Visualization of ATP synthase dimers in mitochondria by electron cryo-tomography

This is the final version of the article. Available from the publisher via the DOI in this recordThe video component of this article can be found at http://www.jove.com/video/51228/Electron cryo-tomography is a powerful tool in structural biology, capable of visualizing the three-dimensional structure of biological samples, such as cells, organelles, membrane vesicles, or viruses at molecular detail. To achieve this, the aqueous sample is rapidly vitrified in liquid ethane, which preserves it in a close-to-native, frozen-hydrated state. In the electron microscope, tilt series are recorded at liquid nitrogen temperature, from which 3D tomograms are reconstructed. The signal-to-noise ratio of the tomographic volume is inherently low. Recognizable, recurring features are enhanced by subtomogram averaging, by which individual subvolumes are cut out, aligned and averaged to reduce noise. In this way, 3D maps with a resolution of 2 nm or better can be obtained. A fit of available high-resolution structures to the 3D volume then produces atomic models of protein complexes in their native environment. Here we show how we use electron cryo-tomography to study the in situ organization of large membrane protein complexes in mitochondria. We find that ATP synthases are organized in rows of dimers along highly curved apices of the inner membrane cristae, whereas complex I is randomly distributed in the membrane regions on either side of the rows. By subtomogram averaging we obtained a structure of the mitochondrial ATP synthase dimer within the cristae membrane.This work was supported by the Max Planck Society (K.M.D., B.D., A.W.M., T.B., T.B.B., D.J.M., and W.K.), the Cluster of Excellence Frankfurt “Macromolecular Complexes” funded by the Deutsche Forschungsgemeinschaft (W.K.) and a postdoctoral EMBO Long-Term Fellowship (V.A.M.G.)

Clades and clans: a comparison study of two evolutionary models

The Yule-Harding-Kingman (YHK) model and the proportional to distinguishable arrangements (PDA) model are two binary tree generating models that are widely used in evolutionary biology. Understanding the distributions of clade sizes under these two models provides valuable insights into macro-evolutionary processes, and is important in hypothesis testing and Bayesian analyses in phylogenetics. Here we show that these distributions are log-convex, which implies that very large clades or very small clades are more likely to occur under these two models. Moreover, we prove that there exists a critical value $\kappa(n)$ for each $n\geqslant 4$ such that for a given clade with size $k$, the probability that this clade is contained in a random tree with $n$ leaves generated under the YHK model is higher than that under the PDA model if $1<k<\kappa(n)$, and lower if $\kappa(n)<k<n$. Finally, we extend our results to binary unrooted trees, and obtain similar results for the distributions of clan sizes.Comment: 21page

Scalar-mediated ttˉt\bar t forward-backward asymmetry

A large forward-backward asymmetry in $t\bar t$ production, for large invariant mass of the $t\bar t$ system, has been recently observed by the CDF collaboration. Among the scalar mediated mechanisms that can explain such a large asymmetry, only the t-channel exchange of a color-singlet weak-doublet scalar is consistent with both differential and integrated $t\bar t$ cross section measurements. Constraints from flavor changing processes dictate a very specific structure for the Yukawa couplings of such a new scalar. No sizable deviation in the differential or integrated $t\bar t$ production cross section is expected at the LHC.Comment: 22 pages, 1 figure and 2 tables. v2: Corrected Eqs.(50,51,74), adapted Fig.1, Tab.1 and relevant discussions. Extended discussion of top decay and single to

Syntaxin 16 is a master recruitment factor for cytokinesis

Recently it was shown that both recycling endosome and endosomal sorting complex required for transport (ESCRT) components are required for cytokinesis, in which they are believed to act in a sequential manner to bring about secondary ingression and abscission, respectively. However, it is not clear how either of these complexes is targeted to the midbody and whether their delivery is coordinated. The trafficking of membrane vesicles between different intracellular organelles involves the formation of soluble N-ethylmalei­mide–sensitive factor attachment protein receptor (SNARE) complexes. Although membrane traffic is known to play an important role in cytokinesis, the contribution and identity of intracellular SNAREs to cytokinesis remain unclear. Here we demonstrate that syntaxin 16 is a key regulator of cytokinesis, as it is required for recruitment of both recycling endosome–associated Exocyst and ESCRT machinery during late telophase, and therefore that these two distinct facets of cytokinesis are inextricably linked

Establishment of a human cell-based in vitro battery to assess developmental neurotoxicity hazard of chemicals

