is made up of a header followed by several lists, each list containing a sequence of identical elements. There are currently twelve main lists, described below. Several other lists of items are used to described the page data at a finer level. According to the molecular complex described in the page, some of the lists can be empty.The Molecular Page header contains the name of the molecular complex described in the page, an abbreviation, the unique ontology code used to identify the page, the dates of creation and last modification of the page, and the page status. The possible status are:The Molecular Page has been submitted by the maintainers and is ready for public release.A new version of the Molecular Page, not yet ready for public release.A new Molecular Page in construction, that has never been submitted for public release.α4)2(β2)3 is described in the Page describing the complex "_2(beta2)_3 nAChR" . The related Ontology term can be found at For instance, the nicotinic acetylcholine receptor _2(beta2)_3 nAChR"                         status="stable">                         The main lists that compose a Molecular Page are:Maintainers are the only people authorized to directly modify the Molecular Pages. They are responsible for the quality and the completeness of the data included in the Page. However, maintainers are not assumed to systematically gather the information all by themselves. They are encouraged to contact experts to help them. Helpful people should be acknowledged as contributors.Contributors are all the people who bring new information about a Molecular Page, or correct an existing piece of information. Contributors can be seen as the equivalent of authors of an article. Except maintainers (who are contributors by definition), they cannot directly modify a Molecular Page. They have to contact a maintainer instead. Note that the database administration team can directly modify the Molecular Pages to comply with the guidelines.A Molecular Page describes a molecular complex. This complex is made up of components (at least one). The listOfComponents describes those components, their stoichiometry, and lists useful related resources. Each component is annotated by its ontology code.α4 and the subunit β2.The complex "_2(beta2)_3 nAChR" [DA:0000027] is made up of two components, the subunit <listOfComponents> <component DopaNetontology="DA:0000188"  name="alpha4 nicotinic receptor subunit"                     stoichiometry="2">                     <listOfResources>   <resource identifier="ACHa4hosa"     name="Ligand-Gated Ion Channel database"                     references="1"                   "> url="                    <taxon>Homo sapiens</taxon>             </resource>     </listOfResources>     </component>  </listOfComponents> The function of a molecular complex is most often modulated by permutations between various states . Accordingly, most of the quantitative data are actually relevant only for one state or a subset of states. Those states should therefore be listed, described and annotated. The quantitative data described in the "functional" lists (see below) will refer both to the states of the molecular complex itself, listed here, and the list of states of other relevant Molecular Pages.The complex "_2(beta2)_3 nAChR" may exist under (at least) three different states: "basal", "active", and "desensitized".<listOfStates>  <state identifier="basal" name="basal">         <description>                In the basal state, the ionic pore is closed. This state displays a weak affinity for agonists such as acetylcholine or nicotine.                 </description>                 </state>       </listOfStates>  A list of properties that depends solely on the molecular complex itself, and not on its relationships with other entities, such as ligands or substrates. Example of such properties are molecular weight or Stoke radius.<listOfGenericProperties>  <property name="MW" stateMolecule="basal">        <taxon>Homo sapiens</taxon>            <listOfValues>                <value mean="310971" unit="Dalton">                        <comment>without covalent modifications.</comment>                             </value>                        </listOfValues>                 </property>        </listOfGenericProperties>  listOfExtracellular shall be necessary at some point.The distribution of the molecular complex and its components is described within the relevant DopaNet target cells: cortical glutamatergic pyramidal neuron, mesencephalic dopaminergic neuron, striatal cholinergic interneuron, striatal enkephalinergic/GABAergic medium spiny neuron, striatal substance p/GABAergic medium spiny neuron. It is likely that a Each cell is divided into compartments, where the distribution of transcripts and molecules can be described. The approach used to explore the distribution is specified, since both the accuracy and the quantitativeness of the observations strongly depends on the method chosen. As for all the following data, the species where the study has been conducted is also mandatory.α4 is present in 100% of neurons and β2 is probably also present in 100% of neurons.One entry in the complex "_2(beta2)_3 nAChR" is the fact that in the cell soma of the rat mesencephalic dopaminergic neuron, single cell RT-PCR experiments showed that <listOfCells>  <cell cellName="mesencephalic dopaminergic neuron" DopaNetontology=" DA:0000702">    <listOfCompartments>         <compartment DopaNetontology="DA:0000137" name="cell soma">           <listOfTranscripts>               <transcript method="single cell RT-PCR" references="17">                     <taxon>Rattus norvegicus</taxon>                         <description>                            a4 is present in 100% of neurons. b2 is probably also present in 100% of neurons.                               </description>                           </transcript>                     </listOfTranscripts>               </compartment>          </listOfCompartments>      </cell>  </listOfCells>The ligands of a molecular complex are molecules or ions that bind to it. The size of the ligand relative to the molecular complex is irrelevant. Within the Molecular Page of "transforming growth factor receptor type I", one ligand is "transforming growth factor betal". Conversely, in the Molecular Page of "transforming growth factor beta1", one ligand is "transforming growth factor receptor type I"! See table kon, koff or Km can be stored in a controlled manner, in order to be easily retrieved later. Whenever possible, the quantitative values are related to the states of the molecular complexes involved, not only the state of the molecular complex subject of the Molecular Page but also the state of the ligand. This remark holds for the substrates, the translocators and the modulated substances as well (see below). See table Functional parameters such as The desensitized "_2(beta2)_3 nAChR" of the rat binds acetylcholine with a Ki versus the epibatidine of 8.6 ± 1.98 nM.<listOfLigands>   <ligand DopaNetontology="DA:0000184"       name="acetylcholine"                    origin="endogenous">                    <listOfProperties>          <property name="Ki_epibatidine"               references="10 18"                          stateMolecule="desensitized">                             <taxon>Rattus norvegicus</taxon>                <listOfValues>                 <value mean="8.6" sd="1.98" unit="nanomole per litre"/>                      </listOfValues>                 </property>             </listOfProperties>         </ligand>       </listOfLigands> Km, kcat or Vmax.All substances modified as a result of an interaction with the molecular complex. The parameters stored here are for instance The translocators are substances that go from one subcellular compartment to another, the translocation being mediated by the molecular complex. Typical parameters are conductance or relative permeability.The active complex "_2(beta2)_3 nAChR" of the rat translocates cations with a conductance of 13.3 ± 1.5 pS.<listOfTranslocators>  <translocator DopaNetontology="DA:0000264"            name="cation"                         origin="endogenous">                              <listOfProperties>          <property name="conductance" references="14" stateMolecule="active">            <taxon>Rattus norvegicus</taxon>                   <listOfValues>                 <value mean="13.3" sd="1.5" unit="picosiemens"/>                        </listOfValues>                  </property>            </listOfProperties>          </translocator>       </listOfTranslocators>  modulated entries are to be avoided as much as possible, since they generally reflect a set of binding and/or enzymatic events.In many case, one knows about the effect of a molecular complex on a substance, without knowing the detailed mechanism of action. The Possible conversions between the states described in the listOfStates, such as a conformational transition, or a covalent modification.The complex "_2(beta2)_3 nAChR" undergoes conformational transitions between the basal and active states. <listOfTransitions>  <transition state 1="basal" state2="active">        <comment>                       In the absence of ligand, the equilibrium is strongly displaced toward the basal state. Agonists, such as acetylcholine and nicotine, stabilise the active state and shift the equilibrium. The transition from basal to active corresponds to an opening of the ionic pore.                  </comment>             </transition>       </listOfTransitions>  The list of bibliographic resources used to gather and annotate the data. Each piece of data included in the Molecular Page should be linked to those bibliographic items by internal references.Molecular Pages are saved as XML files , and theMolecular Pages XML files are stored within two different repositories, depending on the status of the Page. One repository contains only the stable Pages ready for public release , while the other repository contains also the unstable and the forthcoming Pages .In addition to the two XML repositories, there is also a third HTML repository, containing the human-readable HTML versions of the stable Pages, automatically generated from their XML counterparts using XSL Transformations  with theDopaNet Web Service has been designed and implemented, which provide functionalities to:As described above, Molecular Pages are continuously modified and updated by the maintainers, with the help of the contributors. In order to automatize, safe-guard and simplify as much as possible the work required by a maintainer to create and edit a Molecular Page, an application called the 1. authenticate Page maintainers2. browse pages by maintainers3. grant exclusive Page editing rights to a maintainer4. create and edit a Page via a rich user interface5. save or submit the edited Page, setting the "stable/unstable" statusThe DopaNet Web Service is made of both server-side and client-side components, all written in Java, and communicating via either the SOAP  or the HIn addition to support the remote creation and editing of Molecular Pages, the DopaNet Web Service provide also functionalities to:1. register new DopaNet contributors2. update existing DopaNet contributor information3. browse Molecular Pages by status4. search Molecular PagesSearching of Molecular Pages is implemented by using the API provided by the Apache Xindice  native XAlthough in their early stage of development, DopaNet Molecular Pages provide a unique source of structured, annotated quantitative data about the molecules involved in neuronal signaling. They will feed both the experimental biologist and the theoretician with the best available estimates for all kind of knowledge, whether biochemical, anatomical or functional. This will allow them to design better experiments or formal models, and to benchmark their results. As a side-effect triggered by the mandatory annotations, DopaNet Molecular Pages will also a bibliographic resource, each page being the equivalent of a small review of the literature.Gene Ontology is now a fully grown project, and is being widely used in several biological domains. Nevertheless, in its present form, Gene Ontology was not found suitable to be directly used by the DopaNet project. We hope to collaborate with Gene Ontology maintainers in the future. In particular, effort will be made to complete Gene Ontology in the area of Neurobiology. However, DopaNet Neuronal Ontology will never actually be a subset of Gene Ontology. Indeed, the purpose of the latter is to classify the gene products – and one of its most useful application so far has been the annotation of sequence database entries. The purpose of DopaNet Ontology is broader in term of knowledge, and not limited to the classification of gene products. At the same time it is focused onto a specific system, and therefore of interest for a narrower audience.molecular function, biological process, and cellular component. Only the latter is at the moment relevant to DopaNet purposes, that is the Molecular Pages. However, it is anticipated that the biological process vocabulary will be needed in the near future, for instance to annotate electrophysiological data. DopaNet cellular component vocabulary is larger than Gene Ontology one, since it contains the different kinds of neuronal cells  In additology, .A cellular component may be for instance an anatomical structure, e.g. "dendrite" or "synaptic vesicle" but also a cell or a protein. Note that a "molecule" is defined in the Neuronal Ontology as a set of atoms covalently linked. A molecule cannot contains other molecules. Hence, a protein made up of several subunits, or a polypeptide and a co-enzyme are not "molecules", but "molecular complexes". Although our ontology is built for DopaNet purposes, it can be viewed as a more general "Neuronal Ontology". Therefore, we incorporate terms related to components present (or events taking place) in any neuron, not necessarily DopaNet target cells. In particular, such additions are advised if they clarify some hierarchical relationship.As described above, a "molecular complex" in DopaNet Neuronal Ontology contains one or several components, also present in the "molecule" branch. It could be considered redundant that all monomeric proteins are represented by two terms, as a "molecule" part of a "molecular complex". However, the meanings of the two branches are different. The "molecule" can be seen as an ideal entity, while the latter would rather represent an actual physical object of the cell. Moreover, the hierarchical structures of the two branches are different. In addition, a lot of proteins have only recently been discovered as functional complexes (e.g. the polymeric G-protein coupled receptors), and more are to be discovered. Finally, the systematic dissociation between the functional molecular complex and its components is handy when it comes to write the Molecular Pages.The Alliance for Cellular Signaling was a pioneer in designing Molecule Page. Contrary to DopaNet Molecular Pages, their focus is truly a "molecule" rather than a "molecular complex". For instance, an heteropolymeric receptor will not be represented by a Molecule Page, but rather by a collection of Pages, one per subunit.Kd In addition, pieces of quantitative knowledge, like binding or enzymatic reactions, should be provided in standardized format such as the Systems Biology Markup Language [DopaNet Molecular Pages are highly structured. While this could appear as an obvious choice, it actually comes with a double burden. First, the edition interface has to be sufficiently complex to reflect the underlying structure. This complexity certainly acts as a repellent for the biologist who wish to build a Molecular Page. Second, the high quality required, in particular concerning the annotations, leads to the rejection of a significant portion of the published knowledge. However, we think that a piece of data that cannot be properly annotated is of limited use for the community. For instance, a large amount of pharmacological properties is published without the species. Since those properties vary from one species to the other, one cannot easily re-use the value provided. Similarly, a numerical piece of knowledge cannot be used without caution if one does not know the method used to collect it, and the variability attached to it. Currently, the access to the data is only possible through the web interface. Moreover, although the user is able to search the content of the Molecular Pages using various criteria, the result is always presented as one or several Molecular Pages. However, the DopaNet Web Service should be enriched on a steady pace, and specific pieces of data should be served soon. One can envision interfaces providing precise and meaningful responses to queries like "All Kd for the ligand X of all molecules that bind it", under the form of a list of Language .Ka, Kd, Ki, Kp, IC50, but all those quantities can only be analyzed in regards of the knowledge about the various states of the complex, and its conformational transitions. The distributed annotation can cause concerns related to peer-validation and quality control. With the help of Nature Publishing Group, a peer review process has been set-up by the Alliance for Cellular Signaling to survey the edition of its Molecule Pages. Such an infrastructure is currently out of reach of DopaNet. However, we ensure that the maintainers are always recognized experts in the fields, or, for members of the EBI group, work in close relation. In addition, we included as much as possible guidance through the constraints imposed by the Page editing environment. That way, any Molecular Page complies with at least a minimal set of quality rules. Such an approach has already been successful in other areas. One of the most striking example is the Debian operating system project ([The Molecular Pages are maintained in a distributed fashion, with one or several experts in charge of each complex. Such an approach is mandatory for two reasons. Firstly, the knowledge accumulated by the project will soon become much too large to be handled by one individual, or even one team. Secondly, the level of detail and accuracy sought by the resource is such that only experts can fruitfully mine the adequate literature for relevant information. To extract the simple affinity of a receptor for a ligand can be a daunting prospect. Not only that affinity can be expressed by various parameters with different meaning, project , that mOn the contrary of the Molecular Pages, the Neuronal Ontology is currently developed only by the EBI team. Everyone can contribute by sending their suggestions, but for the sake of coherence the final building is centralized.DopaNet Molecular Pages allow to store annotated numerical data about molecular complexes involved in neuronal signaling. Although the Pages are one of the core resources of the DopaNet project, and therefore their focus on the mesotelencephalic dopamine system, the repository should be of widespread utility in the field of Systems Neurobiology. This is also the case of The DopaNet Neuronal Ontology. The resource is in its early stage of development and will benefit much from the feedback of users.All data contained in the DopaNet Molecular Pages may be copied and redistributed freely, under terms derived from the MIT license ..More information about the DopaNet project can be found at the URL DopaNet ontology is available at the URL DopaNet Molecular Pages are available at the URLNLN designed the database DTDs and schemas, wrote the XSL and acted as the final editorial authority on Molecule Pages. MD implemented all the edition and validation software, as well as the user interface, including the servers.


