On the verge of <Emphasis Type="Italic">Umdeutung</Emphasis> in Minnesota: Van Vleck and the correspondence principle. Part one

In October 1924, The Physical Review, a relatively minor journal at the time, published a remarkable two-part paper by John H. Van Vleck, working in virtual isolation at the University of Minnesota. Using Bohr’s correspondence principle and Einstein’s quantum theory of radiation along with advanced techniques from classical mechanics, Van Vleck showed that quantum formulae for emission, absorption, and dispersion of radiation merge with their classical counterparts in the limit of high quantum numbers. For modern readers Van Vleck’s paper is much easier to follow than the famous paper by Kramers and Heisenberg on dispersion theory, which covers similar terrain and is widely credited to have led directly to Heisenberg’s Umdeutung paper. This makes Van Vleck’s paper extremely valuable for the reconstruction of the genesis of matrix mechanics. It also makes it tempting to ask why Van Vleck did not take the next step and develop matrix mechanics himself. This paper was written as part of a joint project in the history of quantum physics of the Max Planck Institut für Wissenschaftsgeschichte and the Fritz-Haber-Institut in Berlin.     

Transient and constitutive repression of cytoplasmic translation signaling in cells with mtDNA mutation

Cytoplasmic translation is under sophisticated control but how cells adapt its rate to constitutive loss of mitochondrial oxidative phosphorylation is unknown. Here we show that translation is repressed in cells with the pathogenic A3243G mtDNA mutation or in mtDNA-less ρ⁰ cells by at least two distinct pathways, one transiently targeting elongation factor eEF-2 and the other initiation factor eIF-2α constitutively. Under conditions of exponential cell growth and mammalian target of rapamycin (mTOR) activation, eEF-2 becomes transiently phosphorylated by an AMP-activated protein kinase (AMPK)-dependent pathway, especially high in mutant cells. Independent of AMPK and mTOR, eIF-2α is constitutively phosphorylated in mutant cells, likely a signature of endoplasmic reticulum (ER)-stress response induced by the loss of oxidative phosphorylation. While the AMPK/eEF-2K/eEF-2 pathway appears to function in adaptation to physiological fluctuations in ATP levels in the mutant cells, the ER stress signified by constitutive protein synthesis inhibition through eIF-2α-mediated repression of translation initiation may have pathobiochemical consequences. Received 29 October 2008; received after revision 11 December 2008; accepted 16 December 2008     

The twins and the bucket: How Einstein made gravity rather than motion relative in general relativity

In publications in 1914 and 1918, Einstein claimed that his new theory of gravity in some sense relativizes the rotation of a body with respect to the distant stars (a stripped-down version of Newton's rotating bucket experiment) and the acceleration of the traveler with respect to the stay-at-home in the twin paradox. What he showed was that phenomena seen as inertial effects in a space-time coordinate system in which the non-accelerating body is at rest can be seen as a combination of inertial and gravitational effects in a (suitably chosen) space-time coordinate system in which the accelerating body is at rest. Two different relativity principles play a role in these accounts: (a) the relativity of non-uniform motion, in the weak sense that the laws of physics are the same in the two space-time coordinate systems involved; (b) what Einstein in 1920 called the relativity of the gravitational field, the notion that there is a unified inertio-gravitational field that splits differently into inertial and gravitational components in different coordinate systems. I provide a detailed reconstruction of Einstein's rather sketchy accounts of the twins and the bucket and examine the role of these two relativity principles. I argue that we can hold on to (b) but that (a) is either false or trivial.     

Mutations in a new member of the chromodomain gene family cause CHARGE syndrome

CHARGE syndrome is a common cause of congenital anomalies affecting several tissues in a nonrandom fashion. We report a 2.3-Mb de novo overlapping microdeletion on chromosome 8q12 identified by array comparative genomic hybridization in two individuals with CHARGE syndrome. Sequence analysis of genes located in this region detected mutations in the gene CHD7 in 10 of 17 individuals with CHARGE syndrome without microdeletions, accounting for the disease in most affected individuals.     

Fluorescence response of acridine orange to changes in pH gradients across liposome membranes

Summary The influence that changes in proton distribution have on the fluorescence of acridine orange was examined using negatively charged liposomes. Our results indicate that at least two mechanisms are involved: distribution of the probe between the internal aqueous phase of the liposomes and the outside medium, and binding of the probe to the liposome membranes.     

Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2

Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3αβ(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.     

De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome

Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous.     

Structure of C3b reveals conformational changes that underlie complement activity

Resistance to infection and clearance of cell debris in mammals depend on the activation of the complement system, which is an important component of innate and adaptive immunity. Central to the complement system is the activated form of C3, called C3b, which attaches covalently to target surfaces to amplify complement response, label cells for phagocytosis and stimulate the adaptive immune response. C3b consists of 1,560 amino-acid residues and has 12 domains. It binds various proteins and receptors to effect its functions. However, it is not known how C3 changes its conformation into C3b and thereby exposes its many binding sites. Here we present the crystal structure at 4-A resolution of the activated complement protein C3b and describe the conformational rearrangements of the 12 domains that take place upon proteolytic activation. In the activated form the thioester is fully exposed for covalent attachment to target surfaces and is more than 85 A away from the buried site in native C3 (ref. 5). Marked domain rearrangements in the alpha-chain present an altered molecular surface, exposing hidden and cryptic sites that are consistent with known putative binding sites of factor B and several complement regulators. The structural data indicate that the large conformational changes in the proteolytic activation and regulation of C3 take place mainly in the first conversion step, from C3 to C3b. These insights are important for the development of strategies to treat immune disorders that involve complement-mediated inflammation.