bluuebunny/crossref_metadata_2025 huggingface dataset:
Reversible inhibition of the ClpP protease via an N-terminal conformational switch
Authors: Vahidi Siavash , Ripstein Zev A. , Bonomi Massimiliano , Yuwen Tairan , Mabanglo Mark F. , Juravsky Jordan B. , Rizzolo Kamran , Velyvis Algirdas , Houry Walid A. , Vendruscolo Michele , Rubinstein John L. , Kay Lewis E.
Published: June 2018

Significance

ClpP is a protease that degrades damaged or misfolded proteins. Consistent with its critical role in maintaining cellular homeostasis, inhibiting and dysregulating ClpP function has shown promise in fighting antibiotic resistance and in targeting cancer cells in acute myeloid leukemia. Here we identify a conformational switch in ClpP that, upon mutagenesis, leads to a catalytically inactive structure that can be reactivated through the binding of small-molecule activators. This functional hotspot therefore represents a drug target for allosteric inhibition of ClpP. The combination of methyl–transverse relaxation-optimized spectroscopy (TROSY) NMR, cryo-EM, and molecular simulation methods employed here provides a detailed characterization of ClpP along with the promise of crucial insights into the structure–function relationship of molecular machines in general.
Kv2 potassium channels form endoplasmic reticulum/plasma membrane junctions via interaction with VAPA and VAPB
Authors: Johnson Ben , Leek Ashley N. , Solé Laura , Maverick Emily E. , Levine Tim P. , Tamkun Michael M.
Published: June 2018

Significance

In addition to functioning as a delayed-rectifier K
+
channel, Kv2.1 interacts with the cortical endoplasmic reticulum (ER) in hippocampal neurons to form somatic ER/plasma membrane (ER/PM) junctions. Neuronal activity and insult induce Kv2.1 release from the cortical ER and subsequent ER withdrawal from the PM. Neuronal ER/PM contacts represent >10% of the cell surface and play roles in membrane trafficking, the regulation of burst firing, Ca
2+
homeostasis, and control of PM lipid. We report here that Kv2 channel–VAMP-associated protein (VAP) interaction tethers the cortical ER to the PM via a noncanonical FFAT motif contained within the channel C terminus. Since VAPs have a wide-ranging interactome, Kv2-induced ER remodeling and VAP concentration at ER/PM contacts likely play a central role in neuronal physiology.
Inhibitor of intramembrane protease RseP blocks the σ
E
response causing lethal accumulation of unfolded outer membrane proteins
Authors: Konovalova Anna , Grabowicz Marcin , Balibar Carl J. , Malinverni Juliana C. , Painter Ronald E. , Riley Daniel , Mann Paul A. , Wang Hao , Garlisi Charles G. , Sherborne Brad , Rigel Nathan W. , Ricci Dante P. , Black Todd A. , Roemer Terry , Silhavy Thomas J. , Walker Scott S.
Published: June 2018

Significance

The σ
E
stress response monitors outer membrane protein (OMP) assembly. Uninduced, σ
E
is sequestered to the plasma membrane by its anti-sigma factor, RseA. Mutations perturbing OMP biogenesis induce degradation of RseA by the proteases DegS and RseP, liberating σ
E
so it can activate gene expression. σ
E
activity is essential in wild-type
Escherichia coli
, although why it is essential has remained unclear. We report that batimastat is an inhibitor of RseP, preventing it from cleaving RseA and thereby causing a lethal decrease in σ
E
activity. Surprisingly, lethality is caused by the accumulation of unfolded OMPs, despite a wild-type OMP biogenesis pathway. Hence, σ
E
is essential because it must fine-tune OMP synthesis, assembly, and degradation to prevent the appearance of toxic unfolded OMPs.
The mutagen and carcinogen cadmium is a high-affinity inhibitor of the zinc-dependent MutLα endonuclease
Authors: Sherrer Shanen M. , Penland Elisabeth , Modrich Paul
Published: June 2018

Significance

MutLα (MLH1-PMS2 heterodimer) is an endonuclease that acts during an early step of eukaryotic mismatch repair. We show that human MutLα endonuclease copurifies with two equivalents of bound zinc, at least one of which resides within the endonuclease active site. We also show that cadmium, a known inhibitor of zinc-dependent enzymes and a potent mutagen and carcinogen, is a high-affinity inhibitor of MutLα endonuclease and that exogenous MutLα significantly reverses the mismatch repair defect in cadmium-treated human cell nuclear extract or nuclear extract prepared from cadmium-treated cells. Because the mutagenic action of cadmium is largely due to the selective inhibition of mismatch repair, these findings suggest that MutLα is a primary cadmium target for mutagenesis and presumably, carcinogenesis as well.
The molecular recognition of phosphatidic acid by an amphipathic helix in Opi1
Authors: Hofbauer Harald F. , Gecht Michael , Fischer Sabine C. , Seybert Anja , Frangakis Achilleas S. , Stelzer Ernst H.K. , Covino Roberto , Hummer Gerhard , Ernst Robert
Published: June 2018

