Actin dynamics in the regulation of endothelial barrier functions and neutrophil recruitment during endotoxemia and sepsis

Sepsis is a leading cause of death worldwide. Increased vascular permeability is a major hallmark of sepsis. Dynamic alterations in actin fiber formation play an important role in the regulation of endothelial barrier functions and thus vascular permeability. Endothelial integrity requires a delicate balance between the formation of cortical actin filaments that maintain endothelial cell contact stability and the formation of actin stress fibers that generate pulling forces, and thus compromise endothelial cell contact stability. Current research has revealed multiple molecular pathways that regulate actin dynamics and endothelial barrier dysfunction during sepsis. These include intracellular signaling proteins of the small GTPases family (e.g., Rap1, RhoA and Rac1) as well as the molecules that are directly acting on the actomyosin cytoskeleton such as myosin light chain kinase and Rho kinases. Another hallmark of sepsis is an excessive recruitment of neutrophils that also involves changes in the actin cytoskeleton in both endothelial cells and neutrophils. This review focuses on the available evidence about molecules that control actin dynamics and regulate endothelial barrier functions and neutrophil recruitment. We also discuss treatment strategies using pharmaceutical enzyme inhibitors to target excessive vascular permeability and leukocyte recruitment in septic patients.     

Group II metabotropic glutamate receptors and schizophrenia

Schizophrenia is one of the most common mental illnesses, with hereditary and environmental factors important for its etiology. All antipsychotics have in common a high affinity for monoaminergic receptors. Whereas hallucinations and delusions usually respond to typical (haloperidol-like) and atypical (clozapine-like) monoaminergic antipsychotics, their efficacy in improving negative symptoms and cognitive deficits remains inadequate. In addition, devastating side effects are a common characteristic of monoaminergic antipsychotics. Recent biochemical, preclinical and clinical findings support group II metabotropic glutamate receptors (mGluR2 and mGluR3) as a new approach to treat schizophrenia. This paper reviews the status of general knowledge of mGluR2 and mGluR3 in the psychopharmacology, genetics and neuropathology of schizophrenia     

Deep winds beneath Saturn's upper clouds from a seasonal long-lived planetary-scale storm

Convective storms occur regularly in Saturn's atmosphere. Huge storms known as Great White Spots, which are ten times larger than the regular storms, are rarer and occur about once per Saturnian year (29.5 Earth years). Current models propose that the outbreak of a Great White Spot is due to moist convection induced by water. However, the generation of the global disturbance and its effect on Saturn's permanent winds have hitherto been unconstrained by data, because there was insufficient spatial resolution and temporal sampling to infer the dynamics of Saturn's weather layer (the layer in the troposphere where the cloud forms). Theoretically, it has been suggested that this phenomenon is seasonally controlled. Here we report observations of a storm at northern latitudes in the peak of a weak westward jet during the beginning of northern springtime, in accord with the seasonal cycle but earlier than expected. The storm head moved faster than the jet, was active during the two-month observation period, and triggered a planetary-scale disturbance that circled Saturn but did not significantly alter the ambient zonal winds. Numerical simulations of the phenomenon show that, as on Jupiter, Saturn's winds extend without decay deep down into the weather layer, at least to the water-cloud base at pressures of 10-12 bar, which is much deeper than solar radiation penetrates.     

Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function

Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.     

Modelling gene regulation: (De)compositional and template-based strategies

Although the interdisciplinary nature of contemporary biological sciences has been addressed by philosophers, historians, and sociologists of science, the different ways in which engineering concepts and methods have been applied in biology have been somewhat neglected. We examine – using the mechanistic philosophy of science as an analytic springboard – the transfer of network methods from engineering to biology through the cases of two biology laboratories operating at the California Institute of Technology. The two laboratories study gene regulatory networks, but in remarkably different ways. The research strategy of the Davidson lab fits squarely into the traditional mechanist philosophy in its aim to decompose and reconstruct, in detail, gene regulatory networks of a chosen model organism. In contrast, the Elowitz lab constructs minimal models that do not attempt to represent any particular naturally evolved genetic circuits. Instead, it studies the principles of gene regulation through a template-based approach that is applicable to any kinds of networks, whether biological or not. We call for the mechanists to consider whether the latter approach can be accommodated by the mechanistic approach, and what kinds of modifications it would imply for the mechanistic paradigm of explanation, if it were to address modelling more generally.     

Note on fungi in small mammals from the Nothofagus Forest in Argentina

Fungal spores from the same taxa of fungi that occur in the Pacific Northwest are reported from digestive tracts of31 rodents of 5 genera from the Nothofagus forest of southern Argentina. Mycophagy (fungal feeding) by forest rodents has been well documented in North America (Fogel and Trappe 1978, Maser et al. 1978, Mclntire 1984, and others), Europe (Blaschke and B?umler 1986, Durrieu et al. 1984), and Australia (Malajczuk et al. 1987). The purpose of this note is to report fungi consumed by rodents of the Argentine Andinian Patagonic forest (see Dimitri 1972,McQueen 1977, and Ward 1965 for a discussion of this forest), where mycorrhizal fungi may be an important part of the forest-rodent ecology (Cabrera and Yepes 1960, Pearson 1983, 1948, Pearson and Pearson 1982).     

Fast core rotation in red-giant stars as revealed by gravity-dominated mixed modes

When the core hydrogen is exhausted during stellar evolution, the central region of a star contracts and the outer envelope expands and cools, giving rise to a red giant. Convection takes place over much of the star's radius. Conservation of angular momentum requires that the cores of these stars rotate faster than their envelopes; indirect evidence supports this. Information about the angular-momentum distribution is inaccessible to direct observations, but it can be extracted from the effect of rotation on oscillation modes that probe the stellar interior. Here we report an increasing rotation rate from the surface of the star to the stellar core in the interiors of red giants, obtained using the rotational frequency splitting of recently detected 'mixed modes'. By comparison with theoretical stellar models, we conclude that the core must rotate at least ten times faster than the surface. This observational result confirms the theoretical prediction of a steep gradient in the rotation profile towards the deep stellar interior.     

Late survival of Neanderthals at the southernmost extreme of Europe

The late survival of archaic hominin populations and their long contemporaneity with modern humans is now clear for southeast Asia. In Europe the extinction of the Neanderthals, firmly associated with Mousterian technology, has received much attention, and evidence of their survival after 35 kyr bp has recently been put in doubt. Here we present data, based on a high-resolution record of human occupation from Gorham's Cave, Gibraltar, that establish the survival of a population of Neanderthals to 28 kyr bp. These Neanderthals survived in the southernmost point of Europe, within a particular physiographic context, and are the last currently recorded anywhere. Our results show that the Neanderthals survived in isolated refuges well after the arrival of modern humans in Europe.     

Molecular machines: nanomotor rotates microscale objects

Nanomachines of the future will require molecular-scale motors that can perform work and collectively induce controlled motion of much larger objects. We have designed a synthetic, light-driven molecular motor that is embedded in a liquid-crystal film and can rotate objects placed on the film that exceed the size of the motor molecule by a factor of 10,000. The changes in shape of the motor during the rotary steps cause a remarkable rotational reorganization of the liquid-crystal film and its surface relief, which ultimately causes the rotation of submillimetre-sized particles on the film.