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Dividing the City uses a newly discovered, parcel-level, record of restrictive covenants (circa 1850-1950) to document the scope, variety, location, timing, dissemination, and impact of racial restrictions in the City of St. Louis. We underscore the important differences, in their use and their impact, between new subdivision restrictions and petition-based restrictive agreements in older neighborhoods. And we establish the importance of these restrictions to both a dramatic increase in residential segregation before 1950 and the maintenance of that segregation—through public and private policies that emulated and adapted these restrictions even after the Supreme Court held them unenforceable—across the ensuing decades.

Diagnosis and assessment of patients with prostate cancer is dependent on accurate interpretation and grading of histopathology. However, morphology does not necessarily reflect the complex biological changes occurring in prostate cancer disease progression, and current biomarkers have demonstrated limited clinical utility in patient assessment. This study aimed to develop biomarkers that accurately define prostate cancer biology by distinguishing specific pathological features that enable reliable interpretation of pathology for accurate Gleason grading of patients. Online gene expression databases were interrogated and a pathogenic pathway for prostate cancer was identified. The protein expression of key genes in the pathway, including adaptor protein containing a pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif 1 (Appl1), Sortilin and Syndecan-1, was examined by immunohistochemistry (IHC) in a pilot study of 29 patients with prostate cancer, using monoclonal antibodies designed against unique epitopes. Appl1, Sortilin, and Syndecan-1 expression was first assessed in a tissue microarray cohort of 112 patient samples, demonstrating that the monoclonal antibodies clearly illustrate gland morphologies. To determine the impact of a novel IHC-assisted interpretation (the utility of Appl1, Sortilin, and Syndecan-1 labelling as a panel) of Gleason grading, versus standard haematoxylin and eosin (H&E) Gleason grade assignment, a radical prostatectomy sample cohort comprising 114 patients was assessed. In comparison to H&E, the utility of the biomarker panel reduced subjectivity in interpretation of prostate cancer tissue morphology and improved the reliability of pathology assessment, resulting in Gleason grade redistribution for 41% of patient samples. Importantly, for equivocal IHC-assisted labelling and H&E staining results, the cancer morphology interpretation could be more accurately applied upon re-review of the H&E tissue sections. This study addresses a key issue in the field of prostate cancer pathology by presenting a novel combination of three biomarkers and has the potential to transform clinical pathology practice by standardising the interpretation of the tissue morphology. Refereed/Peer-reviewed

The optical properties of transition metal dichalcogenides have previously been modified at the nanoscale by using mechanical and electrical nanostructuring. However, a clear experimental picture relating the local electronic structure with emission properties in such structures has so far been lacking. Here, we use a combination of scanning tunneling microscopy (STM) and near-field photoluminescence (nano-PL) to probe the electronic and optical properties of single nano-bubbles in bilayer heterostructures of WSe2 on MoSe2. We show from tunneling spectroscopy that there are electronic states deeply localized in the gap at the edge of such bubbles, which are independent of the presence of chemical defects in the layers. We also show a significant change in the local bandgap on the bubble, with a continuous evolution to the edge of the bubble over a length scale of ~20 nm. Nano-PL measurements observe a continuous redshift of the interlayer exciton on entering the bubble, in agreement with the band to band transitions measured by STM. We use self-consistent Schr\"odinger-Poisson (SP) simulations to capture the essence of the experimental results and find that strong doping in the bubble region is a key ingredient to achieving the observed localized states, together with mechanical strain.

The persistence and severity of the gap between black and white wealth, and the role of housing discrimination in creating and sustaining this gap are both well documented. But given the chronologi...

Objectives: The goals of this study were to assess the air quality in subway systems in the northeastern United States and estimate the health risks for transit workers and commuters. Methods: We r...

