Local Nodes in Global Networks: The Geography of Knowledge Flows in Biotechnology Innovation

The literature on innovation and interactive learning has tended to emphasize the importance of local networks, inter-firm collaboration and knowledge flows as the principal source of technological dynamism. More recently, however, this view has come to be challenged by other perspectives that argue for the importance of non-local knowledge flows. According to this alternative approach, truly dynamic economic regions are characterized both by dense local social interaction and knowledge circulation, as well as strong inter-regional and international connections to outside knowledge sources and partners. This paper offers an empirical examination of these issues by examining the geography of knowledge flows associated with innovation in biotechnology. We begin by reviewing the growing literature on the nature and geography of innovation in biotechnology research and the commercialization process. Then, focusing on the Canadian biotech industry, we examine the determinants of innovation (measured through patenting activity), paying particular attention to internal resources and capabilities of the firm, as well as local and global flows of knowledge and capital. Our study is based on the analysis of Statistics Canada’s 1999 Survey of Biotechnology Use and Development, which covers 358 core biotechnology firms. Our findings highlight the importance of in-house technological capability and absorptive capacity as determinants of successful innovation in biotechnology firms. Furthermore, our results document the precise ways in which knowledge circulates, in both embodied and disembodied forms, both locally and globally. We also highlight the role of formal intellectual property transactions (domestic and international) in promoting knowledge flows. Although we document the importance of global networks in our findings, our results also reveal the value of local networks and specific forms of embedding. Local relational linkages are especially important when raising capital—and the expertise that comes with it—to support innovation. Nevertheless, our empirical results raise some troubling questions about the alleged pre-eminence of the local in fostering innovation

Development of novel clinical examination scales for the measurement of disease severity in Creutzfeldt-Jakob disease

OBJECTIVE: To use a robust statistical methodology to develop and validate clinical rating scales quantifying longitudinal motor and cognitive dysfunction in sporadic Creutzfeldt-Jakob disease (sCJD) at the bedside. METHODS: Rasch analysis was used to iteratively construct interval scales measuring composite cognitive and motor dysfunction from pooled bedside neurocognitive examinations collected as part of the prospective National Prion Monitoring Cohort study, October 2008-December 2016.A longitudinal clinical examination dataset constructed from 528 patients with sCJD, comprising 1030 Motor Scale and 757 Cognitive Scale scores over 130 patient-years of study, was used to demonstrate scale utility. RESULTS: The Rasch-derived Motor Scale consists of 8 items, including assessments reliant on pyramidal, extrapyramidal and cerebellar systems. The Cognitive Scale comprises 6 items, and includes measures of executive function, language, visual perception and memory. Both scales are unidimensional, perform independently of age or gender and have excellent inter-rater reliability. They can be completed in minutes at the bedside, as part of a normal neurocognitive examination. A composite Examination Scale can be derived by averaging both scores. Several scale uses, in measuring longitudinal change, prognosis and phenotypic heterogeneity are illustrated. CONCLUSIONS: These two novel sCJD Motor and Cognitive Scales and the composite Examination Scale should prove useful to objectively measure phenotypic and clinical change in future clinical trials and for patient stratification. This statistical approach can help to overcome obstacles to assessing clinical change in rapidly progressive, multisystem conditions with limited longitudinal follow-up

Lipid Droplet Membrane Proteome Remodeling Parallels Ethanol-Induced Hepatic Steatosis and its Resolution

Lipid droplets (LDs) are composed of neutral lipids enclosed in a phospholipid monolayer, which harbors membrane-associated proteins that regulate LD functions. Despite the crucial role of LDs in lipid metabolism, remodeling of LD protein composition in disease contexts, such as steatosis, remains poorly understood. We hypothesized that chronic ethanol consumption, subsequent abstinence from ethanol, or fasting differentially affects the LD membrane proteome content and that these changes influence how LDs interact with other intracellular organelles. Here, male Wistar rats were pair-fed liquid control or ethanol diets for 6 weeks, and then, randomly chosen animals from both groups were either refed a control diet for 7 days or fasted for 48 h before euthanizing. From all groups, LD membrane proteins from purified liver LDs were analyzed immunochemically and by MS proteomics. Liver LD numbers and sizes were greater in ethanol-fed rats than in pair-fed control, 7-day refed, or fasted rats. Compared with control rats, ethanol feeding markedly altered the LD membrane proteome, enriching LD structural perilipins and proteins involved in lipid biosynthesis, while lowering LD lipase levels. Ethanol feeding also lowered LD-associated mitochondrial and lysosomal proteins. In 7-day refed (i.e., ethanol-abstained) or fasted-ethanol-fed rats, we detected distinct remodeling of the LD proteome, as judged by lower levels of lipid biosynthetic proteins, and enhanced LD interaction with mitochondria and lysosomes. Our study reveals evidence of significant remodeling of the LD membrane proteome that regulates ethanol-induced steatosis, its resolution after withdrawal and abstinence, and changes in LD interactions with other intracellular organelles