A key event in cellular physiology is the decision between membrane biogenesis and fat storage. Phosphatidic acid (PA) is an important intermediate at the branch point of these pathways and is continuously monitored by the transcriptional repressor Opi1 to orchestrate lipid metabolism. In this study, we report on the mechanism of membrane recognition by Opi1 and identify an amphipathic helix (AH) for selective binding of PA over phosphatidylserine (PS). The insertion of the AH into the membrane core renders Opi1 sensitive to the lipid acyl chain composition and provides a means to adjust membrane biogenesis. By rational design of the AH, we tune the membrane-binding properties of Opi1 and control its responsiveness in vivo. Using extensive molecular dynamics simulations, we identify two PA-selective three-finger grips that tightly bind the PA phosphate headgroup while interacting less intimately with PS. This work establishes lipid headgroup selectivity as a new feature in the family of AH-containing membrane property sensors.
Spindle rotation in human cells is reliant on a MARK2-mediated equatorial spindle-centering mechanism
Authors: Zulkipli Ihsan , Clark Joanna , Hart Madeleine , Shrestha Roshan L. , Gul Parveen , Dang David , Kasichiwin Tami , Kujawiak Izabela , Sastry Nishanth , Draviam Viji M.
Published: June 2018

The plane of cell division is defined by the final position of the mitotic spindle. The spindle is pulled and rotated to the correct position by cortical dynein. However, it is unclear how the spindle’s rotational center is maintained and what the consequences of an equatorially off centered spindle are in human cells. We analyzed spindle movements in 100s of cells exposed to protein depletions or drug treatments and uncovered a novel role for MARK2 in maintaining the spindle at the cell’s geometric center. Following MARK2 depletion, spindles glide along the cell cortex, leading to a failure in identifying the correct division plane. Surprisingly, spindle off centering in MARK2-depleted cells is not caused by excessive pull by dynein. We show that MARK2 modulates mitotic microtubule growth and length and that codepleting mitotic centromere-associated protein (MCAK), a microtubule destabilizer, rescues spindle off centering in MARK2-depleted cells. Thus, we provide the first insight into a spindle-centering mechanism needed for proper spindle rotation and, in turn, the correct division plane in human cells.
A forward genetic screen identifies chaperone CNX-1 as a conserved biogenesis regulator of ERG K+ channels
Authors: Bai Xue , Li Kai , Yao Li , Kang Xin-Lei , Cai Shi-Qing
Published: June 2018

The human ether-a-go-go–related gene (hERG) encodes a voltage-gated potassium channel that controls repolarization of cardiac action potentials. Accumulating evidence suggests that most disease-related hERG mutations reduce the function of the channel by disrupting protein biogenesis of the channel in the endoplasmic reticulum (ER). However, the molecular mechanism underlying the biogenesis of ERG K+ channels is largely unknown. By forward genetic screening, we identified an ER-located chaperone CNX-1, the worm homologue of mammalian chaperone Calnexin, as a critical regulator for the protein biogenesis of UNC-103, the ERG-type K+ channel in Caenorhabditis elegans. Loss-of-function mutations of cnx-1 decreased the protein level and current density of the UNC-103 K+ channel and suppressed the behavioral defects caused by a gain-of-function mutation in unc-103. Moreover, CNX-1 facilitated tetrameric assembly of UNC-103 channel subunits in a liposome-assisted cell-free translation system. Further studies showed that CNX-1 act in parallel to DNJ-1, another ER-located chaperone known to regulate maturation of UNC-103 channels, on controlling the protein biogenesis of UNC-103. Importantly, Calnexin interacted with hERG proteins in the ER in HEK293T cells. Deletion of calnexin reduced the expression and current densities of endogenous hERG K+ channels in SH-SY5Y cells. Collectively, we reveal an evolutionarily conserved chaperone CNX-1/Calnexin controlling the biogenesis of ERG-type K+ channels.
Soap film spanning an elastic link
Authors: Bevilacqua Giulia , Lussardi Luca , Marzocchi Alfredo
Published: June 2018

We study the equilibrium problem of a system consisting of several Kirchhoff rods linked in an arbitrary way and tied by a soap film, using techniques of the Calculus of Variations. We prove the existence of a solution with minimum energy, which may be quite irregular, and perform experiments confirming the kind of surface predicted by the model.
A Prospective Pilot Study Comparing Rate of Processing Techniques in Autologous Fat Grafting
Authors: Hanson Summer E , Garvey Patrick B , Chang Edward I , Reece Gregory , Liu Jun , Butler Charles E
Published: June 2018

Background

Autologous fat grafting (AFG) is increasing in popularity to address a variety of defects. There is interest in developing techniques to harvest, process, and inject fat to improve clinical outcomes as well as operative efficiency.

Objectives

The purpose of this pilot study is to compare the rate of graft processing of two commercially available systems for graft preparation.

Methods

Twenty consecutive cases using an active filtration system (system-AF) were observed followed by 20 consecutive cases using a passive filtration system (system-PF) to compare efficiency rate. Fat processing rate was quantified in milliliters/minute.

Results

Forty patients underwent AFG with no differences in patient characteristics between the groups. There was 1 incidence of palpable fat necrosis per group (5%). For all patients, this was the first fat grafting procedure; 20% of patients (n = 4 per group) had additional fat grafting. Overall, the rate of adipose tissue preparation was significantly higher with system-AF compared to system-PF (19.8 mL/min vs 5.3 mL/min, P ≤ 0.001). The resulting percent of graftable fat was comparable (AF: 41% vs PF: 42%; P = 0.83).