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Most studies of walkability focus on large urban centres. This paper works to fill the gap in the study of walkability principles and applies them to small towns, and rural communities. Drawing from smart growth and new urbanist ideas, walkability is affected by density, destinations, distance, and design (the 4Ds); each of which affects people’s choice to walk. Rural communities and small towns generally lack one of more of the 4 Ds, creating an inability to fully achieve the status of walkable communities as would be found in more urban places. In addition, rural communities are often part of a collection of communities that make up a region of small places. Each has its unique character and influences that guide development in the node. A focus on creating walkability in these nodal areas makes sense for small communities, and will enable people to park once and use the pedestrian infrastructure to reach multiple destinations within each node. Through an extensive literature review and a series of site visits, the findings are that walkability is a relevant field of study for small communities despite the implied weaknesses in density and distance., Major project submitted in partial fulfillment of the requirements for the degree of Master of Community Planning in the Department of Community Planning, Faculty of Social Sciences., https://viurrspace.ca/bitstream/handle/10613/8632/Brown.MCP.Project.pdf?sequence=3

En essayant de contextualiser les enjeux des interventions de Michel Foucault a propos du droit penal et de retrouver leur logique a l’interieur du deroulement de son travail, ce texte tente de degager en quoi Foucault a pu alors aider, d’un facon singuliere, a ouvrir au moins pour un moment de nouvelles conceptions du possible. Pour faire ceci, il faut reperer a la fois les constantes et les elements de deplacement dans le point de vue de Foucault sur le droit. Sous son refus notoire d’une juridification de l’analyse politique, il faut remarquer et prendre en acte une analyse historique positive, riche et complexe des engrenages entre droit, pouvoir et verite. En reprenant en meme temps les analyses (dites « premonitoires ») de Foucault sur le neoliberalisme et ses travaux des annees 1980 sur les jeux de verite, on essaie enfin de degager quelques pistes pour reouvrir, en notre present a nous, une conception du possible en matiere juridico-penale.

The text that follows brings together two papers about resonances between late lectures: Weber's lectures of 1918 on science and politics as vocations, and Foucault's final courses (1980–84) on subjectivity, truth and the political. The title alludes to Foucault's 1983 discussion of Plato's political experiences in Sicily, as narrated in his Seventh Letter, juxtaposed to Weber's public interventions in Germany at the time of the foundation of the Weimar Republic. Linked to this is an exploration of the centrality in the work of both Weber and Foucault of an historical ethnography and ethology of the political, and of the forms of connectivity in our cultures between ethics, truth and government.

Does technological change breed inequality? This notion, in some version or other, has become a staple explanation for our growing economic divide. It features prominently in the “meritocracy” defense of the 1 percent, which assumes (as Harvard economist Greg Mankiw put it recently) that “changes in technology have allowed a small number of highly educated and exceptionally talented individuals to command superstar incomes in ways that were not possible a generation ago.” It peppers the breathless prose of columnist Thomas Friedman, who makes a living mixing metaphors about our flat, smart, hyperconnected, seamless supply chain of a world.

Background: The structure of Rhp23 is unusual in that it contains two ubiquitin binding domains. Results: Only the internal domain of Rhp23 is required for it to act as a shuttle factor. Conclusion: The C-terminal ubiquitin binding domain is redundant for substrate recognition. Significance: This is the first time that the functions of ubiquitin binding domains have been tested in vivo in S. pombe., The ubiquitin-proteasome system is essential for maintaining a functional cell. Not only does it remove incorrectly folded proteins, it also regulates protein levels to ensure their appropriate spatial and temporal distribution. Proteins marked for degradation by the addition of Lys48-linked ubiquitin (Ub) chains are recognized by shuttle factors and transported to the 26 S proteasome. One of these shuttle factors, Schizosaccharomyces pombe Rhp23, has an unusual domain architecture. It comprises an N-terminal ubiquitin-like domain that can recognize the proteasome followed by two ubiquitin-associated (UBA) domains, termed UBA1 and UBA2, which can bind Ub. This architecture is conserved up to humans, suggesting that both domains are important for Rhp23 function. Such an extent of conservation raises the question as to why, in contrast to all other shuttle proteins, does Rhp23 require two UBA domains? We performed in vitro Ub binding assays using domain swap chimeric proteins and mutated domains in isolation as well as in the context of the full-length protein to reveal that the Ub binding properties of the UBA domains are context-dependent. In vivo, the internal Rhp23 UBA1 domain provides sufficient Ub recognition for the protein to function without UBA2.

