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Since 2008, the Chinese state has been developing new public housing programs, which are widely used to distribute public housing among talent workers. This paper examines public housing allocation...

The process of urbanization and urban land use conversion inevitably disturbs the structure and function of ecosystems and their capacity to provide ecosystem services. Integrating ecosystem services into effective policies and planning at the regional scale to achieve sustainable urban development is still a challenge. The goal of this research is to optimize spatial patterns of urban development by assessing and comparing multiple trade-off scenarios between ecological processes and urban expansion, incorporating planning and design into spatially explicit methods, and integrating ecosystem services into decision-making procedures. We develop a conceptual framework for regional urban-ecological sustainability with six steps: pattern recognition, landscape process, problem diagnosis, integrated ecological network, urbanization simulation, and decision-support. We apply this framework to a case in which planning and design have followed the rational-comprehensive approach. Results demonstrate that landscape multi-functionality and regional ecological networks are significantly improved using our integrated approach to planning and design, because it provides vital information for regional planning to cope with the urgent need for ecological protection and urban development. By comparing urban growth under three scenarios, we found that the trade-off scenario based on ecological conservation and restoration (medium security level) resolved conflict more effectively, which restricted urban expansion on land of high ecological importance by constructing regional ecological networks. In addition, using field survey and species distribution model approaches, we design plant community types with complementary tree, shrub, and herb species as part of the decision-making procedure, which can restore zonal vegetation and the hydrological cycle in rugged mountain regions. The research concludes that regional urban-ecological sustainability based on scientific assessment, planning, and design provides a rational basis for sustainable urban development and landscape management.

Ebolaviruses and marburgviruses belong to the family Filoviridae and cause high lethality in infected patients. There are currently no licensed filovirus vaccines or antiviral therapies. The development of broad-spectrum therapies against members of the Marburgvirus genus, including Marburg virus (MARV) and Ravn virus (RAVV), is difficult because of substantial sequence variability. RNAi therapeutics offer a potential solution, as identification of conserved target nucleotide sequences may confer activity across marburgvirus variants. Here, we assessed the therapeutic efficacy of lipid nanoparticle (LNP) delivery of a single nucleoprotein–targeting (NP-targeting) siRNA in nonhuman primates at advanced stages of MARV or RAVV disease to mimic cases in which patients begin treatment for fulminant disease. Sixteen rhesus monkeys were lethally infected with MARV or RAVV and treated with NP siRNA-LNP, with MARV-infected animals beginning treatment four or five days after infection and RAVV-infected animals starting treatment three or six days after infection. While all untreated animals succumbed to disease, NP siRNA-LNP treatment conferred 100% survival of RAVV-infected macaques, even when treatment began just 1 day prior to the death of the control animals. In MARV-infected animals, day-4 treatment initiation resulted in 100% survival, and day-5 treatment resulted in 50% survival. These results identify a single siRNA therapeutic that provides broad-spectrum protection against both MARV and RAVV.

Intensive human land use and climate change have led to widespread ecological degradation which requires optimizing species distributions to achieve ecological restoration. In this paper, we combine predictive species distribution models (SDMs) with field investigations in the mountainous areas of northern China to determine where ecological restoration should be implemented. Using three species distribution models, i.e., generalized additive models (GAMs), generalized linear models, and classification tree models, we predict optimal species algorithms for ecological restoration. The results show that GAMs have more accurate predictive power to detect relationships between biogeographic factors and species distributions than the other two models based on cross-validation. In addition, the regionalization schemes designed in this study provide scientific guidance for ecological restoration by combining simulation results of SDMs with field investigations. By considering the suitability of different land use/cover types, restoration scenarios could be used to guide ecological restoration. The methodology proposed here provides a scientific basis for the restoration of species diversity, improved ecosystem services provision, and can be adopted in regions with extensive human disturbance and environmental change.

High-speed rail (HSR) has played an important role in China’s long-distance travel. However, the potential of this transport technology to meet the demand of passenger mobility at the metropolitan scale is still unclear. This research examines this potential by studying transportation investment for intercity passenger mobility in the Shenzhen-Dongguan-Huizhou Metropolitan Area, where multiple fixed guideway transit systems have been proposed and HSR service has been implemented to carry passengers between central Shenzhen and outer portions of this metropolitan region. Comparison of alternative modes explains why HSR is competitive at the metropolitan scale. Interviews with relevant stakeholders reveal the institutional conditions for utilizing the national HSR system for regional passenger mobility.

