‘Down-shifting’ among top UK scientists? – The decline of ‘revolutionary science’ and the rise of ‘normal science’ in the UK compared with the USA

It is sometimes asserted that UK science is thriving, at other times that it has declined. We suggest that both assertions are partly true because the UK is thriving with respect to the volume of 'normal' science production but at the same time declining in the highest level of 'revolutionary' science. Revolutionary science may be distinguished from normal science in that revolutionary science aims at generating qualitative advances which change the direction of established science, while 'normal' science aims at incremental progress extrapolating from established science. Revolutionary science has been measured by counting national numbers of science Nobel laureates and ISI Highly Cited (HiCi) scientists; normal science has been measured using the total volume of scientific publications and citations at both national and institutional levels. By these criteria the UK has been progressively catching-up with the USA in terms of normal science since the 1990s. At the same time the UK has declined in revolutionary science over recent decades by a significant brain drain of future Nobel laureates and HiCi scientists, and a sharply reduced success (both in absolute and compared with the USA) at winning science Nobel prizes. One possible cause for this pattern could be a time-lag, such that the UK's improved science production since about 1990 may eventually work-through into improved UK performance in revolutionary science. More pessimistically, this pattern may reflect a strategic down-shift of the best UK-resident scientists away from revolutionary science and towards less-ambitious and safer normal science which is more productive in the short term.     

Effect of classic convulsants on Cl<Superscript>−</Superscript> conductance of the GABA<Subscript>A</Subscript> receptor complex in membranes of cerebral cortex cells at the early stage of kindling

Muscimol-stimulated Cl- conductance of synaptoneurosomes from the cerebral cortex of Wistar rats increased during the early stage of pharmacological kindling not inducing the seizure response in animals. Picrotoxin, bicuculline, and pentylenetetrazole potentiated inhibition of muscimol-dependent 36Cl- entry into synaptoneurosomes, which attested to increased sensitivity of the GABA(A) receptor/Cl- ionophore complex to classic convulsants.     

Cl<Superscript>−</Superscript> conduction of GABA<Subscript>A</Subscript> receptor complex of synaptic membranes in the cortex of rats at the middle stage of chronic cerebral epileptization (pharmacological kindling)

Experiments on Wistar rats showed a decrease in basal and muscimol-stimulated ³⁶Cl⁻ entry into synaptoneurosomes isolated from the cerebral cortex during the middle stage of kindling (30 mg/kg pentylenetetrazole intraperitoneally for 14 days) characterized by the development of convulsions of higher (2 points) severity in comparison with the previous stage. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 11, pp. 507–509, November, 2007     

“The seven sins” of the Hebbian synapse: Can the hypothesis of synaptic plasticity explain long-term memory consolidation?

Memorizing new facts and events means that entering information produces specific physical changes within the brain. According to the commonly accepted view, traces of memory are stored through the structural modifications of synaptic connections, which result in changes of synaptic efficiency and, therefore, in formations of new patterns of neural activity (the hypothesis of synaptic plasticity). Most of the current knowledge on learning and initial stages of memory consolidation ("synaptic consolidation") is based on this hypothesis. However, the hypothesis of synaptic plasticity faces a number of conceptual and experimental difficulties when it deals with potentially permanent consolidation of declarative memory ("system consolidation"). These difficulties are rooted in the major intrinsic self-contradiction of the hypothesis: stable declarative memory is unlikely to be based on such a non-stable foundation as synaptic plasticity. Memory that can last throughout an entire lifespan should be "etched in stone." The only "stone-like" molecules within living cells are DNA molecules. Therefore, I advocate an alternative, genomic hypothesis of memory, which suggests that acquired information is persistently stored within individual neurons through modifications of DNA, and that these modifications serve as the carriers of elementary memory traces.     

The effects of quercetin on the gene expression of the GABA<Subscript>A</Subscript> receptor α5 subunit gene in a mouse model of kainic acid-induced seizure

The flavonoid quercetin has recently been reported to have neuroprotective effects, and the role of the gamma-aminobutyric acid A alpha 5 subunit (GABA_A α5) receptor has been determined in some nervous system disorders. The aim of this study was to identify the molecular mechanism of the effect of quercetin administered at anticonvulsive doses on the expression of the GABA_A α5 receptor gene in kainic acid (KA)-induced seizures in mice. The experimental animals were divided into four groups: control, KA, and KA + quercetin at 50 or 100 mg/kg, respectively. The results showed a dose-dependent reduction in the behavioral seizure score with quercetin pre-treatment in the KA mouse model. Two hours after the end of the 7-day treatment regimen, expression of the GABA_A α5 receptor gene in the hippocampus was found to be increased in the KA group, but this increase was reduced in the KA + quercetin 50 or 100 mg/kg treatment groups. These results suggest that expression of the GABA_A α5 receptor could be a mechanism for reducing seizure severity or may be a marker of seizure severity. Further studies are necessary to clarify quercetin’s mechanism of action and the relation of GABA_A α5 receptor gene expression to seizure severity.     