Tanamu 1: A 5000 year sequence from Caution Bay

[Extract] Archaeological sites across Caution Bay often contain distinctive artefactual horizons of varying ages, making it possible to investigate cultural trends at a range of spatial and temporal scales over extended periods of time. Tanamu 1 is a site of particular interest because of its three distinct major occupation horizons that start with the pre-ceramic, followed by Lapita, and end with post-Lapita. The aim of this chapter is to report details of the site, focusing on its chronostratigraphy, so that its various cultural materials (reported in detail in Chapters 3–7) can be examined in context

Lipid droplet membrane proteome remodeling parallels ethanol-induced hepatic steatosis and its resolution

Abstract Lipid droplets (LDs) are composed of neutral lipids enclosed in a phospholipid monolayer, which harbors membrane-associated proteins that regulate LD functions. Despite the crucial role of LDs in lipid metabolism, remodeling of LD protein composition in disease contexts, such as steatosis, remains poorly understood. We hypothesized that chronic ethanol consumption, subsequent abstinence from ethanol, or fasting differentially affects the LD membrane proteome content and that these changes influence how LDs interact with other intracellular organelles. Here, male Wistar rats were pair-fed liquid control or ethanol diets for 6 weeks, and then, randomly chosen animals from both groups were either refed a control diet for 7 days or fasted for 48 h before euthanizing. From all groups, LD membrane proteins from purified liver LDs were analyzed immunochemically and by MS proteomics. Liver LD numbers and sizes were greater in ethanolfed rats than in pair-fed control, 7-day refed, or fasted rats. Compared with control rats, ethanol feeding markedly altered the LD membrane proteome, enriching LD structural perilipins and proteins involved in lipid biosynthesis, while lowering LD lipase levels. Ethanol feeding also lowered LDassociated mitochondrial and lysosomal proteins. In 7-day refed (i.e., ethanol-abstained) or fasted-ethanolfed rats, we detected distinct remodeling of the LD proteome, as judged by lower levels of lipid biosynthetic proteins, and enhanced LD interaction with mitochondria and lysosomes. Our study reveals evidence of significant remodeling of the LD membrane proteome that regulates ethanol-induced steatosis, its resolution after withdrawal and abstinence, and changes in LD interactions with other intracellular organelles

Public attitudes to inequality in water distribution: Insights from preferences for water reallocation from irrigators to Aboriginal Australians

Water allocation regimes that adjudicate between competing uses are in many countries under pressure to adapt to increasing demands, climate‐driven shortages, expectations for equity of access, as well as societal changes in values and priorities. International authorities expound standards for national allocation regimes that include robust processes for addressing the needs of ‘new entrants' and for varying existing entitlements within sustainable limits. The claims of Indigenous peoples to water represents a newly recognised set of rights and interests that will test the ability of allocation regimes to address the global water governance goal of equity. No study has sought to identify public attitudes or willingness to pay for a fairer allocation of water rights between Indigenous and non‐Indigenous people. We surveyed households from the jurisdictions of Australia's Murray‐Darling Basin, a region undergoing a historic government‐led recovery of water, and found that 69.2% of respondents support the principle of reallocating a small amount of water from irrigators to Aboriginal people via the water market. Using contingent valuation, we estimated households are willing to pay A$21.78 in a one‐off levy. The aggregate value calculated for households in the basin's jurisdictions was A$74.5 million, which is almost double a recent government commitment to fund the acquisition of entitlements for Aboriginal nations of this basin. Results varied by state of residency and affinity with environmental groups. An information treatment that presented narrative accounts from Aboriginal people influenced the results. Insights from this study can inform water reallocation processes

Development of prognostic models for survival and care status in sporadic Creutzfeldt-Jakob disease