The current outbreak of Ebola virus in West Africa is unprecedented, causing more cases and fatalities than all previous outbreaks combined, and has yet to be controlled. Several post-exposure interventions have been employed under compassionate use to treat patients repatriated to Europe and the United States. However, the in vivo efficacy of these interventions against the new outbreak strain of Ebola virus is unknown. Here we show that lipid-nanoparticle-encapsulated short interfering RNAs (siRNAs) rapidly adapted to target the Makona outbreak strain of Ebola virus are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at 3 days after exposure while animals were viraemic and clinically ill. Although all infected animals showed evidence of advanced disease including abnormal haematology, blood chemistry and coagulopathy, siRNA-treated animals had milder clinical features and fully recovered, while the untreated control animals succumbed to the disease. These results represent the first, to our knowledge, successful demonstration of therapeutic anti-Ebola virus efficacy against the new outbreak strain in nonhuman primates and highlight the rapid development of lipid-nanoparticle-delivered siRNA as a countermeasure against this highly lethal human disease.

Preface Introduction: deconstruction, critical thought, literature, Ian MacIachlan 'Literature'/Literature, Alan Bass Household words: alterity, the unconscious and the text, Ann Wordsworth Skepticism and deconstruction, A.J. Cascardi Un dialogue de sourds? Some implications of the Austin-Searle-Derrida debate, Ian Maclean Autobiography and the case of the signature: reading Derrida's Glas, Jane Marie Todd Metaphorics and metaphysics: Derrida's analysis of Aristotle, Irene E. Harvey Time after time: temporality, temporalization, Timothy Clark Circumcising confession: Derrida, autobiography, Judaism, Jill Robbins Memento Mori, Robert Smith Index.

Rural to urban migrants are the dominant component of population growth in China's coastal cities. China's unique household registration system has excluded migrants from most public housing, resulting in pronounced housing segregation --a social phenomenon that has come to be China's greatest urban social planning challenge. In this paper, we analyze the determinants of migrant housing choices and migrant housing needs following the conventional utility-based approach, but we also emphasize the important role of social capital in migrant decision-making. A case study of Shenzhen shows that quantifiable measures of physical, locational, land use and economic attributes cannot fully explain the congregation of migrants in informal communities and that social capital plays an important role in their housing choices. Social networks, social norms, and trust among neighbors are key factors in the establishment of migrant communities. This study reveals a new aspect of migrant housing needs that will be useful to planners, by paying greater heed to social capital in urban regeneration and migrant housing provision. A more inclusive and humanistic approach to the housing of migrants is suggested.

British slaughter-house reformers campaigned to abolish private urban slaughter-houses and establish public abattoirs in the nineteenth century. Abolition of London's private slaughter-houses was motivated by the congestion created by livestock in city streets, the nuisance of slaughter-house refuse in residential neighbourhoods and public health concerns about diseased meat in the food supply. The butchers successfully defended their private slaughter-houses, illustrating the persistence of the craftsman's workshop and the importance of laissez-faire sentiments in opposition to municipalization in Victorian London.

Trends in location, labor force, and procurement practices in maquiladoras are examined using recent data sources. A growing proportion of maquiladoras are selecting interior locations, south of the borderlands. Once dominated by young women, the labor force is rapidly approaching gender parity. While far below prevailing rates in the United States, maquiladora wages are comparable with equivalent manufacturing sectors in Mexico. Majority ownership of maquiladoras is split almost evenly between Mexico and the U.S., however, maquiladoras have failed to develop domestic sources of materials and parts and remain dependent on imported material inputs. As the North American Free Trade Agreement is phased in, the regulatory environment of maquiladoras will change but their role as low cost assembly specialists will persist.