Developmental neurotoxicity (DNT) is a major safety concern for all chemicals of the human exposome. However, DNT data from animal studies are available for only a small percentage of manufactured compounds. Test methods with a higher throughput than current regulatory guideline methods, and with improved human relevance are urgently needed. We therefore explored the feasibility of DNT hazard assessment based on new approach methods (NAMs). An in vitro battery (IVB) was assembled from ten individual NAMs that had been developed during the past years to probe effects of chemicals on various fundamental neurodevelopmental processes. All assays used human neural cells at different developmental stages. This allowed us to assess disturbances of: (i) proliferation of neural progenitor cells (NPC); (ii) migration of neural crest cells, radial glia cells, neurons and oligodendrocytes; (iii) differentiation of NPC into neurons and oligodendrocytes; and (iv) neurite outgrowth of peripheral and central neurons. In parallel, cytotoxicity measures were obtained. The feasibility of concentration-dependent screening and of a reliable biostatistical processing of the complex multi-dimensional data was explored with a set of 120 test compounds, containing subsets of pre-defined positive and negative DNT compounds. The battery provided alerts (hit or borderline) for 24 of 28 known toxicants (82% sensitivity), and for none of the 17 negative controls. Based on the results from this screen project, strategies were developed on how IVB data may be used in the context of risk assessment scenarios employing integrated approaches for testing and assessment (IATA).European Food Safety Authority (EFSA-Q-2018-00308), the Danish Environmental Protection Agency (EPA), Denmark, under the grant number MST-667-00205, the State Ministry of Baden-Wuerttemberg, Germany, for Economic Affairs, Labour and Tourism (NAM-Accept), the project CERST (Center for Alternatives to Animal Testing) of the Ministry for culture and science of the State of North-Rhine Westphalia, Germany (file number 233–1.08.03.03- 121972/131–1.08.03.03–121972), the European Chemical Industry Council Long-Range Research Initiative (Cefic LRI) under the project name AIMT11 and the BMBF (NeuroTool). It has also received funding from the European Union's Horizon 2020 research and innovation program under grant agreements No. 964537 (RISK-HUNT3R), No. 964518 (ToxFree), No. 101057014 (PARC) and No. 825759 (ENDpoiNTs)

Gambling disorder and suicide: An overview of the associated co-morbidity and clinical characteristics

Context: A high prevalence of suicide and attempted suicide in relation to gambling disorder is in increasing evidence in current scientific data. The objective of this review was to explore if there was a primary correlation between psychiatric co-morbidities and gambling and/or a secondary correlation with suicide acts. Evidence Acquisition: We performed a critical analysis of the most recent papers in the scientific literature in this regard and report on the most significant findings. Results: A direct relationship between gambling and suicidality was highlighted in a number of European, American, and Asian countries. However, it was not clear whether or not gambling increased the risk of suicidal behavior. Twogeneral trends were noted. The first was that gamblers with extreme gambling behavior incurred economic losses and debts to such an extent that suicidal acts appeared to be the only solution. The second was that suicidal acts by gamblers were precipitated by interpersonal and/or working challenges, in conjunction with personality traits of impulsivity and psychiatric co-morbidities. Conclusions: A combination of impulsivity, certain psychiatric disorders, and social factors may explain the frequent occurrence of suicidal behavior in gamblers

Massive Spin-2 States as the Origin of the Top Quark Forward-Backward Asymmetry

We show that the anomalously large top quark forward-backward asymmetry observed by CDF and D\O\, can naturally be accommodated in models with flavor-violating couplings of a new massive spin-2 state to quarks. Regardless of its origin, the lowest-order couplings of a spin-2 boson to fermions are analogous to the coupling of the graviton to energy/momentum, leading to strong sensitivity of the effects associated with its virtual exchange to the energy scales at hand. Precisely due to this fact, the observed dependence of the asymmetry on the $t\bar t$ invariant mass fits nicely into the proposed framework. In particular, we find a vast parameter space which can lead to the central value for the observed forward-backward asymmetry in the high mass bin, while being in accord with all of the existing experimental constraints.Comment: added discussion of differential observables at the LHC, matches version accepted for publication in JHE

LHC diphoton Higgs signal and top quark forward-backward asymmetry in quasi-inert Higgs doublet model

In the quasi-inert Higgs doublet model, we study the LHC diphoton rate for a standard model-like Higgs boson and the top quark forward-backward asymmetry at Tevatron. Taking into account the constraints from the vacuum stability, unitarity, electroweak precision tests, flavor physics and the related experimental data of top quark, we find that compared with the standard model prediction, the diphoton rate of Higgs boson at LHC can be enhanced due to the light charged Higgs contributions, while the measurement of the top quark forward-backward asymmetry at Tevatron can be explained to within $1\sigma$ due to the non-standard model neutral Higgs bosons contributions. Finally, the correlations between the two observables are discussed.Comment: 14 pages, 5 figues. Version to appear in JHEP, some references adde

Quantum dynamics in strong fluctuating fields

A large number of multifaceted quantum transport processes in molecular systems and physical nanosystems can be treated in terms of quantum relaxation processes which couple to one or several fluctuating environments. A thermal equilibrium environment can conveniently be modelled by a thermal bath of harmonic oscillators. An archetype situation provides a two-state dissipative quantum dynamics, commonly known under the label of a spin-boson dynamics. An interesting and nontrivial physical situation emerges, however, when the quantum dynamics evolves far away from thermal equilibrium. This occurs, for example, when a charge transferring medium possesses nonequilibrium degrees of freedom, or when a strong time-dependent control field is applied externally. Accordingly, certain parameters of underlying quantum subsystem acquire stochastic character. Herein, we review the general theoretical framework which is based on the method of projector operators, yielding the quantum master equations for systems that are exposed to strong external fields. This allows one to investigate on a common basis the influence of nonequilibrium fluctuations and periodic electrical fields on quantum transport processes. Most importantly, such strong fluctuating fields induce a whole variety of nonlinear and nonequilibrium phenomena. A characteristic feature of such dynamics is the absence of thermal (quantum) detailed balance.Comment: review article, Advances in Physics (2005), in pres