James Anderson (1812-1867)

... In 1831, James left Britain as an apprentice with the Hudson's Bay Company. For 20 years he served with energy, judgement, and business acumen in the James Bay, Lake Superior, and Athabasca areas. Then-Governor George Simpson entrusted him with the remote and valuable Mackenzie District. He improved profits by better book-keeping and retrenchment on the upper Yukon basin. His preference was to open trade directly with the Inuit via the Anderson River north of Fort Good Hope. Suddenly, in 1855, he was ordered to take part in the search for John Franklin's expedition. The Admiralty had wearied of the expensive probing of the arctic islands, but Dr. Rae of the Hudson's Bay Company had reported finding relics while surveying Boothia Peninsula. Inuit had told him of white men perishing on an island west of a great river. This was obviously the river down which Captain Back and Dr. King had taken a York Boat in 1834. Now the British government asked the Company to use the same route to check out Rae's report. Simpson had confidence that Anderson would see the matter through without creating new disasters. ... Because he could not carry enough supplies to overwinter, Anderson had to accomplish his mission in the short interval between breakup and the onset of the next winter. On Indian advice to bypass frozen lakes, he chose a new, more direct mountain portage route from Great Slave Lake. Solid ice on Lake Aylmer put him 12 days behind the schedule of Captain Back, whose carefully mapped route he joined at that point. ... On July 31, only two days later than Back, Anderson entered Chantrey Inlet. It was choked with wind-driven floes, and the fragile canoes could not operate as icebreakers. When the men managed to reach Montreal Island, they began finding wood and metal fragments along the shore and in Inuit caches. One chip bore the name "Mr. Stanley" of the Erebus. Using an inflatable rubber raft, three men pushed on to Maconochie Island. ... Anderson, with a true instinct, wanted to search Cape Richardson but was prevented by a "millstream" of jagged ice. Had he done so, he would have encountered, a scant eight kilometres to the west in a cul-de-sac later known as Starvation Cove, the last encampment of the Franklin expedition. Instead, he packed up the raft in the canoes, which had been repaired and regummed, and gave the order to return. Not until 1962 was the whole Back River canoed and kayaked again. ... Anderson's official report was brief and restrained. He had found no papers or bodies and could merely confirm Rae's statement that the disaster had occurred somewhere northwest of the Back. ... Anderson's health had been undermined by the trip. After three more years as chief factor in the Mackenzie District, he asked to be transferred. At Mingan on the St. Lawrence, he straightened out the account books and entertained the governor-general with salmon fishing. He finally retired, as a country squire, to Ontario, where his children were entering the professions. James Anderson's service to the Company was exemplary, and he narrowly missed fame at Starvation Cove. Altogether, he was a fine frontiersman - Canadian style

Land, Labour and Cattle: The Political Economy of Zululand, c. 1930-1950.

Abstract not provided

Rethinking path creation: a geographical political economy approach

A burgeoning strand of evolutionary economic geography (EEG) research is addressing questions of regional path creation, based on the idea that place-specific legacies and conditions play a critical role in supporting the emergence of new economic activities. Yet there has been little effort thus far to take stock of this emerging body of research. In response, the aims of this article are to offer a fresh synthesis of recent work and to develop a broader theoretical framework to inform future research. First, it presents a critical appraisal of the state of the art in path creation research. In an effort to address identified gaps in EEG research, this incorporates insights from sociological perspectives, the global production networks approach, and transition studies. Second, the article’s development of a systematic theoretical framework is based on the identification of key dimensions of path creation and their constitutive interrelations. This contribution is underpinned by a geographical political economy (GPE) approach that provides the ontological basis for the integration of the five key dimensions of path creation within an overarching framework and the positioning of regional processes in relation to the broader dynamics of uneven development. Informed by GPE, the argument is that knowledgeable actors, operating within multiscalar institutional environments, create paths through the strategic coupling of regional and extraregional assets to mechanisms of path creation and associated markets. To inform further research, the article outlines four concrete propositions regarding the operation of path creation processes in different types of regions and explores these through case studies of Berlin and Pittsburgh

