Thick filament size changes in contraction of human muscles

Summary Measurements done on electron micrographs show that in myofibres with sarcomeres contracted to below 2.1 m, proportional shortening of the A bands occurs. In muscles from patients with idiopathic scoliosis very short A bands are especially prominent.This work was supported by the Muscular Dystrophy Association of America.We wish to thank H. Orgal and Y. Havivi, for their technical assistance, O. Carmi and B. Ghidoni for their help with the measurements and N. Vagenberg for the computer analyses.     

An evaluation of forecasting using leading indicators

We consider the use of indices of leading indicators in forecasting and macro-economic modelling. The procedures used to select the components and construct the indices are examined, noting that the composition of indicator systems gets altered frequently. Cointegration within the indices, and between their components and macro-economic variables are considered as well as the role of co-breaking to mitigate regime shifts. Issues of model choice and data-based restrictions are investigated. A framework is proposed for index analysis and selecting indices, and applied to the UK longer-leading indicator. The effects of adding leading indicators to macro models are considered theoretically and for UK data.     

Reciprocal interactions of the intestinal microbiota and immune system

The emergence of the adaptive immune system in vertebrates set the stage for evolution of an advanced symbiotic relationship with the intestinal microbiota. The defining features of specificity and memory that characterize adaptive immunity have afforded vertebrates the mechanisms for efficiently tailoring immune responses to diverse types of microbes, whether to promote mutualism or host defence. These same attributes can put the host at risk of immune-mediated diseases that are increasingly linked to the intestinal microbiota. Understanding how the adaptive immune system copes with the remarkable number and diversity of microbes that colonize the digestive tract, and how the system integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise for new approaches to modulate immune networks to treat and prevent disease.     

An oxygenase that forms and deoxygenates toxic epoxide

Catabolism may give rise to toxic intermediates that compromise cell vitality, such as epoxide formation in the recently elucidated and apparently universal bacterial coenzyme A (CoA)-dependent degradation of phenylacetic acid. This compound is central to the catabolism of a variety of aromatics, such as phenylalanine, lignin-related compounds or environmental contaminants. The key phenylacetyl-CoA monooxygenase (epoxidase) of the pathway, PaaABCE, is also connected to the production of various primary and secondary metabolites, as well as to the virulence of certain pathogens. However, the enzyme complex has so far not been investigated in detail. Here we characterize the bacterial multicomponent monooxygenase PaaABCE that, surprisingly, not only transforms phenylacetyl-CoA into its ring-1,2-epoxide, but also mediates the NADPH-dependent removal of the epoxide oxygen, regenerating phenylacetyl-CoA with formation of water. We provide evidence for a catalytic di-iron centre that is probably the key to the unprecedented deoxygenation of an organic compound by an oxygenase. Presumably, the bifunctionality is vital to avoid toxic intracellular epoxide levels if the subsequent catabolic steps are impeded. Our data suggest that detoxification is assisted by two thioesterases (PaaI and PaaY) forming non-reactive breakdown products. Hence, PaaABCE may harbour an intrinsic escape mechanism from its own toxic product and represents the archetype of a bifunctional oxygenase/deoxygenase. Analogous reactions may possibly be catalysed by other di-iron epoxidases.     

Ontological reduction and molecular structure

In this paper I outline how the debate concerning the intertheoretic reduction of chemistry reaches a stalemate. One way forward is to switch discussion to the issue of ontological reduction and emergence, so I present a counternomic criterion of emergence that should be acceptable to both sides of the discussion. I then examine the bearing on this debate of the symmetry problem in molecular quantum mechanics, as presented by Woolley and Sutcliffe (1977). I conclude by addressing some objections to emergentist positions: that they posit miraculous violations of physical laws; that emergence is obscure and of doubtful coherence; that causal theories of property identity render emergence, under the counternomic criterion, metaphysically impossible.     

