Revised rates for the stellar triple-alpha process from measurement of 12C nuclear resonances

In the centres of stars where the temperature is high enough, three alpha-particles (helium nuclei) are able to combine to form 12C because of a resonant reaction leading to a nuclear excited state. (Stars with masses greater than approximately 0.5 times that of the Sun will at some point in their lives have a central temperature high enough for this reaction to proceed.) Although the reaction rate is of critical significance for determining elemental abundances in the Universe, and for determining the size of the iron core of a star just before it goes supernova, it has hitherto been insufficiently determined. Here we report a measurement of the inverse process, where a 12C nucleus decays to three alpha-particles. We find a dominant resonance at an energy of approximately 11 MeV, but do not confirm the presence of a resonance at 9.1 MeV (ref. 3). We show that interference between two resonances has important effects on our measured spectrum. Using these data, we calculate the triple-alpha rate for temperatures from 10(7) K to 10(10) K and find significant deviations from the standard rates. Our rate below approximately 5 x 10(7) K is higher than the previous standard, implying that the critical amounts of carbon that catalysed hydrogen burning in the first stars are produced twice as fast as previously believed. At temperatures above 10(9) K, our rate is much less, which modifies predicted nucleosynthesis in supernovae.     

Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice

Minocycline mediates neuroprotection in experimental models of neurodegeneration. It inhibits the activity of caspase-1, caspase-3, inducible form of nitric oxide synthetase (iNOS) and p38 mitogen-activated protein kinase (MAPK). Although minocycline does not directly inhibit these enzymes, the effects may result from interference with upstream mechanisms resulting in their secondary activation. Because the above-mentioned factors are important in amyotrophic lateral sclerosis (ALS), we tested minocycline in mice with ALS. Here we report that minocycline delays disease onset and extends survival in ALS mice. Given the broad efficacy of minocycline, understanding its mechanisms of action is of great importance. We find that minocycline inhibits mitochondrial permeability-transition-mediated cytochrome c release. Minocycline-mediated inhibition of cytochrome c release is demonstrated in vivo, in cells, and in isolated mitochondria. Understanding the mechanism of action of minocycline will assist in the development and testing of more powerful and effective analogues. Because of the safety record of minocycline, and its ability to penetrate the blood-brain barrier, this drug may be a novel therapy for ALS.     

Low-dose radiation accelerates aging of the T-cell receptor repertoire in CBA/Ca mice

While the biological effects of high-dose-ionizing radiation on human health are well characterized, the consequences of low-dose radiation exposure remain poorly defined, even though they are of major importance for radiological protection. Lymphocytes are very radiosensitive, and radiation-induced health effects may result from immune cell loss and/or immune system impairment. To decipher the mechanisms of effects of low doses, we analyzed the modulation of the T-cell receptor gene repertoire in mice exposed to a single low (0.1 Gy) or high (1 Gy) dose of radiation. High-throughput T-cell receptor gene profiling was used to visualize T-lymphocyte dynamics over time in control and irradiated mice. Radiation exposure induces “aging-like” effects on the T-cell receptor gene repertoire, detectable as early as 1 month post-exposure and for at least 6 months. Surprisingly, these effects are more pronounced in animals exposed to 0.1 Gy than to 1 Gy, where partial correction occurs over time. Importantly, we found that low-dose radiation effects are partially due to the hematopoietic stem cell impairment. Collectively, our findings show that acute low-dose radiation exposure specifically results in long-term alterations of the T-lymphocyte repertoire.     

A recombinant dromedary antibody fragment (VHH or nanobody) directed against human Duffy antigen receptor for chemokines

Fy blood group antigens are carried by the Duffy antigen receptor for chemokines (DARC), a red cells receptor for Plasmodium vivax broadly implicated in human health and diseases. Recombinant VHHs, or nanobodies, the smallest intact antigen binding fragment derivative from the heavy chain-only antibodies present in camelids, were prepared from a dromedary immunized against DARC N-terminal extracellular domain and selected for DARC binding. A described VHH, CA52, does recognize native DARC on cells. It inhibits P. vivax invasion of erythrocytes and displaces interleukin-8 bound to DARC. The targeted epitope overlaps the well-defined DARC Fy6 epitope. K _D of CA52?CDARC equilibrium is sub-nanomolar, hence ideal to develop diagnostic or therapeutic compounds. Immunocapture by immobilized CA52 yielded highly purified DARC from engineered K562 cells. This first report on a VHH with specificity for a red blood cell protein exemplifies VHHs?? potentialities to target, to purify, and to modulate the function of cellular markers.     

