Structure of co-crystals of tropomyosin and troponin

Troponin, a Ca2+-sensitive complex, regulates the motions of tropomyosin on the thin filaments in many muscles. It has three subunits, each with a different architecture and function: TnC binds Ca2+; TnI binds to actin and inhibits contraction; and TnT binds one complex to each tropomyosin molecule. The troponin complex has an elongated shape with TnC and TnI forming a globular 'head' region and TnT a long (approximately 160 A) 'tail'. TnT binds to two widely separated regions of tropomyosin: the head region of the complex is near Cys 190 of tropomyosin and the tail region is near the overlapping joint that links the tropomyosin molecules into filaments. Here we report the X-ray structure determination at 17 A resolution of glutaraldehyde-treated tropomyosin crystals in which native troponin complex or fragments of TnT have been bound. Our results show that the amino-terminal tail end of TnT spans the head-to-tail joint of the tropomyosin filaments, and that the 'head' region of the whole troponin complex binds approximately 200 A away near residues 150-180 of the tropomyosin molecule.     

Peptide sequences of T-cell receptor delta and gamma chains are identical to predicted X and gamma proteins

Although most mature peripheral T lymphocytes express a major histocompatibility complex restricted, CD3-associated, antigen receptor (TCR) which has been well characterized, some T cells carry a different CD3-associated heterodimer on their surface. One of the two disulphide-linked chains of this putative second receptor, which in mice has relative molecular mass (Mr) 35,000 (35K), has been identified as a product of the group of gamma genes. The other chain, termed delta (Mr 45K in mice), is not as well characterized. Although gamma/delta-bearing cells are a minor subset among peripheral T lymphocytes, they are the only CD3+ cells in the thymus early in ontogeny. Taking advantage of these kinetics, we have generated gamma/delta-bearing hybridomas, using a new TCR alpha chain-negative variant of the AKR thymoma BW5147 as tumour parent, fetal thymocytes as normal cell partners, and an anti-CD3 monoclonal antibody (mAb) as screening reagent. Gamma and delta chains from one of these hybrids have been purified and partially sequenced. The sequences obtained indicate that delta is indeed identical to the polypeptide encoded by the recently described gene X, as suggested by Chien et al.     

Pleistocene dates for the human occupation of New Ireland, northern Melanesia

Pleistocene dates from three cave sites indicate the human capacity to colonise across two oceanic straits to the east of a former Tasmania-Australia-New Guinea continent by 33 kyr BP. The sites demonstrate exploitation of costal marine and lowland tropical forest resources. They extend Pleistocene occupation into island Melanesia and demonstrate that the large islands of northern Melanesia have an antiquity of human occupation of the same order as the adjacent Greater Australian continent.     

Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts

Transplantation studies in mice and rats have shown that human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) can improve the function of infarcted hearts, but two critical issues related to their electrophysiological behaviour in vivo remain unresolved. First, the risk of arrhythmias following hESC-CM transplantation in injured hearts has not been determined. Second, the electromechanical integration of hESC-CMs in injured hearts has not been demonstrated, so it is unclear whether these cells improve contractile function directly through addition of new force-generating units. Here we use a guinea-pig model to show that hESC-CM grafts in injured hearts protect against arrhythmias and can contract synchronously with host muscle. Injured hearts with hESC-CM grafts show improved mechanical function and a significantly reduced incidence of both spontaneous and induced ventricular tachycardia. To assess the activity of hESC-CM grafts in vivo, we transplanted hESC-CMs expressing the genetically encoded calcium sensor, GCaMP3 (refs 4, 5). By correlating the GCaMP3 fluorescent signal with the host ECG, we found that grafts in uninjured hearts have consistent 1:1 host–graft coupling. Grafts in injured hearts are more heterogeneous and typically include both coupled and uncoupled regions. Thus, human myocardial grafts meet physiological criteria for true heart regeneration, providing support for the continued development of hESC-based cardiac therapies for both mechanical and electrical repair.     

Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP

The signal transduction cascade comprising Raf, mitogen-activated protein (MAP) kinase kinase (MEK) and MAP kinase is a Ras effector pathway that mediates diverse cellular responses to environmental cues and contributes to Ras-dependent oncogenic transformation. Here we report that the Ras effector protein Impedes Mitogenic signal Propagation (IMP) modulates sensitivity of the MAP kinase cascade to stimulus-dependent activation by limiting functional assembly of the core enzymatic components through the inactivation of KSR, a scaffold/adaptor protein that couples activated Raf to its substrate MEK. IMP is a Ras-responsive E3 ubiquitin ligase that, on activation of Ras, is modified by auto-polyubiquitination, which releases the inhibition of Raf-MEK complex formation. Thus, Ras activates the MAP kinase cascade through simultaneous dual effector interactions: induction of Raf kinase activity and derepression of Raf-MEK complex formation. IMP depletion results in increased stimulus-dependent MEK activation without alterations in the timing or duration of the response. These observations suggest that IMP functions as a threshold modulator, controlling sensitivity of the cascade to stimulus and providing a mechanism to allow adaptive behaviour of the cascade in chronic or complex signalling environments.     

Subjective versus objective combining of forecasts: An experiment

The paper reports results of an experiment conducted to evaluate subjective versus objective combination of forecasts. The subjects were undergraduate students at Texas A&M. The students forecasted two different types of time series. The results found show that the subjective combination of forecasts improves their accuracy as compared with individual efforts. Four ex-ante weighting methods were also used to combine the forecasts. They all improve the accuracy of the forecasts. The best results, though, were from the subjective combination of forecasts.