bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential gene expression in the endometrium reveals cytoskeletal and immunological genes in lactating dairy cows genetically divergent for fertility traits
Authors: Moran Bruce , Butler Stephen T. , Moore Stephen G. , MacHugh David E. , Creevey Christopher J.
Published: August 2015

Profitable milk production in dairy cows requires good reproductive performance. Calving interval is a trait used to measure reproductive efficiency. Herein we used a novel lactating Holstein cow model of fertility that displayed genetic and phenotypic divergence in calving interval, a trait used to define reproductive performance using a national breeding index in Ireland. Cows had similar genetic merit for milk production traits, but either very good genetic merit for fertility (Fert+; n = 7) or very poor genetic merit for fertility (Fert–; n = 6). We tested the hypothesis that Fert+ cows would have a corresponding detectable difference in endometrial gene expression compared with the Fert– cows. To do this, we sequenced the transcriptome of endometrial biopsies collected on Day 7 of the oestrous cycle (non-pregnant). This is an important stage for uterine remodelling and initiation of histotroph secretion. Significant differential expression (false discovery rate-adjusted P < 0.1) of 403 genes between Fert+ and Fert– cows was found. A novel network-based functional analysis highlighted 123 genes from three physiologically relevant networks of the endometrium: (1) actin and cytoskeletal components; (2) immune function; and (3) ion transportation. In particular, our results indicate an overall downregulation of inflammation-related genes and an upregulation of multiple ion transporters and gated-voltage channels and cytoskeletal genes in Fert+ cows. These three topics, which are discussed in terms of the uterus and in the context of fertility, provide molecular evidence for an association between gene expression in the uterine environment and genetic merit for fertility in dairy cows.
Spatially explicit capture–recapture analysis of bobcat (Lynx rufus) density: implications for mesocarnivore monitoring
Authors: Thornton Daniel H. , Pekins Charles E.
Published: August 2015

Context
Accurate density estimation is crucial for conservation and management of elusive species. Camera-trapping may provide an efficient method for density estimation, particularly when analysed with recently developed spatially explicit capture–recapture (SECR) models. Although camera-traps are employed extensively to estimate large carnivore density, their use for smaller carnivores has been limited. Moreover, while camera-trapping studies are typically conducted at local scales, the utility of analysing larger-scale patterns by combining multiple camera studies remains poorly known.

Aims
The goal of the present study was to develop a better understanding of the utility of SECR models and camera-trapping for the estimation of density of small carnivores at local and regional scales.

Methods
Based on data collected from camera-traps, we used SECR to examine density of bobcats (Lynx rufus) at four study sites in north-central Texas. We then combined our density estimates with previous estimates (from multiple methodologies) across the bobcat’s geographic range, and used linear regression to examine drivers of range-wide density patterns.

Key results
Bobcat densities averaged 13.2 per 100 km2 across all four study sites, and were lowest at the site in the most heavily modified landscape. Bobcat capture probability was positively related to forest cover around camera-trap sites. At the range-wide scale, 53% of the variation in density was explained by just two factors: temperature and longitude.

Conclusions
Our results demonstrate the utility of camera-traps, combined with SECR, to generate precise density estimates for mesocarnivores, and reveal the negative effects of landscape disturbance on bobcat populations. The associations revealed in our range-wide analysis, despite variability in techniques used to estimate density, demonstrate how a combination of multiple density estimates for a species can be used for large-scale inference. However, improvement in our understanding of biogeographic density patterns for mesocarnivores could be obtained from a greater number of camera-based density estimates across the range of a species, combined with meta-analytic techniques.