Evaluation of the Interaction Between TGF <Emphasis Type="Italic">β</Emphasis> and Nitric Oxide in the Mechanisms of Progression of Colon Carcinoma

It is recognised that stromal cells determine cancer progression. We have previously shown that active TGFβ produced by rat colon carcinoma cells modulated NO production in rat endothelial cells. To elucidate the role of TGFβ and NO in the mechanisms of interaction of colon carcinoma cells with stromal cells and in cancer progression, we transfected REGb cells, a regressive colon carcinoma clone secreting latent TGFβ, with a cDNA encoding for a constitutively-secreted active TGFβ. Out of 20 injected rats only one tumour progressed, which was resected and sub-cultured (ReBeta cells). ReBeta cells secreted high levels of active TGFβ. The adhesive properties of REGb and Rebeta cells to endothelial cells were similar, showing that the secretion of active TGFβ is not involved in tumour cell adhesion to endothelial cells. ReBeta, but not REGb, cell culture supernatants inhibited cytokine-dependent NO secretion by endothelial cells, but inhibition of NO production was similar in co-cultures of REGb or ReBeta cells with endothelial cells. Therefore, secretion of active TGFβ regulated endothelial NO synthase activity when tumour cells were distant from, but not in direct contact with, endothelial cells. However, only ReBeta cells inhibited cytokine-dependent secretion of NO in coculture with macrophages, indicating that the active-TGFβ–NO axis confers an advantage for tumour cells in their interaction with macrophages rather than endothelial cells in cancer progression.     

What is the Contribution of Counter‐Ions to the Absolute Molar Mass of Polyelectrolytes Determined by SEC‐MALLS?

In this work, the absolute molar mass of well‐defined cationic polyelectrolytes has been determined by size‐exclusion chromatography multiangle laser light scattering (SEC‐MALLS) using different eluents containing different counter‐ions (chloride, bromide or trifluoroacetate). Narrowly polydisperse poly‐l ‐lysines of different degrees of polymerization (from 20 up to ≈400) having a counter‐ion similar to the eluent are analyzed as model compounds. By comparing the average degree of polymerization obtained by SEC‐MALLS with those derived independently from NMR/viscosity experiments, it has been possible to investigate what is the average molar mass of the charged monomer that is measured in SEC‐MALLS experiments. The main result of this study is that the average molar mass of the charged monomer in a SEC‐MALLS experiment only takes into account the fraction of condensed counter‐ion associated to the monomer. This fundamental study is important in practice because the calculation of the degree of polymerization (instead of the molar mass) is often required for subsequent chemical reactions, for instance in the case of polymer functionalization.

     

Oxygen inhibits—even though in traces—the hatching of the eggs of the liver fluke <Emphasis Type="Italic">Dicrocoelium dendriticum</Emphasis> R

A chamber was constructed to investigate the influence of gaseous surroundings on the hatching of Dicrocoelium eggs (Fig. 1). It was found that the exclusion of even traces of oxygen is the prerequisite for successful hatching. Oxygen was removed by baker’s yeast suspensions as well as by dithionite solutions. Hatching rates reached a maximum when the carbon dioxide content of the chamber ranged between 0.1% and 4%. Under natural hatching conditions within the intestine of the pulmonate intermediate hosts, bacteria ensure oxygen consumption and carbon dioxide production. The consequence is the hatching of Dicrocoelium eggs. Carbon monoxide also stimulates hatching in the presence of oxygen and therefore seems to block the inhibition mechanism, which is based on oxygen acting. The hatching of eggs started about 5 min after exposure to hatching conditions and continued over a period of 60–90 min. The experiments were occasionally carried out in 1974–1978 at the following institutes of the University of Hamburg: Zoologisches Institut und Zoologisches Museum, and Institut für Organische Chemie und Biochemie, Abt. Biochemie.     

The mechanobiological aetiopathogenesis of tendinopathy: is it the over‐stimulation or the under‐stimulation of tendon cells?

