Considerations of transcriptional control mechanisms: Do TFIID–core promoter complexes recapitulate nucleosome-like functions?

The general transcription initiation factor TFIID was originally identified, purified, and characterized with a biochemical assay in which accurate transcription initiation is reconstituted with multiple, chromatographically separable activities. Biochemical analyses have demonstrated that TFIID is a multiprotein complex that directs preinitiation complex assembly on both TATA box-containing and TATA-less promoters, and some TFIID subunits have been shown to be molecular targets for activation domains in DNA-binding regulatory proteins. These findings have most commonly been interpreted to support the view that transcriptional activation by upstream factors is the result of enhanced TFIID recruitment to the core promoter. Recent insights into the architecture and cell-cycle regulation of the multiprotein TFIID complex prompt both a reassessment of the functional role of TFIID in gene activation and a review of some of the less well-appreciated literature on TFIID. We present a speculative model for diverse functional roles of TFIID in the cell, explore the merits of the model in the context of published data, and suggest experimental approaches to resolve unanswered questions. Finally, we point out how the proposed functional roles of TFIID in eukaryotic class II transcription fit into a model for promoter recognition and activation that applies to both eubacteria and eukaryotes.

Bacteria are different: Observations, interpretations, speculations, and opinions about the mechanisms of adaptive evolution in prokaryotes

To some extent, the genetic theory of adaptive evolution in bacteria is a simple extension of that developed for sexually reproducing eukaryotes. In other, fundamental ways, the process of adaptive evolution in bacteria is quantitatively and qualitatively different from that of organisms for which recombination is an integral part of the reproduction process. In this speculative and opinionated discussion, we explore these differences. In particular, we consider (i) how, as a consequence of the low rates of recombination, “ordinary” chromosomal gene evolution in bacteria is different from that in organisms where recombination is frequent and (ii) the fundamental role of the horizontal transmission of genes and accessory genetic elements as sources of variation in bacteria. We conclude with speculations about the evolution of accessory elements and their role in the adaptive evolution of bacteria.

Meiosis: how could it work?

A physical connection between homologs is required for reductional segregation at the first division of meiosis. This connection is usually provided by one or a few well-spaced crossovers. A speculative overview of processes leading to formation of these crossovers is presented.

A loop-loop "kissing" complex is the essential part of the dimer linkage of genomic HIV-1 RNA.

RNA-RNA interactions govern a number of biological processes. Several RNAs, including natural sense and antisense RNAs, interact by means of a two-step mechanism: recognition is mediated by a loop-loop complex, which is then stabilized by formation of an extended intermolecular duplex. It was proposed that the same mechanism holds for dimerization of the genomic RNA of human immunodeficiency virus type 1 (HIV-1), an event thought to control crucial steps of HIV-1 replication. However, whereas interaction between the partially self-complementary loop of the dimerization initiation site (DIS) of each monomer is well established, formation of the extended duplex remained speculative. Here we first show that in vitro dimerization of HIV-1 RNA is a specific process, not resulting from simple annealing of denatured molecules. Next we used mutants of the DIS to test the formation of the extended duplex. Four pairs of transcomplementary mutants were designed in such a way that all pairs can form the loop-loop "kissing" complex, but only two of them can potentially form the extended duplex. All pairs of mutants form heterodimers whose thermal stability, dissociation constant, and dynamics were analyzed. Taken together, our results indicate that, in contrast with the interactions between natural sense and antisense RNAs, no extended duplex is formed during dimerization of HIV-1 RNA. We also showed that 55-mer sense RNAs containing the DIS are able to interfere with the preformed HIV-1 RNA dimer.

Rotation of subunits during catalysis by Escherichia coli F1-ATPase.

During oxidative and photo-phosphorylation, F0F1-ATP synthases couple the movement of protons down an electrochemical gradient to the synthesis of ATP. One proposed mechanistic feature that has remained speculative is that this coupling process requires the rotation of subunits within F0F1. Guided by a recent, high-resolution structure for bovine F1 [Abrahams, J. P., Leslie, A. G., Lutter, R. & Walker, J. E. (1994) Nature (London) 370, 621-628], we have developed a critical test for rotation of the central gamma subunit relative to the three catalytic beta subunits in soluble F1 from Escherichia coli. In the bovine F1 structure, a specific point of contact between the gamma subunit and one of the three catalytic beta subunits includes positioning of the homolog of E. coli gamma-subunit C87 (gamma C87) close to the beta-subunit 380DELSEED386 sequence. A beta D380C mutation allowed us to induce formation of a specific disulfide bond between beta and gamma C87 in soluble E. coli F1. Formation of the crosslink inactivated beta D380C-F1, and reduction restored full activity. Using a dissociation/reassembly approach with crosslinked beta D380C-F1, we incorporated radiolabeled beta subunits into the two noncrosslinked beta-subunit positions of F1. After reduction of the initial nonradioactive beta-gamma crosslink, only exposure to conditions for catalytic turnover results in similar reactivities of unlabeled and radiolabeled beta subunits with gamma C87 upon reoxidation. The results demonstrate that gamma subunit rotates relative to the beta subunits during catalysis.