Domestic livestock (defined broadly to include bovines such as cattle and buffalo, swine, horses, sheep, goats, camelids, and poultry) are found in every world region where they may function as draft animals providing a source of primary motive power or as a source of animal products including meat, blood, egg, and dairy foods for human consumption; pharmaceuticals; leather, wool, and feathers; and meat, bone, and blood meal for use as fertilizer and animal feed. The global spread of domestic livestock, mainly from the old world to the new, began as a component of colonial policies to establish self-sustaining settlements in the Americas, Australasia, and South Africa. Facilitated by technological changes in transportation and food preservation, livestock production and meat marketing attained global scope by the late nineteenth century. Rapid growth in meat and dairy product consumption in the late twentieth century and into the first decade of the twenty-first century have so transformed the global production and trade of livestock products that some have described it as a “livestock revolution” (Delgado et al. 1999). Keywords: food; global logistics; international trade

Bovine spongiform encephalopathy (BSE) is an incurable degenerative neurological disorder of cattle that is invariably fatal. It was first identified in 1986 in the United Kingdom and by 1996 it had been associated with a form of the Creutzfeldt-Jakob disease in humans. Though largely concentrated in the United Kingdom, BSE has infected cattle in most of Europe, North America, and Japan, disrupting the international trade of live cattle, beef for human consumption, and beef by-products. BSE has attained global significance by revealing the potential for the intercontinental spread of an infectious animal disease and its implications for risk management, animal health, and human health. Keywords: food; international trade

TPS2621 Background: TKM-080301 is a lipid nanoparticle formulation of a small interfering RNA (siRNA) directed against PLK1, a serine/threonine kinase that regulates multiple critical aspects of cell cycle progression and mitosis. Anti-tumor activity, RNA interference and pharmacodynamic effects of PLK1 inhibition have been conclusively demonstrated in preclinical models. Demonstration of pharmacodynamic effects of PLK1 inhibition in patient biopsy samples is an exploratory objective of this first-in-human study. Methods: TKME080301 is being evaluated in an open-label, non-randomized, dose-escalation study in patients with advanced solid tumors or lymphoma. Sequential cohorts of 3 to 6 patients receive TKME080301 as a 30-minute intravenous infusion on Days 1, 8 and 15 of a 28-day cycle. Treatment can continue until disease progression, based on overall clinical benefit. Tumor response is determined according to RECIST criteria. Primary study objectives include determination of safety, maximum tolerated dose and dose limiting toxicities. Secondary objectives include characterization of pharmacokinetics and the preliminary assessment of anti-tumor activity. Five cohorts have been enrolled and a tentative Phase 2 dose has been identified. An expansion cohort of 10 patients began enrolling in February, 2013. The focus of the expansion cohort will be to collect additional safety and pharmacokinetic data at the tentative Phase 2 dose, as well as pharmacodynamic data from mandatory biopsy samples. Pre- and post-dose biopsy samples will be evaluated for potential evidence of PLK1 inhibition using 5’ RACE (rapid amplification of cDNA ends) polymerase chain reaction (to identify the predicted PLK1 mRNA cleavage product), histology (to assess for the presence of aberrant mitotic figures) and immunohistochemistry. An update on enrollment and pharmacodynamic evaluations will be presented. Clinical trial information: NCT01262235.