The protein called p97 in mammals and Cdc48 in budding and fission yeast is a homo-hexameric, ring-shaped, ubiquitin-dependent ATPase complex involved in a range of cellular functions, including protein degradation, vesicle fusion, DNA repair, and cell division. The cdc48+ gene is essential for viability in fission yeast, and point mutations in the human orthologue have been linked to disease. To analyze the function of p97/Cdc48 further, we performed a screen for cold-sensitive suppressors of the temperature-sensitive cdc48-353 fission yeast strain. In total, 29 independent pseudo revertants that had lost the temperature-sensitive growth defect of the cdc48-353 strain were isolated. Of these, 28 had instead acquired a cold-sensitive phenotype. Since the suppressors were all spontaneous mutants, and not the result of mutagenesis induced by chemicals or UV irradiation, we reasoned that the genome sequences of the 29 independent cdc48-353 suppressors were most likely identical with the exception of the acquired suppressor mutations. This prompted us to test if a whole genome sequencing approach would allow us to map the mutations. Indeed genome sequencing unambiguously revealed that the cold-sensitive suppressors were all second site intragenic cdc48 mutants. Projecting these onto the Cdc48 structure revealed that while the original temperature-sensitive G338D mutation is positioned near the central pore in the hexameric ring, the suppressor mutations locate to subunit-subunit and inter-domain boundaries. This suggests that Cdc48-353 is structurally compromized at the restrictive temperature, but re-established in the suppressor mutants. The last suppressor was an extragenic frame shift mutation in the ufd1 gene, which encodes a known Cdc48 co-factor. In conclusion, we show, using a novel whole genome sequencing approach, that Cdc48-353 is structurally compromized at the restrictive temperature, but stabilized in the suppressors.

Protein ubiquitylation is a recognized signal for protein degradation. However, it is increasingly realized that ubiquitin conjugation to proteins can be used for many other purposes. Furthermore, there are many ubiquitin-like proteins that control the activities of proteins. The central structural element of these post-translational modifications is the ubiquitin superfold. A common ancestor based on this superfold has evolved to give various proteins that are involved in diverse activities in the cell.

Conjugation of proteins to ubiquitin plays a central role for a number of cellular processes including endocytosis, DNA repair and degradation by the 26 S proteasome. However, ubiquitination is reversible as a number of deubiquitinating enzymes mediate the disassembly of ubiquitin–protein conjugates. Some deubiquitinating enzymes are associated with the 26 S proteasome contributing to and regulating the particle's activity. Here, we characterise fission yeast Uch2 and Ubp6, two proteasome associated deubiquitinating enzymes. The human orthologues of these enzymes are known as Uch37 and Usp14, respectively. We report that the subunit Uch2/Uch37 is the major deubiquitinating enzyme associated with the fission yeast 26 S proteasome. In contrast, the activity of Ubp6 appears to play a more regulatory and/or structural role involving the proteasome subunits Mts1/Rpn9, Mts2/Rpt2 and Mts3/Rpn12, as Ubp6 becomes essential when activity of these subunits is compromised by conditional mutations. Finally, when the genes encoding Uch2/Uch37 and Ubp6 are disrupted, the cells are viable without showing obvious signs of impaired ubiquitin-dependent proteolysis, indicating that other deubiquitinating enzymes may remedy for the redundancy of these enzymes.

