Monday, Monday - let's see what's new. As always, you should rate the articles, post notes and comments and send trackbacks when you blog about the papers. You can now also easily place articles on various social services (CiteULike, Mendeley, Connotea, Stumbleupon, Facebook and Digg) with just one click. Here are my own picks for the week - you go and look for your own favourites:
Real Lives and White Lies in the Funding of Scientific Research:
It is a summer day in 2009 in Cambridge, England, and K. (39) looks out of his lab window, wondering why he chose the life of a scientist [1]. Yet it had all begun so well! His undergraduate studies in Prague had excited him about biomedical research, and he went on to a PhD at an international laboratory in Heidelberg. There, he had every advantage, technical and intellectual, and his work had gone swimmingly. He had moved to a Wellcome-funded research institute in England in 1999. And although his postdoc grant, as is typical, was for only two years, he won a rare career development award that gave him some independence for four more years. A six-year postdoc was an unusual opportunity, and it allowed him to define his own research field. By 2004, he had published six experimental papers in good journals, and on four of these, he was first author. It was the high point in his career, and when he applied for posts in Cambridge, London, Stanford, and Tubingen, he was short-listed for them all. He chose Cambridge University and a Royal Society Research Fellowship that offered him up to ten years' salary. This should have brought the peace of mind to plan projects that would take five years, or even longer. So, what went wrong?
Silent Springs: Why Are All the Frogs 'Croaking'?:
Amphibians became the most ancient class of land-dwelling vertebrates when, 360 million years ago, primitive amphibia such as Ichthyostega first hauled themselves out of their aquatic environment. Since that ancient event, the amphibia have ramified into over 6,300 species of breathtaking diversity: they inhabit all continents (excepting Antarctica), from deserts to altitudes of over 5,300 metres, manufacture an astoundingly complex arsenal of chemicals, and undergo complex metamorphic transitions that bridge aquatic and terrestrial ecosystems....
Grading Quality of Evidence and Strength of Recommendations: A Perspective:
Evidence-based practice requires translating research findings into clinical and policy decision making. Clinical practice guidelines (CPGs) serve this purpose by evaluating evidence and making recommendations about therapeutic and diagnostic interventions and clinical management strategies. Systematic reviews are considered the best available evidence and are often used in the development of CPGs [1],[2]. Since guideline development involves an assessment of the overall quality of evidence and complex balancing of trade-offs between the important benefits and harms of any given intervention, arbitrariness, value judgements, and subjectivity ultimately come into play in the guideline development process and associated recommendations [3]. In order to minimize cognitive bias in interpreting evidence and make the inherently subjective process more transparent and consistent, CPGs have traditionally employed formal systems or frameworks to understand and grade the quality of the body of evidence and strength of recommendations [4],[5].
Oxygen Consumption Can Regulate the Growth of Tumors, a New Perspective on the Warburg Effect:
The unique metabolism of tumors was described many years ago by Otto Warburg, who identified tumor cells with increased glycolysis and decreased mitochondrial activity. However, "aerobic glycolysis" generates fewer ATP per glucose molecule than mitochondrial oxidative phosphorylation, so in terms of energy production, it is unclear how increasing a less efficient process provides tumors with a growth advantage. We carried out a screen for loss of genetic elements in pancreatic tumor cells that accelerated their growth as tumors, and identified mitochondrial ribosomal protein L28 (MRPL28). Knockdown of MRPL28 in these cells decreased mitochondrial activity, and increased glycolysis, but paradoxically, decreased cellular growth in vitro. Following Warburg's observations, this mutation causes decreased mitochondrial function, compensatory increase in glycolysis and accelerated growth in vivo. Likewise, knockdown of either mitochondrial ribosomal protein L12 (MRPL12) or cytochrome oxidase had a similar effect. Conversely, expression of the mitochondrial uncoupling protein 1 (UCP1) increased oxygen consumption and decreased tumor growth. Finally, treatment of tumor bearing animals with dichloroacetate (DCA) increased pyruvate consumption in the mitochondria, increased total oxygen consumption, increased tumor hypoxia and slowed tumor growth. We interpret these findings to show that non-oncogenic genetic changes that alter mitochondrial metabolism can regulate tumor growth through modulation of the consumption of oxygen, which appears to be a rate limiting substrate for tumor proliferation.
Characterization of an Enantioselective Odorant Receptor in the Yellow Fever Mosquito Aedes aegypti:
Enantiomers differ only in the left or right handedness (chirality) of their orientations and exhibit identical chemical and physical properties. In chemical communication systems, enantiomers can be differentially active at the physiological and behavioral levels. Only recently were enantioselective odorant receptors demonstrated in mammals while their existence in insects has remained hypothetical. Using the two-microelectrode voltage clamp of Xenopus oocytes, we show that the yellow fever mosquito, Aedes aegypti, odorant receptor 8 (AaOR8) acts as a chiral selective receptor for the (R)-(--)-enantiomer of 1-octen-3-ol, which in the presence of other kairomones is an attractant used by blood-sucking insects to locate their hosts. In addition to steric constraints, chain length and degree of unsaturation play important roles in this recognition process. This is the first characterization of an enantioselective odorant receptor in insects and the results demonstrate that an OR alone, without helper proteins, can account for chiral specificity exhibited by olfactory sensory neurons (OSNs).
Eye-Hand Coordination during Dynamic Visuomotor Rotations:
For many technology-driven visuomotor tasks such as tele-surgery, human operators face situations in which the frames of reference for vision and action are misaligned and need to be compensated in order to perform the tasks with the necessary precision. The cognitive mechanisms for the selection of appropriate frames of reference are still not fully understood. This study investigated the effect of changing visual and kinesthetic frames of reference during wrist pointing, simulating activities typical for tele-operations. Using a robotic manipulandum, subjects had to perform center-out pointing movements to visual targets presented on a computer screen, by coordinating wrist flexion/extension with abduction/adduction. We compared movements in which the frames of reference were aligned (unperturbed condition) with movements performed under different combinations of visual/kinesthetic dynamic perturbations. The visual frame of reference was centered to the computer screen, while the kinesthetic frame was centered around the wrist joint. Both frames changed their orientation dynamically (angular velocity = 36°/s) with respect to the head-centered frame of reference (the eyes). Perturbations were either unimodal (visual or kinesthetic), or bimodal (visual+kinesthetic). As expected, pointing performance was best in the unperturbed condition. The spatial pointing error dramatically worsened during both unimodal and most bimodal conditions. However, in the bimodal condition, in which both disturbances were in phase, adaptation was very fast and kinematic performance indicators approached the values of the unperturbed condition. This result suggests that subjects learned to exploit an "affordance" made available by the invariant phase relation between the visual and kinesthetic frames. It seems that after detecting such invariance, subjects used the kinesthetic input as an informative signal rather than a disturbance, in order to compensate the visual rotation without going through the lengthy process of building an internal adaptation model. Practical implications are discussed as regards the design of advanced, high-performance man-machine interfaces.
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