During the 1990s, the New York Police Department (NYPD) greatly expanded arrests for smoking marijuana in public view (MPV). By 2000, MPV accounted for 15% of all arrests. The NYPD's supporters report this arrest activity is just part of quality-of-life (QOL) policing, which seeks to promote order in public locations by aggressively patrolling for behaviors that offend the general population. The NYPD's critics contend the NYPD has disproportionately targeted poor, black and Hispanic communities.This paper analyzes the geographic distribution of MPV arrests from 1992 to 2003 to evaluate these alternative perspectives. A sequence of maps identify that the focus of MPV arrests shifted over time.In the early 1990s, most MPV arrests were recorded in the lower half of Manhattan  and by the transit police. However, in the later 1990s and into the 2000s, most MPV arrests were recorded in high poverty, minority communities outside the lower Manhattan area and by the NYPD's policing of low-income housing projects.These findings suggest that current levels of MPV arrests in NYC may not be justifiable, at least based solely on the purpose of QOL policing. Accordingly, we suggest the NYPD seriously consider less stringent measures for public marijuana smokers, especially for use outside of highly public locations in recessed locations hidden from open view (like the stairwell of a housing project). Alternatives could include Desk Appearance Tickets, fines, or simply requiring smokers to desist, discard their product, and move along. King and Mauer noted that by the late 1990s that marijuana arrests (mostly for possession) constituted nearly half of all drug arrests nationwide . Moreoveve grams ." We refThe use of arrest for controlling smoking marijuana in public has been included in the NYPD's focus on quality-of-life (QOL) policing. The QOL program seeks to maintain order in public spaces by aggressively enforcing laws with arrest against minor offenses that occur in public and that can be offensive to the general population. A variety of publications provide extensive descriptions of the QOL program, its implementation, and its evolution -8. JohnsHypothesis 1: QOL policing has targeted public spaces for MPV arrests.th Street) including Central Park, the Theatre District, the midtown business district, skyscrapers, museums, and walking areas with shops, restaurants, cafés and nightclubs including Greenwich Village and Chinatown, among others. Figure To the extent that MPV arrests have been consistent with Hypothesis 1, they should tend to have occurred in areas routinely frequented for leisure by residents and tourists. Most NYC neighborhoods have many streets and public spaces such as parks that serve this purpose. Accordingly, Hypothesis 1 suggests that MPV arrests should occur throughout NYC. However, the showcase of NYC's business center, cultural offerings, and most popular leisure destination has been lower Manhattan .Hypothesis 2 predicts that MPV arrests would tend to be recorded by those precincts serving low-income ethnic minority communities and by the housing police. Figures Two graphs examine the distribution of MPV arrests across the 1992–2003 study period as predicted by each hypothesis to ascertain the extent to which each pertains over time. Regarding Hypothesis 1, a graph examines the percentage of MPV arrests in each year occurring in lower Manhattan as opposed to other neighborhood precincts. The graph also indicates the percentage of arrests citywide recorded by transit and by housing. The other five specialized precincts were combined and displayed as cases not included in the other four categories. The number of MPV arrests in those five specialized precincts never exceeded 2% in any given year.Regarding Hypothesis 2, a graph examines the percentage of MPV arrests in each year recorded in precincts that are in the top third by race/ethnicity group and poverty status  maintains the official arrest records for New York State. These records are routinely used to produce criminal histories (rap sheets) in support of law enforcement activities. Under special arrangement, the project obtained records of all adult arrests recorded in NYC from January 1, 1980 through January 12, 2005. All personal identifiers  were removed from the research dataset. Each record contains a date, an arrest charge and demographic information. Race/ethnicity is coded as either white, black, Hispanic, other or missing.This dataset also includes "sealed" arrests. For many minor arrests, the judge will issue an "adjudication in contemplation of dismissal." If the arrestee is not rearrested within a period of time (often the next six months), the state will seal the record of an arrest. Sealed arrests are not provided on rap sheets generated for subsequent arrests. Golub, Johnson and Dunlap document that over 85% of MPV arrests 1992–2003 were sealed [This study examined MPV arrests occurring in NYC up to December 30, 2003, to assure that the dataset was virtually complete over the period of analysis. NYS law enforcement agencies are sometimes delayed sending their reports to DCJS. Steven Greenstein of DCJS estimated that the data for 2003 should be more than 98% complete . The comEvery ten years, the Decennial Census counts the population of U.S. residents . This anth Street, five of the six community districts contain two precincts. Below 57th Street, there are 10 precincts to six community districts and the borders between them do not match up. For Manhattan, precincts were matched with the community district covering the largest portion of it.The census data for this study were available online in nearly the exact format needed on a website maintained by the NYC Department of City Planning . The onlAnother difficulty is that the census uses different race/ethnicity categories than the NYS arrest data. The census asks separate questions about Hispanic/Latino origin and race . RespondDuring the 1980s, MPV arrests in NYC rose from 1,400  in 1980 up to a peak of 4,500 in 1985 and then declined to a new low of 800 in 1991  Figure . HoweverBy 2003, evidence of MPV as part of QOL policing had become more limited Figure . Not oneFigure Figure This analysis indicates that the geography and perhaps even the purpose of MPV arrests in NYC shifted over time. In the early 1990s, from a third to a half of all MPV arrests were recorded in highly-public sections of Manhattan or in NYC's transit service. This pattern accords with the focus of QOL policing, on maintaining order by enforcing laws against offensive behaviors in public locations. Moreover, it stands in contrast to critics' claims that the NYPD targeted poor ethnic minority communities for MPV arrests. On the other hand, the critics concerns are supported by the fact that most MPV arrestees during the early 1990s were black or Hispanic, even though the arrests took place in areas that were not predominately black or Hispanic .The critics' concerns are further supported by changes over time. Starting in 1995 and continuing into the 2000s, MPV arrests shifted to less public locations. By 2003, MPV arrests were recorded primarily outside of Manhattan and in poorer neighborhoods with higher concentrations of blacks and Hispanics. This transformation raises questions about the purpose of the vast number of MPV arrests in NYC into the 2000s. These MPV arrests do not appear to primarily serve the goals of QOL policing. Moreover, controlling marijuana use in NYC hardly advances other traditional goals of crime control. During the crack epidemic, drug binges and open-air drug markets were associated with extensive violence. Thus, controlling crack and its associated activities could be justified as attacking the roots of much of the prevailing crime and violence. The current situation with marijuana is much less critical. Marijuana use and its sales in NYC have been associated much less with other forms of criminal activity.Recent articles in the New York Times indicate that as of 2006 Mayor Bloomberg planned to continue QOL policing . The finTo some extent, this MPV arrest policy, based on restoring order in highly-public locations may have been quite successful in transit, Central Park, and lower Manhattan, so that fewer MPV arrests now occur where many had occurred in the late 1990s. It is far less clear that the numerous MPV arrests occurring in low-income neighborhoods in the outer boroughs have succeeded at preventing marijuana smoking in public locations. Less stringent alternatives to arrest would likely meet the city's goals of maintaining order. The NYPD may develop special procedures for dealing with marijuana use in recessed locations that are well hidden from open view, but are nonetheless public spaces such as the stairwells of housing projects or a hidden section of a park. Alternatives to MPV arrests and detention could include Desk Appearance Tickets (DATs), C-Summons , or simply requiring smokers to desist, discard their product, and move along (also see [