Implications
Camera-trapping and SECR should be more widely applied to generate local density estimates for many small and medium-sized carnivores, where at least a portion of the individuals are identifiable. If such estimates are more widely obtained, meta-analytic techniques could be used to test biogeographic predictions or for large-scale monitoring efforts.
Two methods for estimating limits to large-scale wind power generation
Authors: Miller Lee M. , Brunsell Nathaniel A. , Mechem David B. , Gans Fabian , Monaghan Andrew J. , Vautard Robert , Keith David W. , Kleidon Axel
Published: August 2015

Significance

Wind turbines generate electricity by removing kinetic energy from the atmosphere. We show that the limited replenishment of kinetic energy from aloft limits wind power generation rates at scales sufficiently large that horizontal fluxes of kinetic energy can be ignored. We evaluate these factors with regional atmospheric model simulations and find that generation limits can be estimated from the ‟preturbine” climatology by comparatively simple means, working best when the atmosphere between the surface and hub height is naturally well-mixed during the day. Our results show that the reduction of wind speeds and limited downward fluxes determine the limits in large-scale wind power generation to less than 1 W⋅m
−2
.
Tectonics, climate, and the rise and demise of continental aquatic species richness hotspots
Authors: Neubauer Thomas A. , Harzhauser Mathias , Georgopoulou Elisavet , Kroh Andreas , Mandic Oleg
Published: August 2015

Significance

To our knowledge, this study is the first investigation of the evolution of species richness hotspots in continental aquatic systems. We demonstrate the development of European richness hotspots over the last 23 My based on a comprehensive dataset combining recent and fossil occurrences of gastropod species. We show that changes in species richness patterns can be related to geodynamic and climatic processes. The addition of tectonics, geological time, and spatial scales to ecology and climate is essential for understanding hotspot development in general. These insights also provide a foundation to explain the modern, uneven distribution of species richness as a whole. The pattern for Recent European faunas is a geologically young phenomenon, triggered by the ice sheet retreat after the Last Glacial Maximum.
RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states
Authors: Mitsi Vasiliki , Terzi Dimitra , Purushothaman Immanuel , Manouras Lefteris , Gaspari Sevasti , Neve Rachael L. , Stratinaki Maria , Feng Jian , Shen Li , Zachariou Venetia
Published: August 2015

Significance

Neuropathic pain is a complex disorder, characterized by affective and sensory symptoms. Efficient treatment of this condition should target both pain-modulating pathways and mood/affect networks. We show that tricyclic antidepressants (TCAs), which modulate spinal pain processing, also act in the brain reward center to alleviate allodynia and depression-like behaviors. We reveal how one key protein of nucleus accumbens (NAc)-specific signaling affects several molecules/pathways with emerging roles in antinociceptive and antidepressant mechanisms. Our study provides information about the cellular adaptations induced by TCAs in the NAc and novel targets for pain treatment.
Cohesin recruits the Esco1 acetyltransferase genome wide to repress transcription and promote cohesion in somatic cells
Authors: Rahman Sadia , Jones Mathew J. K. , Jallepalli Prasad V.
Published: August 2015

Significance

The cohesin complex holds sister chromatids together from their duplication in S phase to their separation in anaphase. Cohesin is also involved in other aspects of chromosome structure and function, including the regulation of gene expression. To connect sister chromatids, cohesin must be modified by conserved acetyltransferases, known as Esco1 and Esco2 in humans. We investigated how Esco1 and Esco2 interact with chromosomes. Surprisingly, cohesin recruits Esco1 to numerous sites throughout the genome, while Esco2 is rarely seen at these sites. Esco1’s colocalization with cohesin requires two short regions that have been conserved throughout its evolution. Deleting these regions prevents Esco1 from establishing cohesion, and from silencing genes near its binding sites, a newly identified function of this factor.
A parthenogenesis gene of apomict origin elicits embryo formation from unfertilized eggs in a sexual plant
Authors: Conner Joann A. , Mookkan Muruganantham , Huo Heqiang , Chae Keun , Ozias-Akins Peggy
Published: August 2015