Regulation of Transforming Growth Factor-β1–driven Lung Fibrosis by Galectin-3

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic dysregulated response to alveolar epithelial injury with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. Galectin-3 is a beta-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies. Objectives: To examine the role of galectin-3 in pulmonary fibrosis. Methods: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung fibrosis. Further mechanistic studies were performed in vitro and on samples from patients with IPF. Measurements and Main Results: Transforming growth factor (TGF)-beta and bleomycin-induced lung fibrosis was dramatically reduced in mice deficient in galectin-3, manifest by reduced TGF-beta 1 induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of beta-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of galectin -3, TD139, blocked TGF-beta-induced beta-catenin activation in vitro and in vivo and attenuated the late-stage progression of lung fibrosis after bleomycin. There was increased expression of galectin-3 in the bronchoalveolar lavage fluid and serum from patients with stable IPF compared with nonspecific interstitial pneumonitis and controls, which rose sharply during an acute exacerbation suggesting that. galectin-3 may be a marker of active fibrosis in IPF and that strategies that block galectin-3 may be effective in treating acute fibrotic exacerbations of IPF. Conclusions: This study identifies galectin-3 as an important regulator of lung fibrosis and provides a proof of principle for galectin-3 inhibition as a potential novel therapeutic strategy for IPF

On mitigating the analytical limitations of finely stratified experiments

Although attractive from a theoretical perspective, finely stratified experiments such as paired designs suffer from certain analytical limitations that are not present in block-randomized experiments with multiple treated and control individuals in each block. In short, when using a weighted difference in means to estimate the sample average treatment effect, the traditional variance estimator in a paired experiment is conservative unless the pairwise average treatment effects are constant across pairs; however, in more coarsely stratified experiments, the corresponding variance estimator is unbiased if treatment effects are constant within blocks, even if they vary across blocks. Using insights from classical least squares theory, we present an improved variance estimator that is appropriate in finely stratified experiments. The variance estimator remains conservative in expectation but is asymptotically no more conservative than the classical estimator and can be considerably less conservative. The magnitude of the improvement depends on the extent to which effect heterogeneity can be explained by observed covariates. Aided by this estimator, a new test for the null hypothesis of a constant treatment effect is proposed. These findings extend to some, but not all, superpopulation models, depending on whether the covariates are viewed as fixed across samples

Population Genomics of the Immune Evasion (var) Genes of Plasmodium falciparum

Var genes encode the major surface antigen (PfEMP1) of the blood stages of the human malaria parasite Plasmodium falciparum. Differential expression of up to 60 diverse var genes in each parasite genome underlies immune evasion. We compared the diversity of the DBLα domain of var genes sampled from 30 parasite isolates from a malaria endemic area of Papua New Guinea (PNG) and 59 from widespread geographic origins (global). Overall, we obtained over 8,000 quality-controlled DBLα sequences. Within our sampling frame, the global population had a total of 895 distinct DBLα “types” and negligible overlap among repertoires. This indicated that var gene diversity on a global scale is so immense that many genomes would need to be sequenced to capture its true extent. In contrast, we found a much lower diversity in PNG of 185 DBLα types, with an average of approximately 7% overlap among repertoires. While we identify marked geographic structuring, nearly 40% of types identified in PNG were also found in samples from different countries showing a cosmopolitan distribution for much of the diversity. We also present evidence to suggest that recombination plays a key role in maintaining the unprecedented levels of polymorphism found in these immune evasion genes. This population genomic framework provides a cost effective molecular epidemiological tool to rapidly explore the geographic diversity of var genes