Conclusions

Time and motion studies such as this provide a means to systematically document each of the steps involved in fat grafting in a reliable fashion. The authors demonstrate a significantly higher rate of lipoaspirate processing using an active filtration system compared to a passive system. Further large-scale studies of the efficacy and cost analysis of AFG are a necessary component of determining best practices in the field.

Level of Evidence: 2
A Rigidity Theorem for Surfaces in Schwarzschild Manifold
Authors: Chen Po-Ning , Zhang Xiangwen
Published: June 2018

In this article, we prove a rigidity theorem for isometric embeddings into the Schwarzschild manifold, by using the variational formula of quasi-local mass.
Intraneural IFG-1 in Cryopreserved Nerve Isografts Increase Neural Regeneration and Functional Recovery in the Rat Sciatic Nerve
Authors: González Porto Sara Alicia , Domenech Nieves , Blanco Francisco J , Centeno Cortés Alberto , Rivadulla Fernández Casto , Álvarez Jorge Ángel , Sánchez Ibáñez Jacinto , Rendal Vázquez Esther
Published: June 2018

BACKGROUND

Insulin-like growth factor 1 (IGF-1) was found to stimulate Schwann cell mitosis. Exogenous IGF-1 may improve nerve regeneration after cryopreservation.

OBJECTIVE

To evaulate the effect of intraneural administration of IGF-1 in cryopreserved nerve isografts.

METHODS

Eighteen millimeter grafts were used for bridging an 18-mm defect in the rat sciatic nerve. A total of 57 rats were randomly divided into three groups: (1) autograft (Group 1); (2) cryopreserved isograft (Group 2); (3) cryopreserved isograft with intraneural IGF-1 administration (Group 3). 12 weeks after surgery, functional recovery (Sciatic functional index [SFI], Swing speed [SS], nerve conduction velocity [NCV], amplitude of compound motor action potentials [CMAP], and gastrocnemius muscle index [GMI]) and nerve regeneration (myelin sheath area, total fiber counts, fiber density, and fiber width) were all evaluated.

RESULTS

The intraneural injection of IGF-1 significantly improved SFI and SS at weeks 10 and 12. There were no statistical differences between Groups 1 and 3 in any of the SFI or SS evaluations. CMAP and NCV in Group 1 were significantly higher than in Groups 2 and 3, and Group 3 had significantly higher CMAP and NCV compared to Group 2. No significant differences were found in fiber width. The number of nerve fibers, percentage of myelinated fibers, fiber density, and GMI was significantly higher in Group 1 compared to Group 2, but no significant differences were found between Groups 1 and 3.

CONCLUSION

The results show that intraneural injection of IGF-1 in an 18 mm cryopreserved isograft improve axonal regeneration and functional recovery.
Orthodox and Unorthodox Uses of Electronic Cigarettes: A Surveillance of YouTube Video Content
Authors: Guy Mignonne C , Helt Jacob , Palafox Sherilyn , Green Kellie , Soule Eric K , Maloney Sarah F , Eissenberg Thomas , Fagan Pebbles
Published: June 2018

Introduction

Open electronic cigarette (e-cigarette) systems are customizable by consumers and often allow for potential “unorthodox” use of the product; that is, use not as intended by the manufacturer. Little is known about the types and prevalence of unorthodox uses and how these practices are transmitted via popular social media.

Methods

Monthly searches of YouTube were conducted from June through November 2016 using the following search terms: “e-cigarettes,” “vaping,” and “e-juice.” After collecting static and dynamic data on the 150 videos identified, two coders independently coded videos for general information, unorthodox use behaviors, health claims, and production quality and characteristics for orthodox and unorthodox use. Intercoder reliability was high (Cohen’s κ 0.81, p < .001).

Results

One hundred fifty videos were included in the study with a total of 115 551 563 views. We identified nine categories of unorthodox uses of e-cigarettes. Unorthodox use was three times as prevalent as orthodox use. Seventy-seven percent of the unorthodox use videos included recreational e-cigarette use, 57% included modification of mechanical parts and components, and 44.6% included unorthodox substance application (dripping). There were more than twice as many social media links in videos depicting unorthodox compared to orthodox use, but the level of engagement was lower for unorthodox use.

Conclusions

E-cigarette unorthodox use on YouTube is more prevalent than orthodox use, suggesting the need to further investigate the prevalence of unorthodox use among e-cigarette users and the influence of social media on consumer uptake of unorthodox and orthodox uses of e-cigarettes.

Implications

The US Food and Drug Administration has regulatory authority over e-cigarettes, parts and components. Many e-cigarettes currently marketed are open systems. Closed systems may allow less manipulation and may influence the safety of these products. This study provides valuable information on ways that open system e-cigarettes are used and it can inform safety tests that can be conducted by the US Food and Drug Administration to determine whether or not these products should remain on the market. In addition, our definitions of unorthodox use can be incorporated into the Population Assessment of Tobacco on Health Study to better understand the prevalence of these behaviors.
Spin-triplet supercurrents in Josephson junctions containing strong ferromagnetic materials
Authors: Birge Norman O.
Published: June 2018

