Trichomonas hydrogenosomes contain the NADH dehydrogenase module of mitochondrial complex I

Hydrogenosomes are double-membraned ATP-producing and hydrogen-producing organelles of diverse anaerobic eukaryotes. In some versions of endosymbiotic theory they are suggested to be homologues of mitochondria, but alternative views suggest they arose from an anaerobic bacterium that was distinct from the mitochondrial endosymbiont. Here we show that the 51-kDa and 24-kDa subunits of the NADH dehydrogenase module in complex I, the first step in the mitochondrial respiratory chain, are active in hydrogenosomes of Trichomonas vaginalis. Like mitochondrial NADH dehydrogenase, the purified Trichomonas enzyme can reduce a variety of electron carriers including ubiquinone, but unlike the mitochondrial enzyme it can also reduce ferredoxin, the electron carrier used for hydrogen production. The presence of NADH dehydrogenase solves the long-standing conundrum of how hydrogenosomes regenerate NAD+ after malate oxidation. Phylogenetic analyses show that the Trichomonas 51-kDa homologue shares common ancestry with the mitochondrial enzyme. Recruitment of complex I subunits into a H2-producing pathway provides evidence that mitochondria and hydrogenosomes are aerobic and anaerobic homologues of the same endosymbiotically derived organelle.     

Temporal difference models describe higher-order learning in humans

The ability to use environmental stimuli to predict impending harm is critical for survival. Such predictions should be available as early as they are reliable. In pavlovian conditioning, chains of successively earlier predictors are studied in terms of higher-order relationships, and have inspired computational theories such as temporal difference learning. However, there is at present no adequate neurobiological account of how this learning occurs. Here, in a functional magnetic resonance imaging (fMRI) study of higher-order aversive conditioning, we describe a key computational strategy that humans use to learn predictions about pain. We show that neural activity in the ventral striatum and the anterior insula displays a marked correspondence to the signals for sequential learning predicted by temporal difference models. This result reveals a flexible aversive learning process ideally suited to the changing and uncertain nature of real-world environments. Taken with existing data on reward learning, our results suggest a critical role for the ventral striatum in integrating complex appetitive and aversive predictions to coordinate behaviour.     

Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox

The potential use of smallpox as a biological weapon has led to the production and stockpiling of smallpox vaccine and the immunization of some healthcare workers. Another public health goal is the licensing of a safer vaccine that could benefit the millions of people advised not to take the current one because they or their contacts have increased susceptibility to severe vaccine side effects. As vaccines can no longer be tested for their ability to prevent smallpox, licensing will necessarily include comparative immunogenicity and protection studies in non-human primates. Here we compare the highly attenuated modified vaccinia virus Ankara (MVA) with the licensed Dryvax vaccine in a monkey model. After two doses of MVA or one dose of MVA followed by Dryvax, antibody binding and neutralizing titres and T-cell responses were equivalent or higher than those induced by Dryvax alone. After challenge with monkeypox virus, unimmunized animals developed more than 500 pustular skin lesions and became gravely ill or died, whereas vaccinated animals were healthy and asymptomatic, except for a small number of transient skin lesions in animals immunized only with MVA.     

Has the Higgs boson been discovered?

The standard model of particle physics describes the strong and electroweak interactions of fermions (spin-1/2), gauge bosons (spin-1) and a final vital ingredient--the spin-0 Higgs boson, which gives masses to the other particles. But the Higgs boson has yet to be discovered, and its own mass is not specified by the theory. There is some evidence (although statistically not very significant) for its detection at a mass of about 115 GeV/c2, from electron-positron interactions at LEP (the Large Electron Positron collider). Indirect methods can also be used to constrain the mass of the Higgs boson, because it affects other observable quantities (for example, the mass of the W boson and some measurable properties of the Z boson). An indirect determination of the Higgs boson mass from the most recent measurements of such quantities yields a value compatible with 115 GeV/c2, but with some important caveats arising from inconsistencies in the present data.     

Contrasting origins of the upper mantle revealed by hafnium and lead isotopes from the Southeast Indian Ridge

The origin of the isotopic signature of Indian mid-ocean ridge basalts has remained enigmatic, because the geochemical composition of these basalts is consistent either with pollution from recycled, ancient altered oceanic crust and sediments, or with ancient continental crust or lithosphere. The radiogenic isotopic signature may therefore be the result of contamination of the upper mantle by plumes containing recycled altered ancient oceanic crust and sediments, detachment and dispersal of continental material into the shallow mantle during rifting and breakup of Gondwana, or contamination of the upper mantle by ancient subduction processes. The identification of a process operating on a scale large enough to affect major portions of the Indian mid-ocean ridge basalt source region has been a long-standing problem. Here we present hafnium and lead isotope data from across the Indian-Pacific mantle boundary at the Australian-Antarctic discordance region of the Southeast Indian Ridge, which demonstrate that the Pacific and Indian upper mantle basalt source domains were each affected by different mechanisms. We infer that the Indian upper-mantle isotope signature in this region is affected mainly by lower continental crust entrained during Gondwana rifting, whereas the isotope signature of the Pacific upper mantle is influenced predominantly by ocean floor subduction-related processes.     

Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity

Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced beta-cell mass. However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced beta-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. Moreover, wild-type mice on a high fat diet as well as K/K A(y) and ob/ob (also known as Lep/Lep) mice-two genetic models of obesity-have markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.