Background: Polo-like kinase 1 (PLK1) is a serine/threonine kinase that regulates multiple critical aspects of cell progression. PLK1 is over-expressed in many human tumor types and its over-expression is a negative prognostic indicator of patient outcome in a variety of cancers. TKM-080301 is a lipid nanoparticle formulation of a small interfering RNA (siRNA) directed against PLK1 that has been shown to effect highly selective reductions in PLK1 mRNA in vitro and in tumor xenograft models in mice. Methods: A phase I multi-center, open-label, non-randomized, dose-escalation study of TKM-080301 is ongoing in patients with advanced solid tumors or lymphoma. Sequential cohorts of 3 to 6 patients receive TKM-080301 as a 30-minute IV infusion on Days 1, 8, and 15 of a 28-day cycle. Primary objectives include determination of safety, maximum tolerated dose (MTD) and dose limiting toxicities (DLTs). Secondary objectives include characterization of pharmacokinetics (PK) and preliminary assessment of anti-tumor activity and pharmacodynamic effects. Pre-and post-dose biopsy samples are being collected from patients treated after DLT has been established. Results: Twenty-three (23) patients, receiving a cumulative total of 128 doses, have been treated with TKM-080301 at doses ranging from 0.15 to 0.9 mg/kg/week. The most common drug-related adverse events have been mild-to-moderate infusion related reactions with delayed onset, pyrexia, chills, nausea, vomiting, and fatigue. Mild, transient increases in certain cytokines (e.g., IL-6, IL-8, MCP-1) have been observed at dose levels ≤0.75 mg/kg/week and generally correlated with the timing of delayed infusion reactions. DLTs were observed at 0.9 mg/kg/week and included hypoxia/dyspnea in one patient (with a previous history of asthma) and thrombocytopenia in another patient. The dose level was subsequently reduced to 0.75 mg/kg/week. Pharmacokinetic parameters determined after the first dose in Cycles 1 and 2 demonstrated dose proportional Cmax and AUC and no obvious accumulation. Two patients have received TKM-080301 for at least 6 months (6 cycles) with no evidence of cumulative toxicity, including one patient with stable disease (colon) and one patient with a durable confirmed partial response (carcinoid tumor) who has received 8+ cycles of treatment. Conclusions: Preliminary results from this first-in-human trial indicate TKM-080301 was generally well-tolerated by the majority of patients. Preliminary antitumor efficacy has been observed, supporting PLK1 as a therapeutic target. As two DLTs were observed at the dose of 0.9 mg/kg/week, patient accrual is continuing at the 0.75 mg/kg/week dose level. Citation Format: Ramesh K. Ramanathan, Solomon I. Hamburg, Mitesh J. Borad, Mahesh Seetharam, Madappa N. Kundranda, Peter Lee, Paul Fredlund, Mark Gilbert, Cathy Mast, Sean C. Semple, Adam D. Judge, Brynne Crowell, Linda Vocila, Ian MacLachlan, Donald W. Northfelt. A phase I dose escalation study of TKM-080301, a RNAi therapeutic directed against PLK1, in patients with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-289. doi:10.1158/1538-7445.AM2013-LB-289

Background: We have previously demonstrated the therapeutic effect of lipid nanoparticles (LNP) loaded with single siRNA targeting CSN5 and WEE1 against human HCC in mouse models. Aim: To test the benefit of a combinatorial versus single siRNA therapy in mouse models of human HCC and to identify molecular mechanism(s) involved in therapeutic response by extensive microarray analyses. Materials and Methods: LNP formulations of chemically modified siRNAs targeting CSN5 and WEE1 were produced by Tekmira® Pharmaceuticals. SCID-beige mice were used for subcutaneous (Hep3B) and intra-hepatic (Huh7-luciferase) tumor transplantation. Mice with established tumors were treated intravenously with 4 mg/kg single agent siRNA or 2 mg/kg + 2 mg/kg siCSN5:siWEE1 siRNA co-encapsulated in the same LNP. Tumors were assayed following 1 to 9 injected doses. Tumor progression in the Huh7 orthotopic model was monitored by bioluminescence imaging and metastases were evaluated at endpoint. Results: Significant target silencing was observed in tumors after single or repeat administration with no antagonism between siRNAs occurring in the CSN5:WEE1 combination. We observed significant inhibition of tumor growth and metastases in mice treated with active siRNAs compared to LNP containing a non-targeting control sequence. Potency was not lost with siCSN5:siWEE1 LNP, where the concentration of each siRNA is halved in combination, relative to the most efficacious single agent. Data from preliminary microarray analyses demonstrate a strong transcriptome difference between each treatment group. Conclusion: We demonstrate a clear efficacy of a LNP based combinatorial siRNA therapy in human mouse models of HCC. Overall this therapy led to a significant decrease of tumor size induced by mRNA inhibition Citation Format: Thomas Decaens, Valentina M. Factor, Iva Kulic, Jesper B. Andersen, Daekwan Seo, Yun-Han Lee, Adam D. Judge, Elizabeth A. Conner, Ian MacLachlan, Snorri S. Thorgeirsson. Nanoparticle based combinatorial siRNA therapy against human hepatocellular carcinoma (HCC) . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5661. doi:10.1158/1538-7445.AM2013-5661