Fission yeast Rhp23 and Pus1 represent two families of multiubiquitin chain-binding proteins that associate with the proteasome. We show that both proteins bind to different regions of the proteasome subunit Mts4. The binding site for Pus1 was mapped to a cluster of repetitive sequences also found in the proteasome subunit SpRpn2 and the anaphase-promoting complex/cyclosome (APC/C) subunit Cut4. The putative role of Pus1 as a factor involved in allocation of ubiquitinylated substrates for the proteasome is discussed.

The ubiquitin-proteasome pathway for intracellular proteolysis is involved in a series of cellular and molecular functions, including the degradation of bulk proteins, cell cycle control, DNA repair, antigen presentation, vesicle transport and the regulation of signal transudation pathways and transcription. Considering this variety of cell biological processes, it is puzzling that until recently only very few proteins were known to possess the ability to interact specifically with ubiquitin chains. However, several ubiquitin binding proteins have now been identified and the binding domains have been characterised on both the functional and structural levels. One example of a widespread ubiquitin binding module is the ubiquitin associated (UBA) domain. Here, we discuss the approximately 15 UBA domain containing proteins encoded in the relatively small genome of the fission yeast Schizosaccharomyces pombe. The proteins display remarkable differences in their domain organisation, indicating that these potential ubiquitin binding proteins are involved in various cell activities.

Federal protection of the environment, food safety, and occupational health now routinely relies on the oxymoron of "voluntary compliance." The current Administration has undertaken a broad effort to restructure federal advisory committees to both the Center for Disease Control and Health and Human Services, displacing "renowned scientists" with, as the National Resources Defense Council notes acidly, "pro-industry representatives with questionable expertise." In recent months alone, the Environmental Protection Agency (EPA) has delayed smog abatement requirements, reversed or weakened restrictions (in violation of international agreements) on the use of the pesticides atrazine, methyl bromide, and carbofuran, and only reluctantly withdrawn a proposal to loosen the regulations that govern screening of lowincome children for lead poisoning. And a proposed expansion of the Patriot Act features provisions that would both limit citizen access to information about possible risks from local chemical plants and grant companies broad immunity form civil liability.' These facts, mere illustrations of a deregulatory impulse that is now three decades old, underscore (even as they ignore) the remarkable history uncovered by David Rosner and Gerald Markowitz in Deceit and Denial: The Deadly Politics of Industrial Pollution. From two paradigmatic case studies-lead in the first half of the twentieth century, and plastics in the latter half-the authors draw three important ethical and political conclusions. First, the economic principle that "there is no reason to hold up production of useful products if danger has not been proven" has proven disastrous in terms of occupational health, public health, and environmental health (p. 6). Second, leading firms and trade associations have proven unable and unwilling to consider the "externalities" of modern industry (death, sickness, environmental degradation) as much more than a marketing or public relations challenge. And third, the very institutions that might be expected to broach these questions less

Cells are regularly exposed to stress conditions that may lead to protein misfolding. To cope with this challenge, molecular chaperones selectively target structurally perturbed proteins for degradation via the ubiquitin-proteasome pathway. In mammals the co-chaperone BAG-1 plays an important role in this system. BAG-1 has two orthologues, Bag101 and Bag102, in the fission yeast Schizosaccharomyces pombe. We show that both Bag101 and Bag102 interact with 26S proteasomes and Hsp70. By epistasis mapping we identify a mutant in the conserved kinetochore component Spc7 (Spc105/Blinkin) as a target for a quality control system that also involves, Hsp70, Bag102, the 26S proteasome, Ubc4 and the ubiquitin-ligases Ubr11 and San1. Accordingly, chromosome missegregation of spc7 mutant strains is alleviated by mutation of components in this pathway. In addition, we isolated a dominant negative version of the deubiquitylating enzyme, Ubp3, as a suppressor of the spc7-23 phenotype, suggesting that the proteasome-associated Ubp3 is required for this degradation system. Finally, our data suggest that the identified pathway is also involved in quality control of other kinetochore components and therefore likely to be a common degradation mechanism to ensure nuclear protein homeostasis and genome integrity., Author Summary The accumulation of misfolded proteins represents a considerable threat to the health of individual cells and has been linked to severe diseases, including cancer and neurodegenerative disorders. To cope with this threat, especially under stress conditions, cells have evolved efficient quality control mechanisms. In general, these rely on molecular chaperones to either seize and refold misfolded proteins, or target them for degradation via the ubiquitin-proteasome system. At present, our understanding of what determines whether a chaperone commits to a folding or a degradation mode is limited. However, studies suggest that association with certain regulatory co-chaperones contributes to this process. Here, we show that certain BAG-1-type co-chaperones function in quality control by targeting misfolded kinetochore components for proteolysis. The presented genetic and biochemical data show that specific ubiquitin conjugating enzymes and ubiquitin-protein ligases maintain nuclear protein homeostasis and are required for upholding genome integrity.