EHP, many of you have no doubt followed the recent discussions over the fateof this publication as a publicly supported journal. I initiated thesediscussions last year as part of the process of evaluating the priorities, resources, anddirection of the NIEHS. Many factors have beenconsidered during this process, including public comments from the scientificand broader environmental health community, input from the institute’sadvisory boards, and evidence of EHP ’s standing in the world of scientific journals. After listeningvery carefully to these comments and considering all the potentialpossibilities, I have decided that the NIEHS should continue to support EHP because it is simply the right thing to do.As readers of EHP has become the leading environmental health science journal in the world, providingcutting-edge research and information on the effects ofthe environment on human health. As a steward of the NIEHS and, consequently, thefield of environmental health sciences, I recognize that itis our responsibility to ensure that EHP continues to exercise complete editorial independence in publishing thevery best research in our field, as well as to provide open access tothese critical research findings to those around the world who needit. In weighing the options, it became clear that the only way to ensurethese essential characteristics was to continue to support EHP at the NIEHS.Over the past decade, EHP was ranked by the Institute for Scientific Information’s Journal Citation Reports ( JCR ) as the number one journal in the categories of environmental sciencesand public, environmental, and occupational health. JCR, which evaluates over 8,400 scholarly and technical journals worldwide, basesits rankings on journals’ impact factor, a calculationof how often an “average” journal article is cited ina particular year and a measure of a journal’s relative importance. Theincrease in EHP ’s impact factor and its new rankings serve to illustrate boththe stature of the journal and the importance of the field of environmentalhealth sciences to informing many scientific disciplines. I believewe have an opportunity to further develop EHP as a top-tier journal and am initiating steps to strengthen the sciencepublished by the journal while ensuring its continued publication inthe face of budgetary limitations.Just last month, EHP has a long history of editorial independence and has recently emergedas a leader in crafting and enforcing strong policies to address competingfinancial interests and awareness of potential conflicts of interest. Bothof these qualities are absolutely essential to enhancing theresearch process and ensuring public trust and support for scientificendeavors. While EHP ’s financial dependence on the NIEHS could be viewed by some asa potential conflict, we will continue to use the safeguards that existas well as to implement new ones, including having an outside editor-in-chief, tosuccessfully guard against this.First and foremost, I have begun the process of forming a search committeeto recruit a new editor-in-chief to succeed the current leadership. Unlikeprevious editors-in-chief, who were NIEHS staff, this new positionwill reside outside the institute and will be a practicing scientistand thought leader in our field. This person, supported by a strongeditorial board, will provide scientific leadership for the journaland be responsible for all of its editorial decisions. An advantage ofthis arrangement is that it will serve to further strengthen both theeditorial independence of the journal and the quality of the publishedscience. EHP to the NIEHS. One way to do this is by reducing the size of certain sectionsof the journal including the Environews and sections focusing onNIEHS-specific information. Although the Environews section of the journalis incredibly successful, it is also relatively costly to produce. However, giventhe importance of this information, we will continueto publish a modest news section and selected editorials. NIEHS-specificsections will become available on our newly redesigned institutewebsite, expected to launch in early 2007.In addition to the changes to editorial leadership, I am taking steps toreduce the overall costs of EHP will continue to work with strategic partners to facilitate the translationof our journal, but we will no longer assume financial responsibilityfor this activity. Cutting back in certain areas, moreover, willreduce the overall cost of the journal and allow us to continue to maintain EHP at the NIEHS. This will also enable us to expand sections focused on publicationof novel scientific findings.I recognize that the translation of science for our broader readershipis important, and EHP ’s future was the commitment of the journal—and the NIEHS—toopen access. As a journal, EHP has been among the pioneers of open access to scientific information, allowingthousands of scientists, as well as governments, advocates, andothers free access to the tools and information they need to improvethe health of millions of people around the world. Many journals havefollowed EHP ’s lead and more would likely do so if not for the restraintsof the bottom line. It has been EHP ’s unique relationship with the NIEHS that has allowed the journalto provide this invaluable access. Maintaining EHP at the NIEHS is the only way to ensure continuation of this policy. Asa publicly funded agency, the NIEHS has a responsibility to use its appropriationswisely and for the good of all U.S. citizens. I believethat ensuring open access to the research published in EHP is firmly in line with the priorities and direction of this institute.My final concern in considering EHP while retaining its position as a scientific communications leader. Iam confident that the plan we’ve put in place will allow EHP to flourish and further develop as an independent scientific journal providingstate-of-the-science research and information to the broadestpossible audience.While I recognize that change is difficult, I believe that these changeswill allow us to control the costs of publishing