The proximity effect between a superconducting material and a non-superconducting normal metal can extend over distances of the order of micrometres at sufficiently low temperatures. If the normal metal is replaced by a ferromagnetic material, the spatial extent of the proximity effect drops precipitously due to the exchange splitting between the majority and minority spin bands in the ferromagnet. In 2001, several theorists predicted that spin-triplet pair correlations could be induced in proximity systems involving multiple ferromagnetic materials (or multiple domains in one material) with non-collinear magnetizations. Such spin-triplet pair correlations should extend deep into the ferromagnet, producing a long-range proximity effect. In this paper, we review our experimental work in this area, which has focused primarily on Josephson junctions containing strong ferromagnetic materials. We show that Josephson junctions containing particular combinations of strong ferromagnetic materials can carry spin-triplet supercurrent over distances of at least several tens of nanometres, whereas spin-singlet supercurrent in similar samples decays over a length scale of about 1 nm. We also mention important work by other groups; however, this article is not intended to be a review of the whole field.

This article is part of the theme issue ‘Andreev bound states’.
Non-equilibrium charge and spin transport in superconducting–ferromagnetic–superconducting point contacts
Authors: Holmqvist C. , Belzig W. , Fogelström M.
Published: June 2018

The conventional Josephson effect may be modified by introducing spin-active scattering in the interface layer of the junction. Here, we discuss a Josephson junction consisting of two s-wave superconducting leads coupled over a classical spin that precesses with the Larmor frequency due to an external magnetic field. This magnetically active interface results in a time-dependent boundary condition with different tunnelling amplitudes for spin-up and -down quasi-particles and where the precession produces spin-flip scattering processes. As a result, the Andreev states develop sidebands and a non-equilibrium population that depend on the details of the spin precession. The Andreev states carry a steady-state Josephson charge current and a time-dependent spin current, whose current–phase relations could be used to characterize the precessing spin. The spin current is supported by spin-triplet correlations induced by the spin precession and creates a feedback effect on the classical spin in the form of a torque that shifts the precession frequency. By applying a bias voltage, the Josephson frequency adds another complexity to the situation and may create resonances together with the Larmor frequency. These Shapiro resonances manifest as torques and, under suitable conditions, are able to reverse the direction of the classical spin in sub-nanosecond time. Another characteristic feature is the subharmonic gap structure in the DC charge current displaying an even–odd effect attributable to precession-assisted multiple Andreev reflections.

This article is part of the theme issue ‘Andreev bound states’.
Study on Green’s function on topological insulator surface
Authors: Lu Bo , Tanaka Yukio
Published: June 2018

In the theory of superconducting junctions, Green’s function has an important role for obtaining Andreev bound states, local density of states and Josephson current in a systematic way. In this article, we show how to construct Green’s function on the surface of a topological insulator following McMillan’s formalism where the energy spectrum of electrons obeys a linear dispersion. For a model of a superconductor (S)/ferromagnet (F)/normal metal (N) junction, we show that the generation of a Majorana fermion gives rise to the enhanced local density of states and pair amplitude of odd-frequency pairing. We also derive an extended Furusaki–Tsukada’s formula of DC Josephson current in S/F/S junctions. The obtained Josephson current depends on the direction and magnitude of the magnetization.

This article is part of the theme issue ‘Andreev bound states’.
Out-of-equilibrium spin transport in mesoscopic superconductors
Authors: Quay C. H. L. , Aprili M.
Published: June 2018

The excitations in conventional superconductors, Bogoliubov quasi-particles, are spin-

fermions but their charge is energy-dependent and, in fact, zero at the gap edge. Therefore, in superconductors (unlike normal metals) spin and charge degrees of freedom may be separated. In this article, we review spin injection into conventional superconductors and focus on recent experiments on mesoscopic superconductors. We show how quasi-particle spin transport and out-of-equilibrium spin-dependent superconductivity can be triggered using the Zeeman splitting of the quasi-particle density of states in thin-film superconductors with small spin-mixing scattering. Finally, we address the spin dynamics and the feedback of quasi-particle spin imbalances on the amplitude of the superconducting energy gap.

This article is part of the theme issue ‘Andreev bound states’.
Multifaceted properties of Andreev bound states: interplay of symmetry and topology
Authors: Mizushima T. , Machida K.
Published: June 2018

Andreev bound states (ABSs) ubiquitously emerge as a consequence of non-trivial topological structures of the order parameter of superfluids and superconductors and significantly contribute to thermodynamics and low-energy quantum transport phenomena. We here share the current status of our knowledge on their multifaceted properties such as Majorana fermions and odd-frequency pairing. A unified concept behind ABSs originates from a soliton state in the one-dimensional Dirac equation with mass domain wall and interplay of ABSs with symmetry and topology enrich their physical characteristics. We make an overview of ABSs with a special focus on superfluid
3
He. The quantum liquid confined to restricted geometries serves as a rich repository of noteworthy quantum phenomena, such as the mass acquisition of Majorana fermions driven by spontaneous symmetry breaking, topological quantum criticality, Weyl superfluidity and the anomalous magnetic response. The marriage of the superfluid
3
He and nano-fabrication techniques will take one to a new horizon of topological quantum phenomena associated with ABSs.

This article is part of the theme issue ‘Andreev bound states’.
Andreev bound states and their signatures
Authors: Sauls J. A.
Published: June 2018

Many of the properties of superconductors related to quantum coherence are revealed when the superconducting state is forced to vary in space in response to an external magnetic field, a proximity contact, an interface to a ferromagnet or to impurities embedded in the superconductor. Among the earliest examples is
Andreev reflection
of an electron into a retro-reflected hole at a normal-superconducting interface. In regions of strong inhomogeneity, multiple Andreev reflection leads to the formation of sub-gap states,
Andreev bound states
, with excitation energies below the superconducting gap. These states play a central role in our understanding of inhomogeneous superconductors. The discoveries of unconventional superconductivity in many classes of materials, advances in fabrication of superconducting/ferromagnetic hybrids and nanostructures for confining superfluid
3
He, combined with theoretical developments in topological quantum matter have dramatically expanded the significance of branch conversion scattering and Andreev bound state formation. This collection of articles highlights developments in inhomogeneous superconductivity, unconventional superconductivity and topological phases of superfluid
3
He, in which Andreev scattering and bound states underpin much of the physics of these systems. This article provides an introduction to the basic physics of Andreev scattering, bound-state formation and their signatures. The goal is both an introduction for interested readers who are not already experts in the field, and to highlight examples in which branch conversion scattering and Andreev bound states provide unique signatures in the transport properties of superconductors.

This article is part of the theme issue ‘Andreev bound states’.
A tradeoff between tolerance and resistance to a major fungal pathogen in elite wheat cultivars
Authors: Mikaberidze Alexey , McDonald Bruce A.
Published: June 2018

Tolerance and resistance represent two strategies that hosts evolved to protect themselves from pathogens. Tolerance alleviates the reduction in host fitness due to infection without reducing a pathogen’s growth, while resistance reduces pathogen growth. We investigated tolerance of wheat to the major fungal pathogen Zymoseptoria tritici in 335 elite wheat cultivars.

We used a novel digital phenotyping approach that included 11,152 infected leaves and counted 2,069,048 pathogen fruiting bodies.

We discovered a new component of tolerance that is based on the relationship between the green area remaining on a leaf and the number of pathogen fruiting bodies. We found a negative correlation between tolerance and resistance among intolerant cultivars, presenting the first compelling evidence for a tradeoff between tolerance and resistance to plant pathogens. Surprisingly, the tradeoff arises due to limits in the host resources available to the pathogen and not due to metabolic constraints, contrary to what ecological theory suggests.

The mechanism underlying this tradeoff may be relevant for many plant diseases in which the amount of host resources available to the pathogen can limit the pathogen population. Our analysis indicates that European wheat breeders may have selected for tolerance instead of resistance to an important pathogen.
Software update: Moving the R package sommer to multivariate mixed models for genome-assisted prediction
Authors: Covarrubias-Pazaran Giovanny
Published: June 2018

In the last decade the use of mixed models has become a pivotal part in the implementation of genome-assisted prediction in plant and animal breeding programs. Exploiting the use genetic correlation among traits through multivariate predictions has been proposed in recent years as a way to boost prediction accuracy and understand pleiotropy and other genetic and ecological phenomena better. Multiple mixed model solvers able to use relationship matrices or deal with marker-based incidence matrices have been released in the last years but multivariate versions are scarse. Such solvers have become quite popular in plant and animal breeding thanks to user-friendly platforms such as R. Among such software one of the most recent and popular is the sommer package. In this short communication we discuss the update of the package that is able to run multivariate mixed models with multiple random effects and different covariance structures at the level of random effects and trait-to-trait covariance along with other functionalities for genetic analysis and field trial analysis to enhance the genome-assisted prediction capabilities of researchers.
Recent mixing of Vibrio parahaemolyticus populations
Authors: Yang Chao , Pei Xiaoyan , Wu Yarong , Yan Lin , Yan Yanfeng , Song Yuqin , Coyle Nicola , Martinez-Urtaza Jaime , Quince Christopher , Hu Qinghua , Jiang Min , Feil Edward , Yang Dajin , Song Yajun , Zhou Dongsheng , Yang Ruifu , Falush Daniel , Cui Yujun
Published: June 2018

Background

Humans have profoundly affected the ocean environment but little is known about anthropogenic effects on the distribution of microbes. Vibrio parahaemolyticus is found in warm coastal waters and causes gastroenteritis in humans and economically significant disease in shrimps.

Results

Based on data from 1,103 genomes, we show that V. parahaemolyticus is divided into four diverse populations, VppUS1, VppUS2, VppX and VppAsia. The first two are largely restricted to the US and Northern Europe, while the others are found worldwide, with VppAsia making up the great majority of isolates in the seas around Asia. Patterns of diversity within and between the populations are consistent with them having arisen by progressive divergence via genetic drift during geographical isolation. However, we find that there is substantial overlap in their current distribution. These observations can be reconciled without requiring genetic barriers to exchange between populations if dispersal between oceans has increased dramatically in the recent past. We found that VppAsia isolates from the US have an average of 1.01% more shared ancestry with VppUS1 and VppUS2 isolates than VppAsia isolates from Asia itself. Based on time calibrated trees of divergence within epidemic lineages, we estimate that recombination affects about 0.017% of the genome per year, implying that the genetic mixture has taken place within the last few decades.

Conclusions

These results suggest that human activity, such as shipping and aquatic products trade, are responsible for the change of distribution pattern of this marine species.
Mechanics of exploration inDrosophila melanogaster
Authors: Loveless Jane , Lagogiannis Konstantinos , Webb Barbara
Published: June 2018

TheDrosophilalarva executes a stereotypical exploratory routine that appears to consist of stochastic alternation between straight peristaltic crawling and reorientation events through lateral bending. We present a model of larval mechanics for axial and transverse motion over a planar substrate, and use it to develop a simple, reflexive neuromuscular model from physical principles. In the absence of damping and driving, the mechanics of the body produces axial travelling waves, lateral oscillations, and unpredictable, chaotic deformations. The neuromuscular system counteracts friction to recover these motion patterns, giving rise to forward and backward peristalsis in addition to turning. The model produces spontaneous exploration, even though the model nervous system has no intrinsic pattern generating or decision making ability, and neither senses nor drives bending motions. Ultimately, our model suggests a novel view of larval exploration as a deterministic superdiffusion process which is mechanistically grounded in the chaotic mechanics of the body.
Reproducible Data Analysis Pipelines for Precision Medicine
Authors: Fjukstad Bjørn , Dumeaux Vanessa , Hallett Michael , Ailo Bongo Lars
Published: June 2018

Precision medicine brings the promise of more precise diagnosis and individualized therapeutic strategies from analyzing a cancer’s genomic signature. Technologies such as high-throughput sequencing enable cheaper data collection at higher speed, but rely on modern data analysis platforms to extract knowledge from these high dimensional datasets. Since this is a rapidly advancing field, new diagnoses and therapies often require tailoring of the analysis. These pipelines are therefore developed iteratively, continuously modifying analysis parameters before arriving at the final results. To enable reproducible results it is important to record all these modifications and decisions made during the analysis process.

We built a system, walrus, to support reproducible analyses for iteratively developed analysis pipelines. The approach is based on our experiences developing and using deep analysis pipelines to provide insights and recommendations for treatment in an actual breast cancer case. We designed walrus for the single servers or small compute clusters typically available for novel treatments in the clinical setting. walrus leverages software containers to provide reproducible execution environments, and integrates with modern version control systems to capture provenance of data and pipeline parameters.

We have used walrus to analyze a patient’s primary tumor and adjacent normal tissue, including subsequent metastatic lesions. Although we have used walrus for specialized analyses of whole-exome sequencing datasets, it is a general data analysis tool that can be applied in a variety of scientific disciplines. We have open sourced walrus along with example data analysis pipelines at github.com/uit-bdps/walrus.
A repressor-decay timer for robust temporal patterning in embryonic Drosophila neuroblast lineages
Authors: Averbukh Inna , Lai Sen-Lin , Doe Chris Q. , Barkai Naama
Published: June 2018

Biological timers synchronize patterning processes during embryonic development. In theDrosophilaembryo, neural progenitors (neuroblasts; NBs) produce a sequence of unique neurons whose identities depend on the sequential expression of temporal transcription factors (TTFs). The stereotypy and precision of the NB lineages indicate reproducible temporal progression of the TTF timer. To examine the basis of this robustness, we combine theory and experiments. The TTF timer is commonly described as a relay of activators, but its regulatory circuit is also consistent with a repressor-decay timer, in which expression of each TTF begins once its repressor is sufficiently reduced. We find that repressor-decay timers are more robust to parameter variations compared to activator-relay timers. This suggests that thein-vivoTTF sequence progresses primarily by repressor-decay, a prediction that we support experimentally. Our results emphasize the role of robustness in the evolutionary design of patterning circuits.
HPAanalyze: An R Package that Facilitates the Retrieval and Analysis of The Human Protein Atlas Data
Authors: Tran Anh Nhat , Dussaq Alex M. , Kennell Timothy , Willey Christopher D. , Hjelmeland Anita B.
Published: June 2018

Background

The Human Protein Atlas (HPA) aims to map human proteins via multiple technologies including imaging, proteomics and transcriptomics. Access of the HPA data is mainly via web-based interface allowing views of individual proteins, which may not be optimal for data analysis of a gene set, or automatic retrieval of original images.

Results

HPAanalyze is an R package for retrieving and performing exploratory analysis of data from HPA. HPAanalyze provides functionality for importing data tables and xml files from HPA, exporting and visualizing data, as well as downloading all staining images of interest. The package is free, open source, and available via Bioconductor and Github.

Conclusions

HPAanalyze integrates into the R workflow via the tidyverse philosophy and data structures, and it can be used in combination with Bioconductor packages for easy analysis of HPA data.
Neural representations of social valence bias economic interpersonal choices
Authors: Díaz-Gutiérrez Paloma , Arco Juan E. , Alguacil Sonia , González-García Carlos , Ruz María
Published: June 2018

Prior personal information is highly relevant during social interactions. Such knowledge aids in the prediction of others, and it affects choices even when it is unrelated to actual behaviour. In this investigation, we aimed to study the neural representation of positive and negative personal expectations, how these impact subsequent choices, and the effect of mismatches between expectations and encountered behaviour. We employed functional Magnetic Resonance Imaging in combination with a version of the Ultimatum Game (UG) where participants were provided with information about their partners’ moral traits previous to their fair or unfair offers. Univariate and multivariate analyses revealed the implication of the supplementary motor area (SMA) and inferior frontal gyrus (IFG) in the representation of expectations about the partners in the game. Further, these regions also represented the valence of expectations, together with the ventromedial prefrontal cortex (vmPFC). Importantly, the performance of multivariate classifiers in these clusters correlated with a behavioural choice bias to accept more offers following positive descriptions, highlighting the impact of the valence on the expectations on participants’ economic decisions. Altogether, our results suggest that expectations based on social information guide future interpersonal decisions and that the neural representation of such expectations in the vmPFC is related to their influence on behaviour.
Capturing remote activation of epilepsy source?
Authors: Paraskevov A.V. , Zendrikov D.K.
Published: June 2018

Spontaneous focal synchronization of collective spiking followed by induced traveling waves can occur in the cortical sheet and in cultured planar neuronal networks. In the first case, it is well-known focal epilepsy leading to a seizure and, in the second, this synchronization originates from one of a few steady nucleation sites resulting in a so-called population spike. Assuming functional similarity between the nucleation sites and non-lesional epileptic foci, the major unsolved problem in both cases is that it is unclear whether activation of the focus originates internally (i.e., autonomously relative to interaction with surrounding neuronal tissue) or externally. The ’internal’ scenario implies that the focus spatially contains some pacemakers. In turn, several experimental findings indicate a complex spatially non-local activation of epileptic focus. Here, we suggest a generative mechanistic model of planar neuronal network, where the spatial configuration of pacemaker neurons is artificially engineered in order to resolve the above mentioned problem: all pacemakers are placed within a circular central spot. Leaving the global dynamic regime unaffected, this crucially helps to clarify the activation process, visualizing of which is hindered in the natural spatially-uniform configuration. We show in simulations that the nucleation sites (i) can emerge in spatial regions, where pacemakers are completely absent and (ii) can be activated even without direct links from pacemakers. These results demonstrate the principle possibility of external, or remote, activation of a focal source of epileptic activity in the brain. The suggested deterministic model provides the means to study this network phenomenon systematically and reproducibly.
Effects of pathogenic CNVs on physical traits in participants of the UK Biobank
Authors: Owen David , Bracher-Smith Mathew , Kendall Kimberley , Rees Elliott , Einon Mark , Escott-Price Valentina , Owen Michael J , O’Donovan Michael C , Kirov George
Published: June 2018

Background

Copy number variants (CNVs) have been shown to increase risk for physical anomalies, developmental, psychiatric and medical disorders. Some of them have been associated with changes in weight, height, and other physical traits. As most studies have been performed on children and young people, these effects of CNVs in adulthood are not well established.

Methods

The UK Biobank recruited half a million adults who provided a variety of physical measurements. We called all CNVs from the Affymetrix microarrays and selected a set of 54 CNVs implicated as pathogenic (including their reciprocal deletions/duplications) and that were present in five or more persons. Linear regression analysis was used to establish their association with 16 physical traits, relevant to human health.

Results

396,725 participants of white British or Irish descent (excluding first-degree relatives) passed our quality control filters. There were 214 CNV/trait associations significant at a false discovery rate of 0.1, most of them novel. These traits are associated with adverse health outcomes: e.g. increased weight, waist-to-hip ratio, pulse rate and body fat composition. Deletions at 16p11.2, 16p12.1,NRXN1and duplications at 16p13.11 and 22q11.2 produced the highest numbers of significant associations. CNVs at 1q21.1, 2q13, 16p11.2, 16p11.2 distal, 16p12.1, 17p12 and 17q12 demonstrated one or more mirror image effects of deletions versus duplications.

Conclusions

Carriers of many CNVs should be monitored for physical traits that increase morbidity and mortality. Genes within these CNVs can give insights into biological processes and therapeutic interventions.
Differential profiles of soluble and cellular toll like receptor 2 and 4 in chronic periodontitis
Authors: AlQallaf H. , Hamada Y. , Blanchard S. , Shin D. , Gregory R.L. , Srinivasan M.
Published: June 2018

Chronic periodontitis is a common inflammatory disease initiated by a complex microbial biofilm and mediated by the host response causing destruction of the supporting tissues of the teeth. Host recognition of pathogens is mediated by toll-like receptors (TLRs) that bind conserved molecular patterns shared by groups of microorganisms. The oral epithelial cells respond to most periodontopathic bacteria via TLR-2 and TLR-4. Many studies have previously reported the presence of elevated numbers of viable exfoliated epithelial cells (SEC) in the saliva of patients with chronic periodontitis. In addition to the membrane-associated receptors, soluble forms of TLR-2 (sTLR-2) and TLR-4 (sTLR-4) have been identified and are thought to play a regulatory role by binding microbial ligands. sTLR-2 has been shown to arise from ectodomain shedding of the extracellular domain of the membrane receptor and sTLR-4 is thought to be an alternate spliced form. The objective of this study was to investigate the potential value of salivary sTLR-2/4 and the paired epithelial cell-associated TLR-2/4 mRNA as diagnostic markers for chronic periodontitis. Unstimulated whole saliva was collected after obtaining informed consent from 40 individuals in either periodontitis or gingivitis cohorts. The levels of sTLR-2/4 were measured by enzyme-linked immunosorbent assay (ELISA). SEC TLR-2/4 transcripts were quantitated by real time polymerase chain reaction. While levels of sTLR-2 exhibited an inverse correlation, sTLR-4 positively correlated with clinical parameters in the gingivitis cohort. Interestingly, both correlations were lost in the periodontitis cohort indicating a dysregulated host response. On the other hand, while sTLR-2 and the paired SEC associated TLR-2 mRNA exhibited a direct correlation (r2=0.62), that of sTLR4 and SEC TLR-4 mRNA exhibited an inverse correlation (r2=0.53) in the periodontitis cohort. Collectively, assessments of salivary sTLR2 and sTLR4 together with the respective transcripts in SECs could provide clinically relevant markers of disease progression from gingivitis to periodontitis.
De novo transcriptomic characterization of Betta splendens for identifying sex-biased genes potentially involved in aggressive behavior modulation and EST-SSR maker development
Authors: Yang Wei , Wang Yaorong , Zhu Chunhua , Li Guangli , Huang Hai , Chen Huapu
Published: June 2018

Betta splendens is not only a commercially important labyrinth fish but also a nice research model for understanding the biological underpinnings of aggressive behavior. However, the shortage of basic genetic resource severely inhibits investigations on the molecular mechanism in sexual dimorphism of aggressive behavior typicality, which are essential for further behavior-related studies. There is a lack of knowledge regarding the functional genes involved in aggression expression. The scarce marker resource also impedes research progress of population genetics and genomics. In order to enrich genetic data and sequence resources, transcriptomic analysis was conducted for mature B. splendens using a multiple-tissues mixing strategy. A total of 105,505,486 clean reads were obtained and by de novo assembly, 69,836 unigenes were generated. Of which, 35,751 unigenes were annotated in at least one of queried databases. The differential expression analysis resulted in 17,683 transcripts differentially expressed between males and females. Plentiful sex-biased genes involved in aggression exhibition were identified via a screening from Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways, such as htr, drd, gabr, cyp11a1, cyp17a1, hsd17b3, dax1, sf-1, hsd17b7, gsdf1 and fem1c. These putative genes would make good starting points for profound mechanical exploration on aggressive behavioral regulation. Moreover, 12,751 simple sequence repeats were detected from 9,617 unigenes for marker development. Nineteen of the 100 randomly selected primer pairs were demonstrated to be polymorphic. The large amount of transcript sequences will considerably increase available genomic information for gene mining and function analysis, and contribute valuable microsatellite marker resources to in-depth studies on molecular genetics and genomics in the future.
Alien Species of Fish in the Littoral of Volga and Kama Reservoirs (Results of Complex Expeditions of IBIW RAS in 2005-2017)
Authors: Karabanov D.P. , Pavlov D.D. , Bazarov M.I. , Borovikova E.A. , Gerasimov Yu.V. , Kodukhova Yu.V. , Smirnov A.K. , Stolbunov I.A.
Published: June 2018

abstract

The paper provides information on alien species of fish caught in the coastal waters of the Volga and Kama river reservoirs. The material was collected during complex ship expeditions of the IBIW RAS in 2005-2017. We have identified habitats and estimated the relative abundance of mass alien species of the Volga-Kama region.
Probing Protein Allostery as a Residue-specific Concept via Residue Perturbation Maps
Authors: Hayatshahi Hamed S , Ahuactzin Emilio , Tao Peng , Wang Shouyi , Liu Jin
Published: June 2018

Allosteric regulation is a well-established phenomenon classically defined as conformational or dynamical change of a small number of allosteric residues of the protein upon allosteric effector binding at a distance. Here, we developed a novel approach to delineate allosteric effects in proteins. In this approach, we applied robust machine learning methods, including Deep Neural Network and Random Forest, on extensive molecular dynamics (MD) simulations to distinguish otherwise similar allosteric states of proteins. Using PDZ3 domain of PDS-95 as a model protein, we demonstrated that the allosteric effects could be represented as residue-specific properties through two-dimensional property-residue maps, which we refer as “residue perturbation maps”. These maps were constructed through two machine learning methods and could accurately describe how different properties of various residues are affected upon allosteric perturbation on protein. Based on the “residue perturbation maps”, we propose allostery as a residue-specific concept, suggesting all residues could be considered as allosteric residues because each residue “senses” the allosteric events through perturbation of its one or multiple attributes in a quantitatively unique way. The “residue perturbation maps” could be used to fingerprint a protein based on the unique patterns of residue perturbations upon binding events, providing a novel way to systematically describe the protein allosteric effects of each residue upon perturbation.

Author Summary

Allostery is protein regulation at distance. A perturbation at one site of the protein could distantly affect another site. The residues involved in these sites are considered as allosteric residues. The allostery concept has been widely used to understand protein mechanisms and to design allosteric drugs. It is long believed only a small number of residues are allosteric residues. Here, we argue that all residues in a protein are allosteric residues. Upon the perturbation of the allosteric events, the different properties of each residue are affected at the distinct extend. We used hybrid models including molecular dynamics simulations and machine learning components to reveal that not only many properties of residues are affected upon ligand binding, but also each residue is affected through perturbation of its various properties, which makes the residue distinguishable from other residues. According to our findings in a model protein, we defined a “residue perturbation map” as a two-dimensional map that fingerprint a protein based on the extent of perturbation in different properties of all its residues in a quantitative fashion. This “residue perturbation map” provides a novel way to systematically describe the protein allosteric effects of each residue upon perturbation.