Efeitos do treinamento de força no músculo esquelético em ratos com caquexia induzida pelo câncer

A ausência de terapias eficazes para a caquexia permanece como um problema central para o tratamento do câncer no mundo. Em contrapartida, o treinamento de força (i.e. também conhecido como treinamento resistido) tem sido amplamente utilizado como uma estratégia não farmacológica anticatabólica, prevenindo a perda da massa e da função da musculatura esquelética. Entretanto, o papel terapêutico do treinamento de força na caquexia do câncer permanece apenas especulativo. Portanto, nesse estudo avaliamos se o treinamento de força poderia atenuar a perda da massa e da função da musculatura esquelética em um severo modelo de caquexia do câncer em ratos. Para isso, ratos machos da linhagem Wistar foram randomizados em quatro grupos experimentais: 1) ratos sedentários injetados com solução salina na medula óssea (Controle); 2) ratos injetados com solução salina na medula óssea e submetidos ao treinamento de força (Controle + T); 3) ratos sedentários injetados com células do tumor Walker 256 na medula óssea (Tumor); e 4) ratos injetados com células do tumor Walker 256 na medula óssea e submetidos ao treinamento de força (Tumor + T). Foram avaliados a massa e a área de secção transversa da musculatura esquelética, marcadores de disfunção metabólica e do turnover proteico, a função da musculatura esquelética in vivo e ex vivo, o consumo alimentar, o crescimento tumoral e a sobrevida dos grupos experimentais com tumor. O grupo Tumor apresentou atrofia muscular após quinze dias da injeção das células tumorais como pode ser observado pela redução na massa dos músculos Plantaris (- 20,5%) e EDL (-20%). A atrofia no músculo EDL foi confirmada por análises histológicas, demonstrando uma redução de 43,8% na área de secção transversa. Embora o treinamento de força tenha aumentado o conteúdo proteico da lactato desidrogenase e revertido totalmente o conteúdo da forma fosforilada de 4EBP-1 (i.e. repressor da transcrição de mRNA), ele não atuou na morfologia da musculatura esquelética nos animais com tumor. Além disso, o treinamento de força não atenuou a perda de função da musculatura esquelética, a anorexia, o crescimento tumoral ou a taxa de mortalidade. Contudo, a força muscular, avaliada pelo teste de 1RM, apresentou uma correlação negativa com a sobrevida dos animais (p = 0,02), sugerindo que a perda de força prediz a mortalidade nesse modelo experimental de caquexia do câncer. Em suma, a injeção de células do tumor Walker 256 na medula óssea induz caquexia do câncer em ratos. O treinamento de força não foi eficaz em atenuar a perda de massa e função da musculatura esquelética nesse modelo. Entretanto, a força muscular prediz a sobrevida dos animais, sugerindo que novos estudos são necessários para elucidar o possível efeito terapêutico do treinamento de força para atenuar a caquexia do câncer e a progressão tumoral

The future imagined: Exploring fiction as a means of reflecting on today’s Grand Societal Challenges and tomorrow’s options

European science policy (so-called Horizon 2020) is guided by Grand Societal Challenges (GSCs) with the explicit aim of shaping the future. In this paper we propose an innovative approach to the analysis and critique of Europe’s GSCs. The aim is to explore how speculative and creative fiction offer ways of embodying, telling, imagining, and symbolising ‘futures’, that can provide alternative frames and understandings to enrich the grand challenges of the 21st century, and the related rationale and agendas for ERA and H2020. We identify six ways in which filmic and literary representations can be considered creative foresight methods (i.e. through: creative input, detail, warning, reflection, critique, involvement) and can provide alternative perspectives on these central challenges, and warning signals for the science policy they inform. The inquiry involved the selection of 64 novels and movies engaging with notions of the future, produced over the last 150 years. Content analysis based on a standardised matrix of major themes and sub-domains, allows to build a hierarchy of themes and to identify major patterns of long-lasting concerns about humanity’s future. The study highlights how fiction sees oppression, inequality and a range of ethical issues linked to human and nature’s dignity as central to, and inseparable from innovation, technology and science. It concludes identifying warning signals in four major domains, arguing that these signals are compelling, and ought to be heard, not least because elements of such future have already escaped the imaginary world to make part of today’s experience. It identifies areas poorly defined or absent from Europe's science agenda, and argues for the need to increase research into human, social, political and cultural processes involved in techno-science endeavours.