While there is a significant amount of information available on the clinical presentation(s) and pathological changes associated with tendinopathy, the precise aetiopathogenesis of this condition remains a topic of debate. Classically, the aetiology of tendinopathy has been linked to the performance of repetitive activities (so-called overuse injuries). This has led many investigators to suggest that it is the mechanobiologic over-stimulation of tendon cells that is the initial stimulus for the degradative processes which have been shown to accompany tendinopathy. Although several studies have been able to demonstrate that the in vitro over-stimulation of tendon cells in monolayer can result in a pattern(s) of gene expression seen in clinical cases of tendinopathy, the strain magnitudes and durations used in these in vitro studies, as well as the model systems, may not be clinically relevant. Using a rat tail tendon model, we have studied the in vitro mechanobiologic response of tendon cells in situ to various tensile loading regimes. These studies have led to the hypothesis that the aetiopathogenic stimulus for the degenerative cascade which precedes the overt pathologic development of tendinopathy is the catabolic response of tendon cells to mechanobiologic under-stimulation as a result of microscopic damage to the collagen fibres of the tendon. In this review, we examine the rationale for this hypothesis and provide evidence in support of this theory.     

Tracing the origins of “fetal origins” of adult diseases: Programming by oxidative stress?

Too small size at birth (due to poor fetal growth and/or preterm delivery) has been associated with substantially elevated risks of the metabolic syndrome (dislipidemia, insulin resistance, hypertension), type 2 diabetes and cardiovascular disease in adulthood. The mechanisms of such "fetal origins" or "programming" of disease phenomenon remain unresolved. Too large size at birth seems also associated with an increased risk. Many known or suspected causes of or conditions associated with adverse (poor or excessive) fetal growth or preterm birth have been associated with oxidative stress. Plausibly, oxidative stress may be a common link underlying the superficial "programming" associations between adverse fetal growth or preterm birth and elevated risks of certain chronic diseases. The mechanisms of oxidative stress programming may be through directly modulating gene expression or indirectly through the effects of certain oxidized molecules. Experimental investigations have well demonstrated the role of redox balance in modulating gene expression, and recent studies indicate that both the insulin functional axis and blood pressure could be sensitive targets to oxidative stress programming. Adverse programming may occur without affecting fetal growth, but more frequently among low birth weight infants merely because they more frequently experienced known or unknown conditions with oxidative insults. As oxidative stress levels are easily modifiable during pregnancy and early postnatal periods (which are plausible critical windows), the hypothesis, if proved valid, will suggest new measures that could be very helpful on fighting the increasing epidemic of the metabolic syndrome, type 2 diabetes and cardiovascular disease. Currently, there are several ongoing large randomized trials of antioxidant supplementation to counter oxidative stress during pregnancy for the prevention of preeclampsia. It would be invaluable if long-term follow-ups of infants born to women in such trials could be realized to test the oxidative stress programming hypothesis in such experimental trial settings.     

Nephrin—signature molecule of the glomerular podocyte?

In recent years there has been an explosion of interest in the glomerular podocyte, which plays a central role in control of glomerular filtration. A host of new molecules have been identified as playing essential roles in the maintenance of podocyte integrity in both humans and mouse models. Of all of these, arguably the most pivotal is nephrin, a transmembrane receptor molecule located at the specialized podocyte cell–cell junction, termed the slit diaphragm. Mutations in this gene cause the most severe form of congenital nephrotic syndrome, and many interacting proteins have now been described to form a large multiprotein complex with complex dynamics. There is little evidence of functional nephrin expression outside the glomerulus, and there are accumulating data that nephrin is essential for the unique properties of podocyte biology. Utilizing a powerful human cell culture model, comparing wild‐type with nephrin‐null podocytes, we can show that several crucial functional properties of podocytes depend on nephrin, including insulin responsiveness and cytoskeletal reorganization. Thus, it is reasoned that nephrin is a signature molecule required to define distinct podocyte characteristics. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Histochemical study of mast cells from the thymus of mice receiving ACTH<Subscript>1–24</Subscript>

Synthetic ACTH_1–24 analogue administered in a daily dose of 0.01 mg/kg decreased the number and size of mast cells and increased intracellular serotonin concentration. ACTH_1–24 induced degranulation of young mast cells and release of undersulfated heparin. Correlation analysis showed that hormonal imbalance produced by ACTH_1–24 was accompanied by redistribution of bioamines. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 138, No. 7, pp. 107–110, July, 2004