Generation of functional multipotent adult stem cells from GPR125+ germline progenitors

Adult mammalian testis is a source of pluripotent stem cells. However, the lack of specific surface markers has hampered identification and tracking of the unrecognized subset of germ cells that gives rise to multipotent cells. Although embryonic-like cells can be derived from adult testis cultures after only several weeks in vitro, it is not known whether adult self-renewing spermatogonia in long-term culture can generate such stem cells as well. Here, we show that highly proliferative adult spermatogonial progenitor cells (SPCs) can be efficiently obtained by cultivation on mitotically inactivated testicular feeders containing CD34+ stromal cells. SPCs exhibit testicular repopulating activity in vivo and maintain the ability in long-term culture to give rise to multipotent adult spermatogonial-derived stem cells (MASCs). Furthermore, both SPCs and MASCs express GPR125, an orphan adhesion-type G-protein-coupled receptor. In knock-in mice bearing a GPR125-beta-galactosidase (LacZ) fusion protein under control of the native Gpr125 promoter (GPR125-LacZ), expression in the testis was detected exclusively in spermatogonia and not in differentiated germ cells. Primary GPR125-LacZ SPC lines retained GPR125 expression, underwent clonal expansion, maintained the phenotype of germline stem cells, and reconstituted spermatogenesis in busulphan-treated mice. Long-term cultures of GPR125+ SPCs (GSPCs) also converted into GPR125+ MASC colonies. GPR125+ MASCs generated derivatives of the three germ layers and contributed to chimaeric embryos, with concomitant downregulation of GPR125 during differentiation into GPR125- cells. MASCs also differentiated into contractile cardiac tissue in vitro and formed functional blood vessels in vivo. Molecular bookmarking by GPR125 in the adult mouse and, ultimately, in the human testis could enrich for a population of SPCs for derivation of GPR125+ MASCs, which may be employed for genetic manipulation, tissue regeneration and revascularization of ischaemic organs.     

The delayed rise of present-day mammals

Did the end-Cretaceous mass extinction event, by eliminating non-avian dinosaurs and most of the existing fauna, trigger the evolutionary radiation of present-day mammals? Here we construct, date and analyse a species-level phylogeny of nearly all extant Mammalia to bring a new perspective to this question. Our analyses of how extant lineages accumulated through time show that net per-lineage diversification rates barely changed across the Cretaceous/Tertiary boundary. Instead, these rates spiked significantly with the origins of the currently recognized placental superorders and orders approximately 93 million years ago, before falling and remaining low until accelerating again throughout the Eocene and Oligocene epochs. Our results show that the phylogenetic 'fuses' leading to the explosion of extant placental orders are not only very much longer than suspected previously, but also challenge the hypothesis that the end-Cretaceous mass extinction event had a major, direct influence on the diversification of today's mammals.     

High-temperature metal-organic magnets

For over two decades there have been intense efforts aimed at the development of alternatives to conventional magnets, particularly materials comprised in part or wholly of molecular components. Such alternatives offer the prospect of realizing magnets fabricated through controlled, low-temperature, solution-based chemistry, as opposed to high-temperature metallurgical routes, and also the possibility of tuning magnetic properties through synthesis. However, examples of magnetically ordered molecular materials at or near room temperature are extremely rare, and the properties of these materials are often capricious and difficult to reproduce. Here we present a versatile solution-based route to a new class of metal-organic materials exhibiting magnetic order well above room temperature. Reactions of the metal (M) precursor complex bis(1,5-cyclooctadiene)nickel with three different organics A-TCNE (tetracyanoethylene), TCNQ (7,7,8,8-tetracyanoquinodimethane) or DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone)--proceed via electron transfer from nickel to A and lead to materials containing Ni(II) ions and reduced forms of A in a 2:1 Ni:A ratio--that is, opposite to that of conventional (low Curie temperature) MA(2)-type magnets. These materials also contain oxygen-based species within their architectures. Magnetic characterization of the three compounds reveals spontaneous field-dependent magnetization and hysteresis at room temperature, with ordering temperatures well above ambient. The unusual stoichiometry and striking magnetic properties highlight these three compounds as members of a class of stable magnets that are at the interface between conventional inorganic magnets and genuine molecule-based magnets.