Modulation of dopaminergic transmission by alpha-noradrenergic agonists and antagonists: Evidence for antidopaminergic properties of some alpha antagonists

Summary The effects on dopamine (DA) metabolism, on³H-spiperone binding and on amphetamine-induced stereotypies of a variety of drugs with different actions on alpha₁-and alpha₂-noradrenergic (NA) receptors have been investigated.The preferential alpha₂-antagonists yohimbine, rauwolscine, piperoxane and esproquin as well as the preferential alpha₁-antagonists corynanthine and WB4101 increased homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the rat striatum, mesolimbic area, and cortex. Prazosine and clonidine tended to reduce HVA and DOPAC. The preferential alpha₂-antagonists, tolazoline and RX-781094A, had no measurable effects on DA metabolism even at high doses.Those compounds which in comparable doses increased DA metabolism inhibited³H-spiperone binding in the hippocampus. The effects in the striatum and cortex were smaller and did not show a relation to those in hippocampus or on DA metabolism. Only the yohimbine alkaloids antagonized amphetamine-induced stereotypies.The results suggest that the effects on DA metabolism at least of yohimbine, rauwolscine, and corynanthine are related to their intrinsic antidopaminergic properties. The same might be true, although with a lesser degree of certainty, for piperoxane, esproquin, and WB4101.Since many of the tested compounds possessing alpha-antagonistic properties interacted with the DA system, a close molecular relationship between alpha-noradrenergic and DA receptors might be anticipated. The preference of these compounds for the hippocampal subtype of DA receptors might indicate a particular role of the latter in the regulation of DA metabolism. On the other hand, the antagonism against haloperidol's enhancing effect on DA metabolism by clonidine suggests a modulatory NA influence on DA transmission. The observation that clonidine reduced the effects of yohimbine and piperoxane to a lesser degree than that of haloperidol, is in agreement with this notion.Part of this work has been presented at the 13th Meeting of the Union of Swiss Societies of Experimental Biology, Lausanne, March 26/27. 1981 (for abstract see Waldmeier and Bischoff, 1981).     

An intrinsic mechanism of corticogenesis from embryonic stem cells

The cerebral cortex develops through the coordinated generation of dozens of neuronal subtypes, but the mechanisms involved remain unclear. Here we show that mouse embryonic stem cells, cultured without any morphogen but in the presence of a sonic hedgehog inhibitor, recapitulate in vitro the major milestones of cortical development, leading to the sequential generation of a diverse repertoire of neurons that display most salient features of genuine cortical pyramidal neurons. When grafted into the cerebral cortex, these neurons develop patterns of axonal projections corresponding to a wide range of cortical layers, but also to highly specific cortical areas, in particular visual and limbic areas, thereby demonstrating that the identity of a cortical area can be specified without any influence from the brain. The discovery of intrinsic corticogenesis sheds new light on the mechanisms of neuronal specification, and opens new avenues for the modelling and treatment of brain diseases.     

Glial and neuronal control of brain blood flow

Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches.     

Super-chondritic Sm/Nd ratios in Mars, the Earth and the Moon

Small isotopic differences in the atomic abundance of neodymium-142 (142Nd) in silicate rocks represent the time-averaged effect of decay of formerly live samarium-146 (146Sm) and provide constraints on the timescales and mechanisms by which planetary mantles first differentiated. This chronology, however, assumes that the composition of the total planet is identical to that of primitive undifferentiated meteorites called chondrites. The difference in the 142Nd/144Nd ratio between chondrites and terrestrial samples may therefore indicate very early isolation (<30 Myr from the formation of the Solar System) of the upper mantle or a slightly non-chondritic bulk Earth composition. Here we present high-precision 142Nd data for 16 martian meteorites and show that Mars also has a non-chondritic composition. Meteorites belonging to the shergottite subgroup define a planetary isochron yielding an age of differentiation of 40 +/- 18 Myr for the martian mantle. This isochron does not pass through the chondritic reference value (100 x epsilon(142)Nd = -21 +/- 3; 147Sm/144Nd = 0.1966). The Earth, Moon and Mars all seem to have accreted in a portion of the inner Solar System with approximately 5 per cent higher Sm/Nd ratios than material accreted in the asteroid belt. Such chemical heterogeneities may have arisen from sorting of nebular solids or from impact erosion of crustal reservoirs in planetary precursors. The 143Nd composition of the primitive mantle so defined by 142Nd is strikingly similar to the putative endmember component 'FOZO' characterized by high 3He/4He ratios.