Significance

The molecular mechanisms controlling apomixis, a mode of asexual reproduction in plants leading to clonal seed formation, are largely unknown. In
Pennisetum squamulatum
, apomixis segregates as a single dominant locus, the apospory-specific genomic region (ASGR). The ASGR contains multiple copies of the
PsASGR-BABY BOOM-like
(
PsASGR-BBML
) gene, a member of the BBM-like subgroup of APETALA 2 transcription factors. Expression of a
PsASGR-BBML
transgene in sexual tetraploid pearl millet promoted both parthenogenesis (embryo formation without fertilization) and the production of haploid offspring. This study presents the first demonstration, to our knowledge, of function for a gene cloned from a naturally occurring apomictic plant that encodes a key component controlling parthenogenesis.
Allosteric activation of apicomplexan calcium-dependent protein kinases
Authors: Ingram Jessica R. , Knockenhauer Kevin E. , Markus Benedikt M. , Mandelbaum Joseph , Ramek Alexander , Shan Yibing , Shaw David E. , Schwartz Thomas U. , Ploegh Hidde L. , Lourido Sebastian
Published: August 2015

Significance

The activation of kinases by Ca
2+
represents a vital class of signaling interactions that regulates many biological processes. The mechanism of activation for these enzymes is conserved and characterized by removal of an inhibitory element from the kinase domain. We report a previously unidentified mechanism for the activation of essential apicomplexan calcium-dependent protein kinases (CDPKs). Using
Toxoplasma
CDPK1 as a representative, we demonstrate that the kinase domain is intrinsically inactive and requires stabilization for activity. This distinct mechanism of activation reveals a susceptibility in CDPKs, which we exploit to effectively inhibit them. When viewed in the context of the entire protein kinase family, our results emphasize the remarkable adaptability of the kinase fold to diverse forms of regulation.
Hybrid bioinorganic approach to solar-to-chemical conversion
Authors: Nichols Eva M. , Gallagher Joseph J. , Liu Chong , Su Yude , Resasco Joaquin , Yu Yi , Sun Yujie , Yang Peidong , Chang Michelle C. Y. , Chang Christopher J.
Published: August 2015

Significance

Natural photosynthesis, a process of solar-to-chemical conversion, uses light, water, and carbon dioxide to generate the chemical products needed to sustain life. Here we report a strategy inspired by photosynthesis in which compatible inorganic and biological components are used to transform light, water, and carbon dioxide to the value-added product methane. Specifically, this solar-to-chemical conversion platform interfaces photoactive inorganic materials that produce hydrogen from water and sunlight with microorganisms that consume this sustainably derived hydrogen to drive the transformation of carbon dioxide to methane with high efficiency. This system establishes a starting point for a broader materials biology approach to the synthesis of more complex chemical products from carbon dioxide and water.
Induction of USP25 by viral infection promotes innate antiviral responses by mediating the stabilization of TRAF3 and TRAF6
Authors: Lin Dandan , Zhang Man , Zhang Meng-Xin , Ren Yujie , Jin Jie , Zhao Quanyi , Pan Zishu , Wu Min , Shu Hong-Bing , Dong Chen , Zhong Bo
Published: August 2015

Significance

Viral infection activates IRF3 and NF-κB and induces the production of type I interferons and proinflammatory cytokines. In this study, we found that ubiquitin-specific protease 25 (USP25) was required for viral infection-triggered activation of IRF3 and NF-κB and subsequent production of type I IFNs and proinflammatory cytokines. Importantly, the degradation of TRAF3 and TRAF6 was accelerated in
Usp25
−/−
cells compared with wild-type counterparts after viral infection, which could be inhibited by the proteasome inhibitor MG132 and the autophagy inhibitor 3MA, respectively. Reconstitution of TRAF3 and TRAF6 into
Usp25
−/−
MEFs restored virus-triggered production of type I IFNs and proinflammatory cytokines. This study provides insights into an elegant “check and balance” process during innate antiviral responses.
Local host specialization, host-switching, and dispersal shape the regional distributions of avian haemosporidian parasites
Authors: Ellis Vincenzo A. , Collins Michael D. , Medeiros Matthew C. I. , Sari Eloisa H. R. , Coffey Elyse D. , Dickerson Rebecca C. , Lugarini Camile , Stratford Jeffrey A. , Henry Donata R. , Merrill Loren , Matthews Alix E. , Hanson Alison A. , Roberts Jackson R. , Joyce Michael , Kunkel Melanie R. , Ricklefs Robert E.
Published: August 2015