This is the final version. Available on open access from Oxford University Press via the DOI in this recordData availability: Patient data from the National Prion Monitoring Cohort are owned by University College London. This patient data are not currently publicly available. For researchers interested in accessing this data, further information can be found at https://www.ucl.ac.uk/national-prion-clinic/national-prion-monitoring-cohort-npmc.Sporadic Creutzfeldt-Jakob disease, the most common human prion disease, typically presents as a rapidly progressive dementia and has a highly variable prognosis. Despite this heterogeneity, clinicians need to give timely advice on likely prognosis and care needs. No prognostic models have been developed that predict survival or time to increased care status from the point of diagnosis. We aimed to develop clinically useful prognostic models with data from a large prospective observational cohort study. Five hundred and thirty-seven patients were visited by mobile teams of doctors and nurses from the National Health Service National Prion Clinic within 5 days of notification of a suspected diagnosis of sporadic Creutzfeldt-Jakob disease, enrolled to the study between October 2008 and March 2020, and followed up until November 2020. Prediction of survival over 10-, 30- and 100-day periods was the main outcome. Escalation of care status over the same time periods was a secondary outcome for a subsample of 113 patients with low care status at initial assessment. Two hundred and eighty (52.1%) patients were female and the median age was 67.2 (interquartile range 10.5) years. Median survival from initial assessment was 24 days (range 0-1633); 414 patients died within 100 days (77%). Ten variables were included in the final prediction models: sex; days since symptom onset; baseline care status; PRNP codon 129 genotype; Medical Research Council Prion Disease Rating Scale, Motor and Cognitive Examination Scales; count of MRI abnormalities; Mini-Mental State Examination score and categorical disease phenotype. The strongest predictor was PRNP codon 129 genotype (odds ratio 6.65 for methionine homozygous compared with methionine-valine heterozygous; 95% confidence interval 3.02-14.68 for 30-day mortality). Of 113 patients with lower care status at initial assessment, 88 (78%) had escalated care status within 100 days, with a median of 35 days. Area under the curve for models predicting outcomes within 10, 30 and 100 days was 0.94, 0.92 and 0.91 for survival, and 0.87, 0.87 and 0.95 for care status escalation, respectively. Models without PRNP codon 129 genotype, which is not immediately available at initial assessment, were also highly accurate. We have developed a model that can accurately predict survival and care status escalation in sporadic Creutzfeldt-Jakob disease patients using clinical, imaging and genetic data routinely available in a specialist national referral service. The utility and generalizability of these models to other settings could be prospectively evaluated when recruiting to clinical trials and providing clinical care

The role of clathrin in post-golgi trafficking in toxoplasma gondii

Apicomplexan parasites are single eukaryotic cells with a highly polarised secretory system that contains unique secretory organelles (micronemes and rhoptries) that are required for host cell invasion. In contrast, the role of the endosomal system is poorly understood in these parasites. With many typical endocytic factors missing, we speculated that endocytosis depends exclusively on a clathrin-mediated mechanism. Intriguingly, in Toxoplasma gondii we were only able to observe the endogenous clathrin heavy chain 1 (CHC1) at the Golgi, but not at the parasite surface. For the functional characterisation of Toxoplasma gondii CHC1 we generated parasite mutants conditionally expressing the dominant negative clathrin Hub fragment and demonstrate that CHC1 is essential for vesicle formation at the trans-Golgi network. Consequently, the functional ablation of CHC1 results in Golgi aberrations, a block in the biogenesis of the unique secretory microneme and rhoptry organelles, and of the pellicle. However, we found no morphological evidence for clathrin mediating endocytosis in these parasites and speculate that they remodelled their vesicular trafficking system to adapt to an intracellular lifestyle

Cortactin overexpression results in sustained epidermal growth factor receptor signaling by preventing ligand-induced receptor degradation in human carcinoma cells

The chromosome 11q13 region is frequently amplified in human carcinomas and results in an increased expression of various genes including cortactin, and is also associated with an increased invasive potential. Cortactin acts as an important regulator of the actin cytoskeleton. It is therefore very tempting to speculate that cortactin is the crucial gene within the 11q13 amplicon that mediates the invasive potential of these carcinomas. Cortactin also participates in receptor-mediated endocytosis, and recent findings have shown that, during receptor internalization, cortactin overexpression inhibits the ubiquitylation-mediated degradation of the epidermal growth factor receptor, resulting in a sustained ligand-induced epidermal growth factor receptor activity