Russia in Crisis: Year One. OSW Report, January 2010

Economic conditions which had favoured Russia’s development suddenly changed in mid-2008. The Russian economy was hit, on the one hand, by a drastic slump in oil prices (which fell from nearly US$150 to US$50 between July 2008 and January 2009), and on the other by the outflow of investors (a net of US$130 billion of capital left Russia in the fourth quarter of 2008). Within several months, the financial crisis became an economic crisis affecting the entire economy. The financial reserves accumulated in times of prosperity (more than US$162 billion in the stabilisation funds and nearly US$598 billion in the currency and gold reserve) alleviated the negative impact of the crisis, although this failed to prevent the deep declines in macroeconomic indicators. Russia is one of the states most severely affected by the crisis. In the first half of 2009, its GDP fell by 10.4% compared to the same period in the previous year, while industrial production dropped by nearly 15%, and a decrease in investments of over 18% was reported. The poor economic performance has strongly affected the Russian budget, which reported a deficit for the first time in ten years in 2009. During the first year of the crisis (August 2008 – September 2009), Russia’s financial reserves were seriously reduced as a result of the government’s anti-crisis policy and interventions from the central bank: the reserve fund decreased by nearly 45% to US$76 billion, and the central bank’s reserves shrunk by nearly US$200 billion to US$409 billion. Meanwhile, however, the money in the National Welfare Fund, which had been intended almost entirely to subsidise the Pensions Fund between 2010 and 2015, rose almost three-fold (to US$90 billion). According to government forecasts, the money from the reserve fund is also supposed to be spent fully in 2010. The financial crisis has triggered a dynamic outflow of capital from the Russian market. So-called speculative capital was the first to demonstrate the lack of confidence in the Russian market. In the first half of 2009, the growth rate of long-term investments also decreased noticeably, although no spectacular withdrawal of direct investments from Russia has been observed. The economic crisis has also halted the foreign expansion of Russian private capital, while state-owned capital strengthened its position as an investor. Russia’s raw materials companies continue to be the main category of foreign investors; however, new technologies are gaining prominence as the second main direction of Russian investments.

The end of an overlooked European currency war. CEPS Commentary, 21 January 2015

On January 15th the Swiss National Bank (SNB) abandoned the efforts it had taken since September 2011 to ensure that the Swiss franc/euro exchange rate would not fall below 1.2 Swiss francs per euro. The Swiss franc appreciated immediately by almost 20% (after a temporary overshot of an even larger amount).The justification was that speculative capital flows induced by the euro crisis were driving the Swiss franc above its equilibrium value. Daniel Gros draws some important general lessons in this Commentary from the Swiss case and finds that the move by the SNB to stop its interventions will have an important impact on the euro-area economy.

Clay and smectite content in sediment core CRP-3

The Cenozoic sediments of the CRP-3 drill core from the continental shelf of McMurdo Sound in Ross Sea, Pacific sector of the Southern Ocean, have been investigated for their clay mineral assemblages, especially for the smectite abundances, concentrations and crystallinities. The assemblages of CRP-3 are very different from those of the CRP-1 and CRP-2/2A drill cores. Thus, an almost monomineralic assemblage characterizes the sequence below 330 mbsf. This assemblage is made of well-crystallized smectite with probably authigenic origin between 800 mbsf and 625 mbsf. From 625 mbsf to 330 mbsf the assemblage consists of moderately crystallized smectite that, at least in part, seems to be of detrital origin and thus indicates weathering under a relatively warm and wet climate. In the interval 330-145 mbsf, smectite concentrations fluctuate between 50% and 100% and probably document alternating phases of chemical weathering under a warm and wet climate and physical weathering under a relatively cool and dry climate. Above 145 mbsf the smectite decreases dramatically to concentrations of about 20% and becomes poorly crystalline. In contrast, illite and chlorite become more abundant. Such an assemblage is typical for early Oligocene and younger sediments in McMurdo Sound and reflects physical weathering conditions under a cool climate on a glaciated Antarctic continent. Correlations of the changes in the clay mineral spectrum of CRP-3 with other cores from McMurdo Sound and from other parts of the Southern Ocean has to remain speculative at this stage, because of the poor age control.

The progress of the intellect : as exemplified in the religious development of the Greeks and Hebrews /

Includes bibliographical references.

Die italienische philosophie des neunzehnten jahrhunderts /

Each volume has also special t.-p.

The collected writings of Thomas De Quincey,

Title within ornamental borders.

Philosophie des Geistes : oder Encyklopädie der gesammten Geisteslehre.

1. abth. Ontologische und psychologische betrachtung des geistes.--2. abth. Pragmatologie des geistes, philosophie der geschichte und speculative theologie.

Uber Gegensatz, Wendepunkt und Zeil heutiger Philosophie /

The second or speculative portion was published as a distinct work, entitled, Grundzüge zum Systeme der Philosophie.