Malignancies of the liver, including primary (hepatocellular carcinoma) and secondary (metastatic) tumors, represent a significant unmet medical need. In most patients with liver metastases, extra-hepatic tumors are also present. We are developing a therapeutic for solid tumors that is comprised of lipid particle (SNALP)-formulated small interfering RNAs (siRNAs) targeting VEGF and the mitotic kinesin, KSP (Eg5). For each target, potent siRNA duplexes were selected following extensive screening in tissue culture cells. A SNALP-formulated combination of the KSP and VEGF siRNAs (referred to as ALN-VSP) was tested in orthotopic liver tumor models, as well as models of extra-hepatic tumors. To generate orthotopic liver tumors, human hepatoma (Hep3B) or colorectal carcinoma (HCT116) cells were implanted directly into the livers of immunocompromised mice. These cell lines were also used to establish tumors at extra-hepatic sites including the lymph nodes and peritoneal cavity. Studies in which tumor-bearing mice were treated with ALN-VSP demonstrated that each siRNA makes a distinct contribution to efficacy. ALN-VSP treatment led to accumulation of aberrant mitotic figures (monoasters), a hallmark of KSP inhibition, in both types of orthotopic liver tumors, as well as in extra-hepatic tumors of different origin. Evidence of therapeutic VEGF inhibition was shown by marked reductions in tumor microvessel density and intratumoral hemorrhage in orthotopic tumors. Similar effects on tumor vasculature were obtained with a SNALP formulation of the VEGF siRNA alone. Finally, we demonstrated that multi-dose administration of ALN-VSP significantly prolongs survival of mice harboring advanced orthotopic liver tumors. A Phase 1 clinical trial of ALN-VSP is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4064.

Malignancies of the liver, including primary (hepatocellular carcinoma) and secondary (metastatic) tumors, represent a significant unmet medical need. We are developing a therapeutic for solid tumors involving the liver that is comprised of lipid particle-formulated small interfering RNAs (siRNAs) targeting VEGF and the mitotic kinesin, KSP (Eg5). For each target, potent siRNA duplexes were selected following extensive screening in tissue culture cells. To assess efficacy in vivo, a stable nucleic acid lipid particle (SNALP) formulation was developed based on similar formulations previously shown to silence liver-expressed genes via systemic administration in multiple species. A SNALP-formulated combination of the KSP and VEGF siRNAs (referred to as ALN-VSP) was tested in orthotopic liver tumor models in which human tumor cells are implanted directly into the livers of immunocompromised mice. We show that intravenous administration of ALN-VSP leads to silencing of both KSP and VEGF expression in established liver tumors. This is accompanied by the formation of numerous aberrant mitotic figures (“monoasters”) in tumor cells indicative of the pharmacologic inhibition of KSP. In addition, we demonstrate that ALN-VSP treatment provides a clear survival benefit even when treatment is initiated in animals with a significant tumor burden. A Phase 1 clinical trial of ALN-VSP has recently been initiated. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B204.

3585 Background: Malignancies of the liver, including primary (hepatocellular carcinoma) and secondary (metastatic) tumors, represent a significant unmet medical need. We are developing a therapeutic for solid tumors involving the liver that is comprised of lipid particle-formulated short interfering RNAs (siRNAs) targeting VEGF and the mitotic kinesin, KSP (Eg5). For each target, potent siRNA duplexes were selected following extensive screening in tissue culture cells. Efficacy was demonstrated in a mouse liver tumor model. Methods: To assess efficacy in vivo, a stable nucleic acid lipid particle (SNALP) formulation was developed based on similar formulations previously shown to silence liver-expressed genes via systemic administration in multiple species. A SNALP-formulated combination of the KSP and VEGF siRNAs (referred to as ALN-VSP01) was tested in an orthotopic liver tumor model in which human hepatoma cells (Hep3B) are implanted directly into the livers of immunocompromised mice. Results: Intravenous administration of ALN-VSP01 leads to dose-dependent inhibition of both KSP and VEGF expression in established liver tumors. This was accompanied by the formation of numerous aberrant mitotic figures (“monoasters”) in tumor cells indicative of the pharmacologic inhibition of KSP. In addition, tumor growth was significantly inhibited by a course of ALN-VSP01 treatment, and ALN-VSP01 treatment provided a clear survival benefit even when treatment was initiated in animals with a significant tumor burden. As a control, a SNALP-formulated siRNA targeting Luciferase was administered and shown to have no effect in these studies. Conclusions: Systemic administration of ALN-VSP01 exhibited clear efficacy in a mouse orthotopic liver tumor model. Clinical testing of ALN-VSP01 is expected to initiate in early 2009. [Table: see text]