These pocket guides can accompany training sessions or can be handed out separately.As the Gulf Coast was being overwhelmed by Hurricane Katrina on 31 August 2005, the NIEHS Worker Education and Training Program (WETP), its awardees, and its National Clearing-house for Worker Safety and Health Training developed a PowerPoint presentation that covered all of the pertinent government guidance available about safety and health hazards following the destruction caused by this hurricane. This presentation, “Protecting Yourself While Helping Others,” was posted on the NIEHS website and was updated twelve times by the end of November 2005. It was also translated into Spanish and Vietnamese by NIEHS grantees. It was then converted into a downloadable pocket guide. Thousands of copies of the Katrina safety pocket guide .The WETP Katrina training activities were a part of the overall NIEHS Katrina response (James Remington | remingtonj@niehs.nih.gov


EHP Science Selection article on the toxic rocket fuel additive perchlorate  should be of no health concern in iodine-sufficient populations.in utero and perinatally to perchlorate  just a few months earlier, recommending no more than 1 ppb perchlorate in drinking water, on the basis of reduced thyroid hormone levels, abnormal brain morphology, and thyroid cancers in young rat pups exposed chlorate .EHP editors sent Renner’s article to one of the authors of the Greer study, Gay Goodman, of Intertox, Inc., to check the characterization of her study for accuracy. According to an invoice from Intertox to PSG  without disclosure to the EHP readership.We applaud ituation . We stroonflicts . If EHP


EHP [Environ Health Perspect 112:A788 (2004)], the need for full disclosure of all potential conflicts of interest by all coauthors contributing to a publication in EHP is commendable and obviously needed. Might I take this one step further and suggest that all reviewers of EHP manuscripts be required to sign a form listing all of their potential conflicts of interest.Concerning your editorial, “Embracing Scrutiny,” in the October issue of


Molecular signaling is an exponentially growing field that encompasses different molecular aspects of cell signaling underlying normal and pathological conditions. This area also focuses on defining the genetic and epigenetic changes that modulate the signaling properties of cells and the resultant physiological as well as pathological conditions. Therefore, rapid publication of results from these endeavors and, more importantly, free access to such publications can truly accelerate the progress in this field leading to the development of novel targeted drugs. With this goal in mind, Journal of Molecular Signaling, a journal fully devoted to open access publishing of rigorously peer-reviewed quality manuscripts in the molecular signaling area of research, is being launched. The focus, significance, and, the open access model of publishing of Journal of Molecular Signaling are discussed. It is also important to make sure that the dissemination of scientific information transcends the geopolitical as well as economical barriers so that it reaches all in the far corners of the world. A forum for such a free and rapid flow of scientific information is acutely needed for the molecular signaling area of research. Molecular signaling is an exponentially growing field that encompasses different molecular aspects of cell signaling underlying normal and pathological conditions. This area also focuses on defining the genetic and epigenetic changes that modulate the signaling properties of cells and the resultant physiological as well as pathological conditions. Defining molecular events in cell signaling forms the basis for identifying novel diagnostic, prognostic, and therapeutic targets for many different diseases. Therefore, rapid publication of results from these endeavors and, more importantly, free access to such publications can truly accelerate the progress in this field leading to the development of novel targeted drugs. With this goal in mind, The open access model of publishing has several advantages over the traditional subscription-based access (both print as well as online) to research information ,2. The iJournal of Molecular Signaling will be on the signaling pathways involved in proliferation, differentiation, apoptosis, and oncogenesis in the mammalian systems. Specifically, the research area of our journal is on the normal or aberrant molecular mechanisms involving receptors, G-proteins, kinases, phosphatases, and transcription factors in regulating cell proliferation, differentiation, apoptosis, and oncogenesis in mammalian cells. With the launch of this journal, we hope to provide up-to-date information to researchers in this rapidly growing field of interest that is molecular signaling. With this journal, our goals are to a) simplify the search process by focusing on a specific set of signaling pathways and b) provide a high quality scientific journal in an open access forum at the touch of a keyboard. We have an excellent editorial board consisting of highly distinguished scientists [The major focus of ientists , who wilientists  and archientists -6.Journal of Molecular Signaling, will make every effort to publish exceptional and interesting manuscripts that will have great impact in molecular and cell signaling research. We also hope to publish topical reviews and commentaries from the experts in different areas of signaling research. With your comments and input, we will ensure that the journal meets your needs. We are looking forward to the submission of your next important manuscript to the Journal of Molecular Signaling for the continued success of this journal.We, the editorial team of the


EHP, we announced that we would cease publication of the Mini-Monograph series this year, instead publishing more Review articles on topics that might once have been covered by Mini-Monographs. Here, we explain that decision and give some historical perspective on the Mini-Monographs.In the May 2007 issue of EHP was begun in 1972 by David P. Rall, then director of the NIEHS. In addition to publishing original research articles, the journal was intended as a means of publishing proceedings of conferences and workshops on environmental health sciences, a field then in its infancy. In 1992, with new NIEHS director Kenneth Olden at the helm, we began publishing the EHP you know today, and proceedings were published separately as EHP Supplements. In 2003, we moved from the Supplements format to the Mini-Monographs to better serve the changing needs of the environmental health science community with a more concise yet comprehensive publication. Each of these formats served the scientific community well at its respective time.However, scientific publishing has been revolutionized in the past decade. With the explosive growth of the Internet, the introduction of online publishing, and the advent of electronic printing technology, it is critical that research findings be published as soon as possible. We believe that presenting environmental health sciences research in a Review format, rather than as Mini-Monographs, will meet the challenge of constantly changing publishing technologies and the changing needs of our readers; this Review format will also parallel a similar format used by a number of other leading scientific publications.EHP and all authors submitting papers to the journal. Indeed, EHP’s status as the number-one environmental health science journal directly reflects how often its papers are cited.We also believe that this shift toward the Review format will enhance the integrity and quality of the journal. The very nature of this format allows for more current data to be presented concisely and as expeditiously as possible, resulting in a Review that is cited more often. This, in turn, increases the citability of the journal as a whole, which benefits both We . . . believe that this shift toward the Review format will enhance the integrity and quality of the journal. The very nature of this format allows for more current data to be presented concisely and as expeditiously as possible.EHP into a stronger journal than ever.Two more Mini-Monographs will be published in 2007, whereupon the series will end. We look forward to this continuing evolution of


EHP 114:A364–A367 [2006]). The last sentence on page A365 should read: “The current anthraxvaccine works on this very principle by introducing nonvirulent PAinto the body so antibodies are created.” EHP regrets the error.A line of text was inadvertently omitted from the June 2006 Innovationsarticle (“Plant vs. Pathogen: Enlisting Tobacco in the FightAgainst Anthrax,”


