Lines of Descent: Kuhn and Beyond

yesThomas S. Kuhn is famous both for his work on the Copernican Revolution and his ‘paradigm’ view of scientific revolutions. But Kuhn later abandoned the notion of paradigm (and related notions) in favour of a more ‘evolutionary’ view of the history of science. Kuhn’s position therefore moved closer to ‘continuity’ models of scientific progress, for instance ‘chain-of-reasoning’ models, originally championed by D. Shapere. The purpose of this paper is to contribute to the debate around Kuhn’s new ‘developmental’ view and to evaluate these competing models with reference to some major innovations in the history of cosmology, from Copernicanism to modern cosmology. This evaluation is made possible through some unexpected overlap between Kuhn’s earlier discontinuity model and various versions of the later continuity models. It is the thesis of this paper that the ‘chain-of-reasoning’ model accounts better for the cosmological evidence than both Kuhn’s early paradigm model and his later developmental view of the history of science

Post translational changes to α-synuclein control iron and dopamine trafficking : a concept for neuron vulnerability in Parkinson's disease

Parkinson's disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson's disease

Whole-body tissue stabilization and selective extractions via tissue-hydrogel hybrids for high-resolution intact circuit mapping and phenotyping

To facilitate fine-scale phenotyping of whole specimens, we describe here a set of tissue fixation-embedding, detergent-clearing and staining protocols that can be used to transform excised organs and whole organisms into optically transparent samples within 1–2 weeks without compromising their cellular architecture or endogenous fluorescence. PACT (passive CLARITY technique) and PARS (perfusion-assisted agent release in situ) use tissue-hydrogel hybrids to stabilize tissue biomolecules during selective lipid extraction, resulting in enhanced clearing efficiency and sample integrity. Furthermore, the macromolecule permeability of PACT- and PARS-processed tissue hybrids supports the diffusion of immunolabels throughout intact tissue, whereas RIMS (refractive index matching solution) grants high-resolution imaging at depth by further reducing light scattering in cleared and uncleared samples alike. These methods are adaptable to difficult-to-image tissues, such as bone (PACT-deCAL), and to magnified single-cell visualization (ePACT). Together, these protocols and solutions enable phenotyping of subcellular components and tracing cellular connectivity in intact biological networks

Minimal Length Scale Scenarios for Quantum Gravity

We review the question of whether the fundamental laws of nature limit our ability to probe arbitrarily short distances. First, we examine what insights can be gained from thought experiments for probes of shortest distances, and summarize what can be learned from different approaches to a theory of quantum gravity. Then we discuss some models that have been developed to implement a minimal length scale in quantum mechanics and quantum field theory. These models have entered the literature as the generalized uncertainty principle or the modified dispersion relation, and have allowed the study of the effects of a minimal length scale in quantum mechanics, quantum electrodynamics, thermodynamics, black-hole physics and cosmology. Finally, we touch upon the question of ways to circumvent the manifestation of a minimal length scale in short-distance physics.Comment: Published version available at http://www.livingreviews.org/lrr-2013-

Vampires in the village Žrnovo on the island of Korčula: following an archival document from the 18th century

Središnja tema rada usmjerena je na raščlambu spisa pohranjenog u Državnom arhivu u Mlecima (fond: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) koji se odnosi na događaj iz 1748. godine u korčulanskom selu Žrnovo, kada su mještani – vjerujući da su se pojavili vampiri – oskvrnuli nekoliko mjesnih grobova. U radu se podrobno iznose osnovni podaci iz spisa te rečeni događaj analizira u širem društvenom kontekstu i prate se lokalna vjerovanja.The main interest of this essay is the analysis of the document from the State Archive in Venice (file: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) which is connected with the episode from 1748 when the inhabitants of the village Žrnove on the island of Korčula in Croatia opened tombs on the local cemetery in the fear of the vampires treating. This essay try to show some social circumstances connected with this event as well as a local vernacular tradition concerning superstitions

Nortriptyline blood levels and clinical outcome: meta-analysis of published studies Níveis sangüíneos de nortriptilina e resposta clínica: metanálise dos estudos publicados

INTRODUCTION: An optimum range has been suggested for nortriptyline blood levels, above or below which patients respond poorly or do not respond at all to treatment. METHODS: A meta-analysis of published studies was performed to verify the existence of an optimal blood concentration range or therapeutic window in nortriptyline-treated depression patients. A MEDLINE search through the years 1970-1999 was carried out to identify original papers and review articles. Data concerning blood levels and percentage improvement were obtained concerning all included pacients. Univariate and multivariate analyses were performed for data comparison. Possible confounding variables, such as pre-treatment, setting (in or outpatients), and duration of treatment were also evaluated. RESULTS: From the 22 published studies found, only six of them with patients' individual data were included. We found an optimal range for nortriptyline concentrations (OR= 2.25, 95% CI = 1.15 to 4.39, p= 0.02). CONCLUSIONS: There may be a biphasic relationship of efficacy to plasma concentrations of nortriptyline, with a therapeutic window between 46 to 236 ng/ml.<br>INTRODUÇÃO: Sugere-se a existência de uma faixa de concentração ótima para os níveis sangüíneos da nortriptilina, acima e abaixo da qual os pacientes não respondem ao tratamento ou o fazem pobremente. MÉTODOS: Realizamos metanálise dos estudos publicados com o propósito de verificar a existência de uma faixa de concentração sangüínea ótima (janela terapêutica) para os pacientes deprimidos tratados com nortriptilina. A busca através do MEDLINE envolvendo os anos de 1970 a 1999 foi realizada com o objetivo de identificar artigos originais e de revisão. Dados sobre níveis sangüíneos e percentagem de melhora foram obtidos. Foram realizadas análises uni e multivariadas para a comparação dos dados. Avaliamos possíveis variáveis de confusão como: período de pré-tratamento, ambiente (hospitalar ou ambulatorial) e duração do tratamento. RESULTADOS: Dos 22 estudos publicados que foram identificados, apenas seis que forneceram os dados individuais dos pacientes foram incluídos. Encontramos uma faixa de concentração ótima para a nortriptilina (OR = 2,25, IC 95% = 1,15 a 4,39, p = 0,02). CONCLUSÕES: É possível que exista uma associação de tipo bifásico entre as concentrações de nortriptilina e a resposta clínica, com uma janela terapêutica entre 46 e 236 ng/ml