The UBA domain is a motif found in a variety of proteins, some of which are associated with the ubiquitin-proteasome system. We describe the isolation of a fission-yeast gene, mud1+, which encodes a UBA domain containing protein that is able to bind multi-ubiquitin chains. We show that the UBA domain is responsible for this activity. Two other proteins containing this motif, the fission-yeast homologues of Rad23 and Dsk2, are also shown to bind multi-ubiquitin chains via their UBA domains. These two proteins are implicated, along with the fission-yeast Pus1(S5a/Rpn10) subunit of the 26 S proteasome, in the recognition and turnover of substrates by this proteolytic complex.

The COP9 signalosome is a multiprotein complex somewhat similar to the lid component of the 26S proteasome. Recent studies suggest that it regulates the stability of proteins by interfering with the ubiquitin–proteasome pathway via deneddylation and phosphorylation.

Review of: "Staley: The Fight for a New American Labor Movement," by Steven K. Ashby and C. J. Hawking.

The aim of this paper is to examine whether the introduction of new hospital specialties contributed to an increase in GP prescription costs. New specialties were introduced in Dr Gray's hospital, Grampian, North-East Scotland in 1994. Data on prescription costs and volume for groups of drugs associated with the new specialties were obtained for all GP practices in Moray (study practices) and Kincardine and Deeside (control practices). Comparing the periods January-April in 1994 with 1995, and 1995 with 1996, an upward trend in GP prescription costs was detected for ulcer healing drugs and anti-depressants. The trend in Kincardine and Deeside also pointed to rising prescription costs, although to a lesser extent. The number of patients referred to the psychiatric and gynaecology specialties expanded after the introduction of these specialties at Dr Gray's. In conclusion, there is some evidence to support the proposition that the introduction of new specialties at Dr Gray's was associated with an increase in the growth of prescription costs within Moray. Further research should establish more clearly whether this is as a result of increased referrals by GPs or the prescribing of more expensive drugs by consultants. The results have implications for the setting of prescribing budgets. ispartof: Health Policy vol:52 issue:3 pages:171-78 ispartof: location:Ireland status: published

Substrates are targeted for proteolysis by the ubiquitin pathway by the addition of a polyubiquitin chain before being degraded by the 26 S proteasome. Previously, a subunit of the proteasome, S5a, was identified that was able to bind to polyubiquitin in vitro and thus proposed to act as a substrate recognition component. Deletion of the corresponding Saccharomyces cerevisiae gene, MCB1/RPN10, rendered cells viable indicating that other proteasomal polyubiquitin receptors must exist. In this study, we describe pus1(+), the fission yeast homologue of RPN10. This gene is also not required for cell viability; however, the Deltapus1 mutant is synthetically lethal with mutations in other proteasomal component-encoding genes, namely mts3, pad1, and mts4 (RPN12, RPN11, and RPN1). Overexpression of pus1(+) is able to rescue mts3-1 at 32 degrees C but overexpression of a cDNA encoding a version of Pus1 that does not bind to polyubiquitin cannot and leads to greatly reduced viability when used to rescue the mts3-1Deltapus1 double mutant. The Mts3 protein was unable to bind to polyubiquitin in vitro, but the Pus1 and Mts3 proteins were found to bind to one another in vitro, which taken together with the genetic data suggests that they are also closely associated in vivo.

The 26S proteasome is the multiprotein complex that degrades proteins that have been marked for destruction by the ubiquitin pathway. It is made up of two multisubunit complexes, the 20S catalytic core and the 19S regulatory complex. We describe the isolation and characterization of conditional mutants in the regulatory complex and their use to investigate interactions between different subunits. In addition we have investigated the localization of the 26S proteasome in fission yeast, by immunofluorescence in fixed cells and live cells with the use of a GFP-tagged subunit. Surprisingly, we find that in mitotic cells the 26S proteasome occupies a discrete intracellular compartment, the nuclear periphery. Electron microscopic analysis demonstrates that the complex resides inside the nuclear envelope. During meiosis the localization showed a more dynamic distribution. In meiosis I the proteasome remained around the nuclear periphery. However, during meiosis II there was a dramatic relocalization: initially, the signal occupied the area between the dividing nuclei, but at the end of mitosis the signal dispersed, returning to the nuclear periphery on ascospore formation. This observation implies that the nuclear periphery is a major site of proteolysis in yeast during mitotic growth and raises important questions about the function of the 26S proteasome in protein degradation.

International audience; Fission yeast centromeres are transcriptionally silent and form a heterochromatin-like structure essential for normal centromere function; this appears analogous to heterochromatin and position effect variegation in other eukaryotes. Conditional mutations in three genes designated cep (centromere enhancer of position effect) were found to enhance transcriptional silencing within centromeres. Cloning of the cep1(+) and cep2(+) genes by functional complementation revealed that they are identical to the previously described genes pad1(+) and mts2(+), respectively, which both encode subunits of the proteasome 19S cap. Like Mts2 and Mts4, epitope-tagged Cep1/Pad1 localizes to or near the nuclear envelope throughout the cell cycle. The cep mutants display a range of phenotypes depending on the temperature. Silencing within the central domain of centromeres is increased at 36 degrees C. This suggests that the proteasome is involved in regulating silencing and thus centromeric chromatin architecture, possibly by lowering the level of some chromatin-associated protein by ubiquitin-dependent degradation. This is the first report of defective proteasome function affecting heterochromatin-mediated transcriptional silencing. At 36 and 32 degrees C, the cep mutants lose chromosomes at an elevated rate, and at 18 degrees C, the mutants are cryosensitive for growth. Cytological analysis at 18 degrees C revealed a defect in sister chromatid separation while other mitotic events occurred normally, indicating that cep mutations might interfere specifically with the degradation of inhibitor(s) of sister chromatid separation. These observations suggest that 19S subunits confer a level of substrate specificity on the proteasome and raise the possibility of a link between components involved in centromere architecture and sister chromatid cohesion.

Robert Zieger's “Historians and the U.S. Industrial Relations Regime” offers both a crisp historiographical survey of the field and a thoughtful agenda for further research. Iagree with much of what he has to say, particularly concerning our fascination with the first fifteen yearsof modern labor policy (running from the early New Deal through the Taft-Hartley Act) and our relative neglect of the postwar era. Having said this, I want to turn our attention back to 1935, in part because the Wagner Act is such an important and defining moment, and in part becauseZieger casually dismisses critical interpretations of the Wagner Act's passage and logic as “ahistorical” or “ideologically-driven speculations.” As one whose scholarship is caricatured in this way, I appreciate the opportunity to respond.

This paper consists of comments and reflections on the legacy of Canguilhem's work, especially in Britain. After reviewing some aspects of the reception of Canguilhem's thought in Britain, the paper defends Canguilhem's vitalist philosophy, and concludes with hints as to the political uses of Canguilhem's thought in today's bio-political age.