"Preferred reading" of Legal Texts

In the 1970s, British cultural theorist Stuart Hall introduced a concept known as preferred reading. It combines the ideological influence of mass media and dominant ways of understanding any text. This article focuses on mass media as a source of ideological background or context of legal interpretation and of any reading of legal texts. Law operates in culture and culture represents limitations in the law, according to the needs of dominant ideology. Culture introduces structures of domination which manipulate law. An important role is also given to popular culture and mass culture. These parts of the culture industry create borders in which the recipients (audience) think of law. Through mass media – rather than through other channels – dominant ideology infiltrates law. Legal consciousness is formed by dominant cultural frames formed by dominant ideology. Through this formation of mass media, law becomes a commodity. It shares the same values or contents as that of cultural industry and is the place where the theory of preferred reading can be introduced. According to the aforementioned theory, there are methods of interpretation that are more accurate than others are. This is simply because they lead to a result that is more preferred by ‘common opinion’ disseminated by mass culture.V roce 1970, britský kulturní teoretik Stuart Hall představil koncept známý jako preferovaného čtení. Ten v sobě spojuje ideologický vliv masových médií a dominantní způsoby chápání jakéhokoli textu. Tento článek se zaměřuje masová média jako zdroj ideologického pozadí nebo kontextu právního výkladu. Právo působí v kultuře a kultura představuje omezení právo dle potřeb dominantní ideologie. Kultura vytváří struktury dominace, které manipulují právem. Důležitou roli také sehrává populární a masová kultura. Tyto části kulturního průmyslu vytváří hranice, ve kterých příjemci (publikum) uvažují o právu. Prostřednictvím masových médií - spíše než prostřednictvím jiných kanálů - dominantní ideologie infiltruje právo. Právní vědomí je tvořeno dominantními kulturními rámci vytvořenými dominantní ideologií. Prostřednictvím této formace vytvářené masovými médii se právo stává komoditou. Sdílí proto stejné hodnoty, nebo obsah jaké definuje kulturní průmysl. Proto lze i v právním kontextu uvažovat o tzv. preferovaném čtení. Proto lze identifikovat paradigmata výkladu, které jsou mnohem "použeitelnější" než jiné, protože vedou k očekávaným výsledkům. K výsledkům, které odpovídají očekávání masového publika.In the 1970s, British cultural theorist Stuart Hall introduced a concept known as preferred reading. It combines the ideological influence of mass media and dominant ways of understanding any text. This article focuses on mass media as a source of ideological background or context of legal interpretation and of any reading of legal texts. Law operates in culture and culture represents limitations in the law, according to the needs of dominant ideology. Culture introduces structures of domination which manipulate law. An important role is also given to popular culture and mass culture. These parts of the culture industry create borders in which the recipients (audience) think of law. Through mass media – rather than through other channels – dominant ideology infiltrates law. Legal consciousness is formed by dominant cultural frames formed by dominant ideology. Through this formation of mass media, law becomes a commodity. It shares the same values or contents as that of cultural industry and is the place where the theory of preferred reading can be introduced. According to the aforementioned theory, there are methods of interpretation that are more accurate than others are. This is simply because they lead to a result that is more preferred by ‘common opinion’ disseminated by mass culture

Alternatively activated macrophages promotes necrosis resolution following acute liver injury

Background & Aim Following acetaminophen (APAP) overdose, acute liver injury (ALI) can occur in patients that present too late for N-acetylcysteine treatment, potentially leading to acute liver failure, systemic inflammation, and death. Macrophages influence the progression and resolution of ALI due to their innate immunological function and paracrine activity. Syngeneic primary bone marrow-derived macrophages (BMDMs) were tested as a cell-based therapy in a mouse model of APAP-induced ALI (APAP-ALI). Methods Several phenotypically distinct BMDM populations were delivered intravenously to APAP-ALI mice when hepatic necrosis was established, and then evaluated based on their effects on injury, inflammation, immunity, and regeneration. In vivo phagocytosis assays were used to interrogate the phenotype and function of alternatively activated BMDMs (AAMs) post-injection. Finally, primary human AAMs sourced from healthy volunteers were evaluated in immunocompetent APAP-ALI mice. Results BMDMs rapidly localised to the liver and spleen within 4 h of administration. Injection of AAMs specifically reduced hepatocellular necrosis, HMGB1 translocation, and infiltrating neutrophils following APAP-ALI. AAM delivery also stimulated proliferation in hepatocytes and endothelium, and reduced levels of several circulating proinflammatory cytokines within 24 h. AAMs displayed a high phagocytic activity both in vitro and in injured liver tissue post-injection. Crosstalk with the host innate immune system was demonstrated by reduced infiltrating host Ly6Chi macrophages in AAM-treated mice. Importantly, therapeutic efficacy was partially recapitulated using clinical-grade primary human AAMs in immunocompetent APAP-ALI mice, underscoring the translational potential of these findings. Conclusion We identify that AAMs have value as a cell-based therapy in an experimental model of APAP-ALI. Human AAMs warrant further evaluation as a potential cell-based therapy for APAP overdose patients with established liver injury. Lay summary After an overdose of acetaminophen (paracetamol), some patients present to hospital too late for the current antidote (N-acetylcysteine) to be effective. We tested whether macrophages, an injury-responsive leukocyte that can scavenge dead/dying cells, could serve as a cell-based therapy in an experimental model of acetaminophen overdose. Injection of alternatively activated macrophages rapidly reduced liver injury and reduced several mediators of inflammation. Macrophages show promise to serve as a potential cell-based therapy for acute liver injury

An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade

A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non-small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3-/- mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/ Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3-/- mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8 + T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNγ, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers. Significance: A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade