Crowdfunding not fit for clinical trials

Nature 527, 7579 (2015). doi:10.1038/527446e

Author: Phaik Yeong Cheah

Crowdfunding can raise money quickly and with minimal bureaucracy. But it should not be considered as a way to finance clinical trials because of potential ethical implications.One problem is that funding recipients are not accountable to the public because crowdfunding is unregulated. Another is

Lessons from EPA on tracking pollutants

Nature 527, 7579 (2015). doi:10.1038/527446f

Authors: Bo Zhang & Wayne S. Davis

In our opinion, China could learn from the success of the US Environmental Protection Agency (EPA) in providing open-access environmental information to the public. This would enhance the credibility of government decisions.The EPA's Toxics Release Inventory programme, in partnership with state agencies, collects data

Mental health: The mindful way

Nature 527, 7579 (2015). doi:10.1038/nj7579-553a

Author: Sabine Louët

The art of mindfulness offers benefits not only for scientists' mental health, but also for their work performance.

Turning point: Jason Lunden

Nature 527, 7579 (2015). doi:10.1038/nj7579-554a

Author: Virginia Gewin

A researcher who studies autism-like behaviour in mice takes inspiration from his own condition.

Claimed

Nature 527, 7579 (2015). doi:10.1038/527556a

Author: S. J. Rosenstein

First contact.

Correction

Nature 527, 7579 (2015). http://www.nature.com/doifinder/10.1038/527442a

The Comment article 'Einstein was no lone genius' (M.Janssen and J.RennNature527, 298–300; 2015 ) wrongly stated the dates during which Albert Einstein studied at the Swiss Federal Polytechnical School in Zurich. He was there

Imaging techniques: Super-resolution ultrasound

Nature 527, 7579 (2015). doi:10.1038/527451a

Authors: Ben Cox & Paul Beard

By infusing blood vessels with gas-filled microbubbles and using rapid ultrasound imaging to detect the bubbles, super-resolution imaging of an entire vessel system has been achieved in a rat brain. See Letter p.499

Ebola: Hidden reservoirs

Nature 527, 7579 (2015). doi:10.1038/527453a

Authors: Jonathan L. Heeney

West Africa's Ebola epidemic continues to reveal surprises. Although the animal species that originally passed the virus to people remains a mystery, a virus reservoir and persistent disease have been identified in some human survivors.

50 & 100 Years Ago

Nature 527, 7579 (2015). doi:10.1038/527455b

50 Years AgoThe use of rubber gloves during surgical operations became general about 1900 ... The object of an investigation was to obtain an estimation of how frequently wound infection originates from bacteria on the hands of operating staff ... Examination of the wounds

Planetary science: The Moon's tilt for gold

Nature 527, 7579 (2015). doi:10.1038/527455a

Authors: Robin Canup

The Moon's current orbit is at odds with theories predicting that its early orbit was in Earth's equatorial plane. Simulations now suggest that its orbit was tilted by gravitational interactions with a few large bodies. See Letter p.492

Blindness: Assassins of eyesight

Nature 527, 7579 (2015). doi:10.1038/527456a

Authors: Andrew D. Huberman & Rana N. El-Danaf

A molecular cascade involving the transcription factor SIX6 and its target gene p16INK4a causes the death of neurons that link the eye to the brain. This discovery deepens our understanding of a common form of blindness, glaucoma.

Correction

Nature 527, 7579 (2015). http://www.nature.com/doifinder/10.1038/527457a

The News & Views article 'Rehabilitation: Boost for movement' by Randolph J. Nudo (Nature527, 314–315; 2015) omitted to mention that the author has declared competing financial interests. Details are available in the online version of the article.

Collisionless encounters and the origin of the lunar inclination

Nature 527, 7579 (2015). doi:10.1038/nature16137

Authors: Kaveh Pahlevan & Alessandro Morbidelli

The Moon is generally thought to have formed from the debris ejected by the impact of a planet-sized object with the proto-Earth towards the end of planetary accretion. Models of the impact process predict that the lunar material was disaggregated into a circumplanetary disk and that lunar accretion subsequently placed the Moon in a near-equatorial orbit. Forward integration of the lunar orbit from this initial state predicts a modern inclination at least an order of magnitude smaller than the lunar value—a long-standing discrepancy known as the lunar inclination problem. Here we show that the modern lunar orbit provides a sensitive record of gravitational interactions with Earth-crossing planetesimals that were not yet accreted at the time of the Moon-forming event. The currently observed lunar orbit can naturally be reproduced via interaction with a small quantity of mass (corresponding to 0.0075–0.015 Earth masses eventually accreted to the Earth) carried by a few bodies, consistent with the constraints and models of late accretion. Although the encounter process has a stochastic element, the observed value of the lunar inclination is among the most likely outcomes for a wide range of parameters. The excitation of the lunar orbit is most readily reproduced via collisionless encounters of planetesimals with the Earth–Moon system with strong dissipation of tidal energy on the early Earth. This mechanism obviates the need for previously proposed (but idealized) excitation mechanisms, places the Moon-forming event in the context of the formation of Earth, and constrains the pristineness of the dynamical state of the Earth–Moon system.

Type-II Weyl semimetals

Nature 527, 7579 (2015). doi:10.1038/nature15768

Authors: Alexey A. Soluyanov, Dominik Gresch, Zhijun Wang, QuanSheng Wu, Matthias Troyer, Xi Dai & B. Andrei Bernevig

Fermions—elementary particles such as electrons—are classified as Dirac, Majorana or Weyl. Majorana and Weyl fermions had not been observed experimentally until the recent discovery of condensed matter systems such as topological superconductors and semimetals, in which they arise as low-energy excitations. Here we propose the existence of a previously overlooked type of Weyl fermion that emerges at the boundary between electron and hole pockets in a new phase of matter. This particle was missed by Weyl because it breaks the stringent Lorentz symmetry in high-energy physics. Lorentz invariance, however, is not present in condensed matter physics, and by generalizing the Dirac equation, we find the new type of Weyl fermion. In particular, whereas Weyl semimetals—materials hosting Weyl fermions—were previously thought to have standard Weyl points with a point-like Fermi surface (which we refer to as type-I), we discover a type-II Weyl point, which is still a protected crossing, but appears at the contact of electron and hole pockets in type-II Weyl semimetals. We predict that WTe2 is an example of a topological semimetal hosting the new particle as a low-energy excitation around such a type-II Weyl point. The existence of type-II Weyl points in WTe2 means that many of its physical properties are very different to those of standard Weyl semimetals with point-like Fermi surfaces.

Ultrafast ultrasound localization microscopy for deep super-resolution vascular imaging

Nature 527, 7579 (2015). doi:10.1038/nature16066

Authors: Claudia Errico, Juliette Pierre, Sophie Pezet, Yann Desailly, Zsolt Lenkei, Olivier Couture & Mickael Tanter

Non-invasive imaging deep into organs at microscopic scales remains an open quest in biomedical imaging. Although optical microscopy is still limited to surface imaging owing to optical wave diffusion and fast decorrelation in tissue, revolutionary approaches such as fluorescence photo-activated localization microscopy led to a striking increase in resolution by more than an order of magnitude in the last decade. In contrast with optics, ultrasonic waves propagate deep into organs without losing their coherence and are much less affected by in vivo decorrelation processes. However, their resolution is impeded by the fundamental limits of diffraction, which impose a long-standing trade-off between resolution and penetration. This limits clinical and preclinical ultrasound imaging to a sub-millimetre scale. Here we demonstrate in vivo that ultrasound imaging at ultrafast frame rates (more than 500 frames per second) provides an analogue to optical localization microscopy by capturing the transient signal decorrelation of contrast agents—inert gas microbubbles. Ultrafast ultrasound localization microscopy allowed both non-invasive sub-wavelength structural imaging and haemodynamic quantification of rodent cerebral microvessels (less than ten micrometres in diameter) more than ten millimetres below the tissue surface, leading to transcranial whole-brain imaging within short acquisition times (tens of seconds). After intravenous injection, single echoes from individual microbubbles were detected through ultrafast imaging. Their localization, not limited by diffraction, was accumulated over 75,000 images, yielding 1,000,000 events per coronal plane and statistically independent pixels of ten micrometres in size. Precise temporal tracking of microbubble positions allowed us to extract accurately in-plane velocities of the blood flow with a large dynamic range (from one millimetre per second to several centimetres per second). These results pave the way for deep non-invasive microscopy in animals and humans using ultrasound. We anticipate that ultrafast ultrasound localization microscopy may become an invaluable tool for the fundamental understanding and diagnostics of various disease processes that modify the microvascular blood flow, such as cancer, stroke and arteriosclerosis.

Correction

Nature 527, 7579 (2015). http://www.nature.com/doifinder/10.1038/527551a

The Technology Feature 'Connectomes make the map' (Nature526, 147–149; 2015) misnamed the MultiSEM model and gave the wrong citation in reference 3. MultiSEM 505 should have been Zeiss MultiSEM, and ref. 3 should have referred to Zingg,

Background: Analysis of single cells in their native environment is a powerful method to address key questions in developmental systems biology. Confocal microscopy imaging of intact tissues, followed by automatic image segmentation, provides a means to conduct cytometric studies while at the same time preserving crucial information about the spatial organization of the tissue and morphological features of the cells. This technique is rapidly evolving but is still not in widespread use among research groups that do not specialize in technique development, perhaps in part for lack of tools that automate repetitive tasks while allowing experts to make the best use of their time in injecting their domain-specific knowledge. Results: Here we focus on a well-established stem cell model system, the C. elegans gonad, as well as on two other model systems widely used to study cell fate specification and morphogenesis: the pre-implantation mouse embryo and the developing mouse olfactory epithelium. We report a pipeline that integrates machine-learning-based cell detection, fast human-in-the-loop curation of these detections, and running of active contours seeded from detections to segment cells. The procedure can be bootstrapped by a small number of manual detections, and outperforms alternative pieces of software we benchmarked on C. elegans gonad datasets. Using cell segmentations to quantify fluorescence contents, we report previously-uncharacterized cell behaviors in the model systems we used. We further show how cell morphological features can be used to identify cell cycle phase; this provides a basis for future tools that will streamline cell cycle experiments by minimizing the need for exogenous cell cycle phase labels. Conclusions: High-throughput 3D segmentation makes it possible to extract rich information from images that are routinely acquired by biologists, and provides insights — in particular with respect to the cell cycle — that would be difficult to derive otherwise.

Background: In recent years, hyperspectral microscopy techniques such as infrared or Raman microscopy have been applied successfully for diagnostic purposes. In many of the corresponding studies, it is common practice to measure one and the same sample under different types of microscopes. Any joint analysis of the two image modalities requires to overlay the images, so that identical positions in the sample are located at the same coordinate in both images. This step, commonly referred to as image registration, has typically been performed manually in the lack of established automated computational registration tools. Results: We propose a corresponding registration algorithm that addresses this registration problem, and demonstrate the robustness of our approach in different constellations of microscopes. First, we deal with subregion registration of Fourier Transform Infrared (FTIR) microscopic images in whole-slide histopathological staining images. Second, we register FTIR imaged cores of tissue microarrays in their histopathologically stained counterparts, and finally perform registration of Coherent anti-Stokes Raman spectroscopic (CARS) images within histopathological staining images. Conclusions: Our validation involves a large variety of samples obtained from colon, bladder, and lung tissue on three different types of microscopes, and demonstrates that our proposed method works fully automated and highly robust in different constellations of microscopes involving diverse types of tissue samples.

Background: Inferring gene regulatory network (GRN) has been an important topic in Bioinformatics. Many computational methods infer the GRN from high-throughput expression data. Due to the presence of time delays in the regulatory relationships, High-Order Dynamic Bayesian Network (HO-DBN) is a good model of GRN. However, previous GRN inference methods assume causal sufficiency, i.e. no unobserved common cause. This assumption is convenient but unrealistic, because it is possible that relevant factors have not even been conceived of and therefore un-measured. Therefore an inference method that also handles hidden common cause(s) is highly desirable. Also, previous methods for discovering hidden common causes either do not handle multi-step time delays or restrict that the parents of hidden common causes are not observed genes. Results: We have developed a discrete HO-DBN learning algorithm that can infer also hidden common cause(s) from discrete time series expression data, with some assumptions on the conditional distribution, but is less restrictive than previous methods. We assume that each hidden variable has only observed variables as children and parents, with at least two children and possibly no parents. We also make the simplifying assumption that children of hidden variable(s) are not linked to each other. Moreover, our proposed algorithm can also utilize multiple short time series (not necessarily of the same length), as long time series are difficult to obtain. Conclusions: We have performed extensive experiments using synthetic data on GRNs of size up to 100, with up to 10 hidden nodes. Experiment results show that our proposed algorithm can recover the causal GRNs adequately given the incomplete data. Using the limited real expression data and small subnetworks of the YEASTRACT network, we have also demonstrated the potential of our algorithm on real data, though more time series expression data is needed.

by Lin-Tai Da, Chao E, Baogen Duan, Chuanbiao Zhang, Xin Zhou, Jin Yu

Pyrophosphate ion (PPi) release during transcription elongation is a signature step in each nucleotide addition cycle. The kinetics and energetics of the process as well as how it proceeds with substantial conformational changes of the polymerase complex determine the mechano-chemical coupling mechanism of the transcription elongation. Here we investigated detailed dynamics of the PPi release process in a single-subunit RNA polymerase (RNAP) from bacteriophage T7, implementing all-atom molecular dynamics (MD) simulations. We obtained a jump-from-cavity kinetic model of the PPi release utilizing extensive nanosecond MD simulations. We found that the PPi release in T7 RNAP is initiated by the PPi dissociation from two catalytic aspartic acids, followed by a comparatively slow jump-from-cavity activation process. Combining with a number of microsecond long MD simulations, we also found that the activation process is hindered by charged residue associations as well as by local steric and hydrogen bond interactions. On the other hand, the activation is greatly assisted by a highly flexible lysine residue Lys472 that swings its side chain to pull PPi out. The mechanism can apply in general to single subunit RNA and DNA polymerases with similar molecular structures and conserved key residues. Remarkably, the flexible lysine or arginine residue appears to be a universal module that assists the PPi release even in multi-subunit RNAPs with charge facilitated hopping mechanisms. We also noticed that the PPi release is not tightly coupled to opening motions of an O-helix on the fingers domain of T7 RNAP according to the microsecond MD simulations. Our study thus supports the Brownian ratchet scenario of the mechano-chemical coupling in the transcription elongation of the single-subunit polymerase.