EHP bids a warm goodbye to Tom Goehl, our Editor-in-Chief since October 2001. Tom is a true altruist, always believing that the role of EHP is to impact the human condition by providing a forum for scientific information to be used by researchers, policy makers, and individuals to improve human health around the world. His devotion, drive, and integrity in working toward this goal are unmatched. I have no doubt that Tom will continue to be a dedicated contributor to global environmental health, though he claims it may be from a secluded camping spot far, far away. Farewell and safe journeys!With this issue EHP. Over the last few years we have received many compliments on the cover photography and graphic art appearing with each new issue. These images have always been designed to convey a visual link to an environmental health topic in each issue. The new covers will continue in this tradition with some modifications we hope will enhance usability, mainly by providing in the left margin a way for the reader to quickly scan major news and research topics in the issue. The cover titles will also be more descriptive. The Table of Contents will now appear solely inside the journal, leaving the back cover available for announcements or advertisements. As always, we welcome any comments and suggestions you may have.The January 2006 cover introduces a new look for the face of EHP wishes each of you the very best in the coming year and success in meeting the challenges that will inevitably come our way. As a member of a dynamic global environmental health community, EHP will continually strive to provide you with the best information for improving human and global health.The staff of


EHP, to determine adherence to their own policies.The Center for Science in the Public Interest (CSPI) recently investigated conflict of interest disclosures in a cross-section of leading scientific and medical journals, including EHP’s conflict of interest disclosure policy  where either the first or last authors should have disclosed conflicts in accordance with the disclosure policy.EHP article  scientist, William Owens, was identified only as a representative of the Organisation for Economic Co-operation and Development. The article  validate article .Second, a Quebec, Canada, group led by Pierre Ayotte of CHUQ-Laval University Medical Center studied the effects of organochlorines and methyl mercury on a remote coastal population . AlthougThe third group of authors who did not disclose conflicts of interest are scientists at Macquarie University who investigated the sources of lead in children near a zinc–lead smelter . Brian GEHP policy. Owens was directly employed by a company that might be affected by his findings. Gulson’s colleagues stood to gain financially from a company directly affected by the subject matter of their articles.In each of those cases, at least one of the authors of a study may gain financially from publication of the article, thus meeting the test of the Ayotte’s study, although a borderline case, should have contained a disclosure statement because he had collaborated on industry-funded studies in the past and the study in question was funded by an industry-supported group. When a field of research is so closely tied to an industry, future funding for research may involve the goodwill of that industry. The spirit of conflict of interest disclosure is best served by full disclosure in such cases.EHP published a study funded by the National Institutes of Health that claimed polychlorinated biphenyls (PCBs) inhibit a receptor involved in clearing foreign substances from humans  nuclear receptor has any bearing on a paper about a mammalian receptor with an entirely different function?” Strict conflict of interest policies would argue “yes,” because it is impossible to predict how the information in the new study will affect the use of previous knowledge or what inventions considered irrelevant today may be extremely useful (and lucrative) in the future. Even though EHP’s policy  fail to disclose relevant conflicts of interest of authors. We cannot determine whether authors are not disclosing the relevant information to EHP, or if they are providing the information but EHP is not publishing the disclosures. Considering the importance of providing readers with such information, it would seem that EHP needs to develop mechanisms to minimize failures to provide “full disclosure of competing financial interests” (EHP not to accept for 3 years any papers submitted by authors who failed to disclose information about conflicts of interest.Judging from the findings of our limited survey, a significant percentage of articles published in terests” . One posI look forward to your response.


The spectrum of Kaposi's sarcoma (KS) has been expanded to include pre-KS lesions.We report, for the first time, a case providing direct histological evidence of the development of early (in-situ) KS from mediastinal lymphatic vessels in the setting of chronic lymphedema in an HIV-positive patient. Spindle-shaped and endothelial cells in these early KS-appearing lesions were immunoreactive for HHV8, D2-40 and CD34.Our findings suggest that HHV8-infected spindle-shaped cells associated with lymphangiogenesis that evolve into KS lesions, acquire from the outset an aberrant mixed vascular and lymphatic endothelial cell phenotype. Kaposi's sarcoma (KS) is a vascular neoplasm that may involve mucocutaneous and visceral body sites. KS lesions are comprised of aberrant vessels and spindle-shaped tumor cells that increases in frequency from an early patch and plaque and ultimately establishes a tumor (nodular stage). Several lines of evidence support a lymphatic endothelial origin of Kaposi's sarcoma (KS) . SpecifiThe spectrum of KS lesions has been expanded to include pre-KS, a lymphedematous form of KS . We repoA 34-year-old homosexual male with acquired immune deficiency syndrome (AIDS)-related KS presented with chylothoraces due to obstruction of his thoracic duct by KS. He had extensive cutaneous lesions on the face, forehead, upper torso, mid-abdomen, left arm and left flank. He had been initially diagnosed with AIDS when he presented with vomiting and bloody diarrhea, and was found via endoscopy to have KS involving the colon. HIV serology was positive and his CD4 T-lymphocyte count at diagnosis was 30 cells/mm3. He was subsequently found via bronchoscopy to have pulmonary KS.Pleuroperitoneal shunt placement and thoracic duct ligation were performed for management of chylothoraces. Since placement of the shunt, he developed ascites with subcutaneous extravassation of lymph that was associated with xanthogranulomatous bile lakes Figure . He receHe received highly active antiretroviral therapy  and his HIV viral load became undetectable. His KS was treated initially with liposomal daunorubicin and then paclitaxel. He was then switched to SU5416 (an angiogenesis inhibitor) to which he had a temporary response. He was placed on palliative paclitaxel and died of progressive KS about 18 months later.His pleural and lung biopsies showed dilated pleuropulmonary lymphatics Figure  with intImmunohistochemistry was performed using HHV8 associated Latent Nuclear Antigen-1  monoclonal antibody, as well as dual-color immunostaining with the vascular endothelial marker CD34  and lymphatic specific endothelial marker D2-40 . Spindle-shaped and endothelial cells in these early KS-appearing regions were strongly HHV8 positive Figure . Non-lesWe believe that the findings in this case provide direct morphological evidence of the development of an in-situ form of KS directly from lymphatics in the setting of chronic lymphedema. Our results are consistent with previous reports of a cutaneous lymphedematous form of pre-KS ,6. In ouThe author(s) declare that they have no competing interests.PAK, BJD and LP were all involved in conception, design, acquisition of data, analysis and interpretation of data and were directly involved in drafting and revising the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Thrombolytic drugs are widely used for the management of cerebral venous sinus thrombosis patients. Several in vitro models have been developed to study clot lytic activity of thrombolytic drugs, but all of these have certain limitations. There is need of an appropriate model to check the clot lytic efficacy of thrombolytic drugs. In the present study, an attempt has been made to design and develop a new model system to study clot lysis in a simplified and easy way using a thrombolytic drug, streptokinase.n = 20) was allowed to form clots in a pre-weighed sterile microcentrifuge tubes; serum was removed and clot was weighed. After lysis by streptokinase fluid was removed and remnants of clot were again weighed along with the tube. Percentage of Clot lysis was calculated on the basis of the weight difference of microcentrifuge tubes obtained before and after clot lysis.Whole blood from healthy individuals (There was a significant percentage of clot lysis observed when streptokinase was used. On the other hand with water (negative control), minimal (2.5%) clot lysis was observed. There was a significant difference between clot lysis done by streptokinase and water.Our study could be a rapid and effective methodology to study clot-lytic effect of newly developed drugs as well as known drugs. Cerebral venous sinus thrombosis (CVST) is a common disorder that is often accompanied by significant morbidity and mortality ,2. In anBasta et al [Various methods were developed to measure the clot lysis activity of thrombolytic drugs. The best way to study thrombolytic drugs is through in vitro clot lysis model -19. Earlta et al  worked ota et al  or computa et al  skills, n = 20) without a history of oral contraceptive or anticoagulant therapy . 500 μl of blood was transferred to each of the previously weighed microcentrifuge tubes to form clots.Venous blood was drawn from healthy human volunteers  5 ml phosphate buffered saline (PBS) was added and mixed properly. This suspension was used as a stock from which appropriate dilutions were made to observe the thrombolytic activity using the in vitro model developed in our laboratory.n = 20) was transferred in different pre weighed sterile microcentrifuge tube (500 μl/tube) and incubated at 37°C for 45 minutes. After clot formation, serum was completely removed (aspirated out without disturbing the clot formed) and each tube having clot was again weighed to determine the clot weight . Each microcentrifuge tube containing clot was properly labeled and 100 μl of streptokinase along with various dilutions in sterile distilled water  was added to the tubes. Water was also added to one of the tubes containing clot and this serves as a negative thrombolytic control. All the tubes were then incubated at 37°C for 90 minutes and observed for clot lysis. After incubation, fluid obtained was removed and tubes were again weighed to observe the difference in weight after clot disruption. Difference obtained in weight taken before and after clot lysis was expressed as percentage of clot lysis. The test was repeated ten times with all the four dilutions of the thrombolytic drugs (Streptokinase) in blood samples of twenty different healthy volunteers.Venous blood drawn from healthy volunteers  declare that they have no competing interests.SP carried out the study design, data collection, literature search, statistical analysis and manuscript preparation; RSK, JYD, HJP participated in the preparation of the manuscript, data interpretation, and study design; GMT provided assistance in preparation of the manuscript, data interpretation, study design, and funds collection; and HFD supervised the study design, data interpretation, manuscript preparation, and literature search. All authors have read and approved the final version of the manuscript.


EHP in the past explored two ideas in this regard. In the first article, we (a) that ferritin has a stable magnetic moment of 3.8 Bohr magnetons, and b) that on the basis of reports from The article “Magnetic-Field–Induced DNA Strand Breaks in Brain Cells of the Rat” by icle, we  pointed This is an intriguing area of inquiry at the scientific level that may also have health implications.


The epidemiological features of Kaposi's Sarcoma (KS) incidence in England and Wales in the period 1971-1980 are reviewed. The epidemiology of KS in England and Wales in this period is distinct from that associated with the AIDS epidemic. The incidence was probably very low compared to other Western countries, there was little male excess, and no indication, based on marital status data, of a raised incidence in male homosexuals. Half the cases registered were in people born outside the UK. The region of birth distribution in these migrants reflected the known pre-AIDS geographic distribution of KS and also pointed to high risks in those from Middle Eastern countries and the Caribbean. The very low incidence rates of KS in natives of England and Wales suggests that the background prevalence of the causative agent for KS was low in England and Wales prior to the AIDS epidemic.


EHP. Although I thought I made it clear that he was wrong in his allegations, he nevertheless chose to go ahead and include my name in a report published on the Center for Science in the Public Interest’s (CSPI) website (EHP. Here are the facts.Goozner contacted me by e-mail on 24 June 2004, and I promptly, honestly, and to the best of my knowledge answered questions regarding his claim that I did not disclose a conflict of interest while publishing our article  in EHP.  website  and in hEHP, in which funding from these interest groups was acknowledged, along with other sources of funding (In our 2003 manuscript , we ackn funding , 2002. II truly believe that the authors of scientific manuscripts should disclose relevant conflicts of interest, and I support enforcing disclosure by appropriate means. However, because Goozner elected to choose the easy way by conducting an Internet-based research, without actually talking to me, he wrongly associated my name with scientific misconduct. I am presently seeking legal advice on this matter.


An analysis of the protein architecture, genomic distribution and sequence conservation of BTB domain proteins in 17 fully sequenced eukaryotes reveals a high structural conservation and adaptation to different modes of self-association and interactions with non-BTB proteins. The BTB domain  is a versatile protein-protein interaction motif that participates in a wide range of cellular functions, including transcriptional regulation, cytoskeleton dynamics, ion channel assembly and gating, and targeting proteins for ubiquitination. Several BTB domain structures have been experimentally determined, revealing a highly conserved core structure.Caenorhabditis elegans, and BTB-NPH3 proteins in Arabidopsis thaliana. Using the structural homology between Skp1 and the PLZF BTB homodimer, we present a model of a BTB-Cul3 SCF-like E3 ubiquitin ligase complex that shows that the BTB dimer or the T1 tetramer is compatible in this complex.We surveyed the protein architecture, genomic distribution and sequence conservation of BTB domain proteins in 17 fully sequenced eukaryotes. The BTB domain is typically found as a single copy in proteins that contain only one or two other types of domain, and this defines the BTB-zinc finger (BTB-ZF), BTB-BACK-kelch (BBK), voltage-gated potassium channel T1 (T1-Kv), MATH-BTB, BTB-NPH3 and BTB-BACK-PHR (BBP) families of proteins, among others. In contrast, the Skp1 and ElonginC proteins consist almost exclusively of the core BTB fold. There are numerous lineage-specific expansions of BTB proteins, as seen by the relatively large number of BTB-ZF and BBK proteins in vertebrates, MATH-BTB proteins in Despite widely divergent sequences, the BTB fold is structurally well conserved. The fold has adapted to several different modes of self-association and interactions with non-BTB proteins. Drosophila melanogaster bric-à-brac, tramtrack and broad complex transcription regulators and in many pox virus zinc finger proteins XVLAA' signature in the B2-A1 region seen in many other long form BTB families . In contrast to the BTB-ZF proteins, but similar to the BBK proteins, MATH-BTB sequences are highly conserved across the full lengths of the proteins. As a result of this conservation, phylogenetic clustering of the full-length protein sequences can be done with reasonable bootstrap values and shows a clear demarcation between proteins from Arabidopsis, which contains 21 BTB-NPH3 proteins, or over 25% of the BTB proteins in this genome. BTB-NPH3 proteins are not found in any of the other genomes that we considered, and could represent a plant-specific adaptation of the BTB domain. BTB-NPH3 proteins are involved in phototropism in A. thaliana and are thought to be adaptor proteins that bring together components of a signal transduction pathway initiated by the light-activated serine/threonine kinase NPH1 [Another large expansion is found in ase NPH1 ,102. Hetase NPH1 ,102. In ase NPH1 . These pDanio rerio, which has three. These proteins are transcription factors and most closely resemble the BTB-ZF proteins in terms of the BTB sequence and overall protein architecture. The proteins consist of a long form BTB domain, a central region of approximately 400 residues, and a carboxy-terminal basic leucine zipper region 1 and BACH2 ,105, excn Figure . The cloDictyostelium [The Ras homology (Rho)BTB proteins have an unusual architecture, and contain a Rho GTPase domain near the amino terminus, two tandem long form BTB domains, and an approximately 100 residue carboxy-terminal tail with predicted α-helical content Figure . These postelium . The firostelium  and contMutations have been identified in lung cancer patients that do not disrupt the RhoBTB2-Cul3 interaction , and theDrosophila highwire (AAF76150) and C. elegans regulator of presynaptic morphology  and has been called the 'PHR-like' region (Pfam accession PF08005). It has been shown to interact with topoisomerase 1 [Sequence analysis on proteins with the BTB-BACK architecture but no kelch repeats revealed the presence of a conserved carboxy-terminal region of approximately 170 residues. This region in the BTBD1 and BTBD2 proteins has sequence similarity with human protein associated with myc , merase 1 .Searches with various PHR domain sequences against the Pfam, Prodom and SMART databases identified only automatically generated alignments, and BLAST searches against the PDB did not reveal any significant hits. The domain does not contain extended regions of disorder, and secondary structure predictions suggest that the PHR domain is an all-β fold. Despite the lack of a strongly repeating sequence motif, the PHR may represent a novel type of β-propeller structure, by analogy with the BBK proteins. Using HMM searches, we found from four to seven examples of BTB-BACK-PHR (BBP) proteins in the metazoan genomes, including mammalian BTBD1, BTBD2, BTBD3 and BTBD6. We adopted the name 'PHR domain' for this motif and it has been added to the Pfam database as accession PF08005.S. pombe  are components of a SCF-like ubiquitin ligase complex and interact with Pcu3p, a Cul3 homolog [Ankyrin repeats are common protein-protein interaction motifs that are found in proteins of very diverse function, such as transcription regulators, ion transporters and signal transduction proteins ,111. We  homolog . Both BTC. elegans BTB proteins, but only 17% of the human proteins, belong to this family. There may be additional domains in some of these proteins that have yet to be identified.A significant number of BTB proteins do not contain other identified sequence motifs Figure . ExcludiSeveral members of the BTB families described here have been found to interact with Cul3-based SCF-like complexes including BTB-ZF , BBK 1212,14,112Nine of the 49 human BBK proteins have been identified as components of Cul3-based SCF-like complexes ,14 and, C. elegans have been shown to interact with Cul3. As in the BBK proteins, the MATH-BTB proteins are conserved over much of their entire length, and are likely to be internally rigid. In this scenario, the substrate-recognizing MATH domain is found amino-terminal to the BTB domain, but since the amino and carboxyl termini are very close to each other in the long form BTB domain dimer [BTB domains of 5 of the 46 MATH-BTB proteins from in dimer , the MATSome BTB-ZF proteins, including PLZF, have also been shown to bind to Cul3, presumably in a BTB-dependent mode . The rolβ-TrcP1 complexes [To aid in understanding the role of the BTB domain in the SCF-like complex, we generated a structural model of a BBK protein dimerized via its BTB domain in a complex with Cul3, Rbx1, E2 and ubiquitin Figure . Three domplexes , except Interestingly, some T1-Kv proteins interact with Cul3 , and an This study illustrates the diversity in the abundance, distribution, protein architecture and sequence characteristics of BTB proteins in 17 eukaryotic genomes. We surveyed public databases and fully sequenced genomes and identified several lineage-specific expansions. The BTB domain is found in a wide variety of proteins, but it most often occurs as a single copy at or near the protein amino terminus. Residues exposed at the surface of the BTB fold are highly variable across sequence families, reflecting the large number of self-association and protein-protein interaction states seen in solved BTB structures. Most BTB-ZF, BBK and MATH-BTB proteins contain a long form of the domain that has an additional conserved amino-terminal region, and these are predicted to form stable dimers. In at least some of the BTB transcription factors, BTB dimers are required for interaction with co-repressor peptides, and possibly for higher order self-association. Based on structural superpositions, we show that the Cul3 interaction surface on many BTB proteins does not overlap with the dimerization interface and, therefore, these BTB proteins may drive the dimerization of Cul3-based E3 ligase complexes.Twenty-five entries comprising nine unique BTB structures were retrieved from the PDB with DALI , CE 117117 and VA panel of HMMs describing various families of BTB proteins were trained on structure-guided, manually inspected sequence alignments of BTB domains from the BTB-ZF, BBK, MATH-BTB, T1, Skp1, ElonginC and BTB-NPH3 families. HMMs were matured by iteratively building the results from multiple rounds of sequence search, alignment and training. HMM training and calibration were done with hmmbuild and hmmcalibrate, using default options, from HMMER 2.3.2 . Family-Anopheles gambiae, Apis mellifera, Caenorhabditis elegans, Canis familiaris, Danio rerio, Drosophila melanogaster, Gallus gallus, Homo sapiens, Mus musculus, Pan troglodytes, Rattus norvegicus, Takifugu rubripes and Xenopus tropicalus were retrieved from the latest version of Ensembl [Arabidsopsis thaliana, Saccharomyces cerevisiae and Schizosaccharomyces pombe protein sequences were retrieved from Uniprot [Dictyostelium discoideum protein sequences were retrieved from Dictybase ('primary features') [All peptides from the translations of all known and predicted transcripts in the genomes of  Ensembl . Arabids Uniprot . Dictyosatures') . Proteinatures') , with anatures')  includedSecondary structure predictions on representative members of each BTB family were completed using the PredictProtein server and the PHD algorithm . Scores Family-specific HMMs were utilized to generate multiple sequence alignments, which were then merged into larger alignments for clustering. Phylogenetic clustering was attempted with the distance, maximum parsimony and maximum likelihood algorithms in the PAUP*4.0 , MEGA 2.A model of the ubiquitin-E2-Cul3-Rbx1-BBK complex was generated following the approach used in making the ubiquitin-E2-SCF(Cdc4) model . The BBKThe following additional data are available with the online version of this paper. Additional data file Multiple sequence alignment of BTB domains from BTB-ZF, BBK, Skp1, T1-Kv, MATH-BTB and BTB-NPH3 proteins.Click here for file


Environmental Health Perspectives (EHP) is like one of the lighthouses that dot the North Carolina coast; the journal acts as a beacon warning people of potential environmental dangers and, at the same time, welcomes people whose goal is to improve global health. Although we report areas of concern about how our environment can negatively affect us, we also provide information that can give a sense of hope for the improvement of human health. Regardless of the information to be shared, EHP tries to provide the balance between voices that sometimes have competing interests.EHP. The talent, energy, tenacity, and altruism of these wonderful people are beyond compare.I will be retiring at the end of December and have been blessed to have a fulfilling career dating back to 1969 that allowed me to experience industrial, academic, and governmental service. Along the way I have had the honor to work with many wonderful people. However, none of my experiences has been more fulfilling than my time at NIEHS during which I served with the National Toxicology Program and now with EHP since its inception over 30 years ago. NIEHS is an exceptional institution with exceptional people, who are at the forefront of research in environmental health issues. During this time EHP has given a voice to the institute and to the field of environmental health.NIEHS has been the benevolent sponsor of EHP is uncertain, the journal will continue in its mission of serving “as a forum for the discussion of the interrelationships between the environment and human health by publishing in a balanced and objective manner the best peer-reviewed research and most current and credible news of the field.”Although the future sponsorship of not just another pretty face!). I hope to use this time to contemplate new ways to contribute to scientific capacity building and information dissemination in the developing world, which has been my passion at EHP. I am very grateful for, and will always remember, the support and dedication of the EHP staff and the NIEHS administration during my tenure.My immediate plans are to go on extended camping trips across the United States with my wife, Marilyn (who is


EHP. As the new NIEHS director, my goal for this column was to maximize communication with the environmental health sciences community about my vision, goals, and strategy for the institute, as well as convey information and opinion on topics I felt were important to the field. Although it seemed to me at the time that my use of EHP as a forum was a natural and reasonable activity given the journal’s leadership and readership in environmental health sciences, time and experience have led me to a new recognition that this might be viewed as undue editorial influence over the journal’s content. I am fully committed to ensuring the scientific credibility of EHP, for which editorial independence is vital, and thus have decided to remove the Director’s Perspective column from the journal and relocate it to a more appropriate venue on the NIEHS website.Two years ago this month I began writing this column for EHP ’s relationship with the NIEHS has always been somewhat unique. Although many government-supported publications and even scientific journals exist, few have been supported directly by the NIH. EHP was begun as an NIEHS-supported journal in 1972 to fill a much-needed gap in scientific publishing in the fledgling field of environmental health sciences. And in fact, it has been the continued strong support of the NIEHS and the outstanding work of a relatively small group of highly dedicated individuals that have allowed the journal to evolve into the preeminent environmental sciences journal in the world. The journal was established with the tacit understanding that the editorial guidance of EHP would have to function independently in substance for the journal to succeed and serve its purpose, and safeguards including an outside, independent editorial board and appropriate scientific peer-review policies—and with later expansion, expert and outside review of news content and a stringent competing financial interest policy—were put into place, and continue to guide the journal’s practices today.But the scientific climate and public concerns about real and perceived conflicts of interest have changed over the past 35 years. Whereas in the past these safeguards, along with the personal integrity of the editorial leadership, may have been enough to convey the integrity of the journal, in today’s world more is expected. Today, it is not necessarily sufficient for a publication to be true in substance; it must also be true in appearance.EHP has functioned for decades with the utmost editorial freedom while enjoying the strong financial support of the NIEHS. With EHP being as the world’s leading journal in the field of environmental health sciences, it is entirely reasonable that the content of EHP and the activities and goals of the NIEHS often overlap; in fact it would be ludicrous if they did not. However, support and influence are not easily separated in appearance. Because scientific journals rise and fall on the basis of their perceived credibility, I believe the NIEHS has a clear responsibility to ensure that EHP continues to be viewed as entirely credible in publishing the very best research in our field. While the NIEHS has made a commitment to continue to strongly support EHP financially, we are taking new measures to ensure the journal’s editorial independence and to increase the transparency of this feature to the scientific community and the public.In point of fact, EHP who will reside outside the NIEHS. The person we are looking for will be an accomplished scientist and a thought leader in the field who, supported by a strong and active editorial board, will provide independent scientific and editorial leadership for the journal. The capacity of the editorial board to provide input into EHP policies and practices, as well as its everyday impact on the scientific content of the journal, will be enhanced through more regular board meetings and improved methods to handle and review manuscripts. Although the NIEHS News section will be moved from EHP to the new NIEHS website upon its launch in June 2007, our outstanding science news coverage will be maintained in EHP, albeit reduced in scope. And although I may occasionally in the future submit scientific or editorial content to EHP, such pieces will undergo standard peer review and editorial consideration prior to acceptance for publication. I truly believe that everything published in EHP should be the decision of the editorial staff, and not influenced by the source of the journal’s funding.One way in which we are accomplishing this goal is through the recruitment of a new editor-in-chief for I also continue to believe emphatically in the importance of my personally communicating with the environmental health sciences community, and will take advantage of the new venues and technologies that soon will become available through the NIEHS’s transformed website to do so, starting with creating a home for the Director’s Perspective. These columns allow me to let you know what I’m thinking and how I plan to address the ongoing challenges facing our institute and our field. However, it’s important for me to hear and understand your thoughts and concerns as well. I’m hoping that our new website will create opportunities for us to interact in innovative ways that allow us to share ideas and build consensus. Approaches such as e-mail, instant messaging, surveys, blogs, and Wikipedia-like discussion sites may facilitate the open and interactive process that I believe is critically important to the future of environmental health sciences.EHP will continue to play vital roles in furthering environmental health sciences to the betterment of human health and well-being.Independence and transparency are cornerstones of science—and of scientific publishing. It is my hope that with enhancements to both of these, the NIEHS and


Scientists are accustomed to scrutiny such as experimental protocol reviews, oversight on research conduct, and critiques provided during the peer-review publication process.We especially anticipate the post-publication period during which others attempt to reproduce, validate, and then build on our work. All this scrutiny is basic to establishing the credibility of our findings. We therefore should not be put off by the greater attention now being focused on full disclosure of competing financial interests. What is essential to us as scientists is credibility. If our work is to contribute to the scientific and medical knowledge base, full disclosure is just one more process that must be embraced to establish and maintain the credibility of scientific and medical research.“The potential for conflict of interest can exist whether or not an individual believes that the relationship affects his or her scientific judgment” ; this quEHP clarified its policies in 2003. We feel that our disclosure requirements, which focus only on competing financial interests, are clear. However, a recent survey of the disclosure statements of some of our authors raised doubts about compliance.The need for full disclosure has become even more compelling as commercial organizations provide an increasing percentage of research support. Recognizing the growing importance of full disclosure, New England Journal of Medicine, the Journal of the American Medical Association (JAMA), EHP, and Toxicology and Applied Pharmacology. The author of the report, Merrill Goozner, was quoted in USA Today  where either the first or last authors should have disclosed conflicts in accordance with the disclosure policy.A fourth article was noted, but not included, because the issue identified would require a very strict interpretation of conflict of interest policies.EHP ’s gratitude for the work done by the CSPI to help EHP achieve its goal of full disclosure of competing financial interests. I mentioned that we have a standing policy that encourages our readership to scrutinize disclosure issues. I further noted the difficulty that journal editorial offices would have if we undertook the task of checking on the financial interests of each of our authors. I promised Goozner that we would discuss this issue with our editorial board members and publish his letter along with responses that we would solicit from the named authors. These letters appear in this issue of EHP beginning on page A794.In an e-mail to Goozner, I expressed EHP. After careful review of all the responses and discussions with our editorial board members, I am confident that there were no willful attempts to hide any competing financial interests. I judge that the authors named in the CSPI report (EHP disclosure policy.The authors named by the CSPI (2004) have provided explanations for why they did not provide disclosure to I report  have madHowever, lessons learned from examination of the four cases identified in the CSPI report  do proviEHP to continue to update our disclosure policy. We now clearly instruct our authors to err on the sign of caution, and we have added the admonition that authors are to disclose all competing financial interests that might in any way be perceived as representing a competing financial interest. As has been our practice, EHP will continue to publish all disclosures made by our authors.Considering the issues raised by the CSPI report , we feelOur previous policy did not outline specific punitive measures that would be taken when our policies are violated. Because we feel that full disclosure is an absolute requirement, we are now adding clear consequences for any ethical violations. From now on, we will impose a 3-year ban on publication on authors who willfully fail to disclose a competing financial interest. Implementation of the ban will be made in consultation with our editorial board. If complete disclosure of possible conflicts would have caused the journal to have rejected the manuscript, the paper will be retracted. If the paper is not retracted but an ethical omission has occurred, an Expression of Concern will be written, published in the journal, and added to the online version of the article.Once again, I encourage the scientific community to embrace scrutiny of our competing financial interests as we embrace the scrutiny of our research. Full disclosure is in the best interest of the individual scientists, the journals, and society, which must have complete faith that our research is not only of the highest quality but also is open, honest, and unbiased.


The authors review recent research on the molecular mechanisms of addiction and propose a new classification for addictive drugs. The consumption of a variety of natural and synthetic substances can lead to addiction, which is commonly defined by the loss of control and compulsive consumption despite negative consequences. Although addictive drugs have diverse molecular targets in the brain, they share the common initial effect of increasing the concentration of dopamine released from mesocorticolimbic projections.In this article, we review recent research that has advanced our understanding of the molecular mechanisms underlying this increase of dopamine. Based on this research, we propose a new classification for addictive drugs that we believe may help in directing research towards more effective treatment of addiction see .The mesocorticolimbic dopamine system originates in the ventral tegmental area (VTA), which projects most notably to the nucleus accumbens (NAc) and the prefrontal cortex (PFC). It is a defining commonality of all addictive drugs that they increase dopamine concentrations in target structures of the mesocorticolimbic projections ,2. The rMoreover, it is important to realize that, once compulsive use has been established, addiction is thought to be largely dopamine-independent. Nonetheless, it is widely accepted that the induction of addiction crucially involves mesocorticolimbic dopamine.Johnson and North, 1992 A receptoptors [h , nAChRs ptors [h , and 5-Heceptors . In addieceptors . How etheceptors .In the central nervous system, cocaine blocks dopamine, noradrenaline, and serotonin uptake through inhibition of their respective transporters. Blocking of the dopamine transporter (DAT) leads to an increase of dopamine concentrations in the nucleus accumbens.  In micThese exert their effects by reversing the action of biogenic amine transporters at the plasma membrane . AmphetaAs for the amphetamines, MDMA causes the release of biogenic amines by reversing the action of their respective transporters. Although MDMA has a preferential affinity for SERTs and therefore increases the extracellular concentration of serotonin, it also strongly increases dopamine .2A receptors expressed on excitatory afferents from the thalamus [There are a number of abused drugs about which there is no clear consensus concerning their addictive properties . For example, LSD, which is widely abused, does not appear to be addictive. Animals will not self-administer hallucinogens, suggesting that they are not rewarding . Importathalamus .Conditioned place preference: A behavioural test for examining the rewarding properties of drugs. The preference of a particular environment associated with drug exposure is measured by comparing the time an animal spends in the compartment where the drug was previously administered compared to a control compartment.Coupling efficiency: The efficiency with which a given G protein–coupled receptor can activate an effector.DARP32: Dopamine and cAMP-regulated phosphoprotein. A key target protein for increased dopamine that plays a role in signalling the effects of many addictive drugs.DeltaFosB: A transcription factor that is induced in areas such as the NAc in response to many addictive drugs, and thought to be involved in the long-term maintenance of addictive behaviour.50EC: 50% effective concentration, i.e., the concentration of an agonist that produces 50% of the maximal effect.Equilibrative nucleoside transporter ENT1: Transporter responsible for the re-uptake of adenosine.Homomeric α7-containing nAChRs: Nicotinic acetylcholine receptors formed by five subunits of the α7 type.Kir3/GIRK channels: One class of inwardly rectifying potassium channels; Kir3 are also termed G protein–coupled inwardly rectifying K+ channels.Quantal content: The amount of neurotransmitter released by a single vesicle.The main effect of the NMDA receptor antagonists phencyclidine (PCP) and ketamine are feelings of separation of mind and body and, at higher doses, stupor and coma, which is why they are called dissociative anaesthetics. Based on early assessments, NMDA receptor antagonists have been classified as non-addictive drugs of abuse . This clA receptor function [Inhalant abuse is defined by the recreational exposure to chemical vapours, such as nitrates, ketones, and aliphatic and aromatic hydrocarbons. In some countries it is particularly common among children, and some chemicals do induce addiction . The mecfunction . Toluenefunction  and causfunction . Others,We have presented a new mechanistic classification system for addictive drugs. There are a number of key features of this system. First, there are three types of mechanism. Second, each addictive drug only activates the dopamine system through a single mechanism . Third, within each type of mechanism the effect on the dopamine system is similar .Although substantial progress into unravelling the neurobiological bases of addiction has been made, many open questions remain and few effective treatments are currently available. Much current research is therefore aimed at understanding the neuroadaptive changes induced by addictive drugs, such as increased expression of deltaFosB and DARP32  or the eB receptor agonist baclofen would inhibit GABA and dopamine neurons, thus efficiently blocking DA release.Understanding the early phases of the induction of adaptive processes will also be important for the discovery of novel pharmacological treatment strategies. If activation of the dopamine system is indeed crucial for the development of addiction, then an interesting strategy may be to inhibit the mesocorticolimbic DA system . This idea is further supported by the observation that increases in dopamine play an important role in relapse, particularly drug-induced relapse ,60. In tTreatments in use, or at pre-clinical stages of development, are either drug-specific  or target a mechanism that is common to several drugs  . Many neFinally, we hope that our strikingly simple mechanistic classification will provide students and clinicians with a useful conceptual framework for understanding a diverse and often complex literature concerning such an important medical issue.