Significance

Within eastern North America, distributions of vector-transmitted haemosporidian blood parasites of birds, commonly known as “avian malaria parasites,” are associated with the distributions of their host species independently of direct effects of climate on potential vectors. Spatial analyses additionally indicated an absence of dispersal limitation for these parasites. Finally, host-breadth, ranging continuously from specialist to generalist, varies among parasite lineages and is dynamic within parasite assemblages over space and time. The distributions of avian haemosporidian parasites emphasize the ability of parasites to disperse across broad regions and to switch readily between hosts to become emerging infectious diseases.
Dynamic equilibrium between closed and partially closed states of the bacterial Enzyme I unveiled by solution NMR and X-ray scattering
Authors: Venditti Vincenzo , Schwieters Charles D. , Grishaev Alexander , Clore G. Marius
Published: August 2015

Significance

The bacterial phosphotransferase system couples phosphoryl transfer to sugar transport across the cell membrane. The first protein in the pathway, Enzyme I (EI), undergoes two large rigid body domain reorientations between an autophosphorylation-competent closed state and an open state that allows subsequent phosphoryl transfer to its downstream protein partner. Simultaneous use of solution X-ray scattering and NMR dipolar coupling data to guide simulated annealing refinement reveals the existence of a dynamic equilibrium between closed and partially closed conformations in a complex of a mutant of EI with phosphoenolpyruvate. The partially closed conformation represents an intermediate in the open-to-closed transition.
Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia
Authors: Shu Minfeng , Du Te , Zhou Grace , Roizman Bernard
Published: August 2015

Significance

A major unresolved issue confronting infectious diseases is the mechanism by which virulent, potentially lethal viruses remain silent (latent) in selected cells in the human body until induced to replicate and spread in response to stress. The establishment of latent infection by herpes simplex viruses in sensory or autonomic neurons is a common event in a large fraction of the human population. Here we report that activating transcription factor 3 (ATF3) is induced by stress both in infected cells in culture and in ganglia harboring latent virus. The function of ATF3 is to block the reactivation of virus induced by neuronal stress.
The relationship between workplace spirituality and innovative work behavior: the mediating role of perceived person–organization fit
Authors: Afsar Bilal , Rehman Maryam
Published: August 2015

There has been minimal research on the impact of an employee’s workplace spirituality on his/her innovative work behavior (IWB). The current study aims to fill this gap in the literature. In order to understand the psychology of workplace spirituality, this study has longitudinally
analyzed the relationship between workplace spirituality and IWB (self and supervisor-based assessments), and impact of perceived person–organization fit (P–O fit) on this relationship. Data were collected from 448 subordinates and 79 supervisors from two knowledge-intensive industries
of Thailand. Structural equation modeling was used to analyze the relationships. Results of the study indicate that employee’s workplace spirituality is positively related to both self and supervisor ratings of innovative behaviors, and perception of perceived P–O fit acts as a
partial mediator between workplace spirituality and IWB at both Time 1 and Time 2. These results imply that an employee’s experience of workplace spirituality impacts his/her perceived P–O fit which in turn helps in engaging him/her to display IWB more often. Study findings begin
to explain how workplace spirituality impacts IWB of individuals. Specifically, we find that perceived P–O fit explains the relationship between workplace spirituality and IWB.
Greater basal skeletal muscle AMPKα phosphorylation in men than in women: Associations with anaerobic performance
Authors: Guadalupe‐Grau Amelia , Rodríguez‐García Lorena , Torres‐Peralta Rafael , Morales‐Álamo David , Ponce‐González Jesús Gustavo , Pérez‐Suarez Ismael , Santana Alfredo , Calbet Jose Al
Published: August 2015

Objectives: This study was designed to investigate the association of gender, fibre type composition, and anaerobic performance with the basal skeletal muscle signalling cascades regulating muscle phenotype. Design: Muscle biopsies were obtained from 25 men and 10 women all young and healthy. Methods. Protein phosphorylation of Thr172AMPKα, Ser221ACCβ, Thr286CaMKII as well as total protein abundance of PGC‐1α, SIRT1, and CnA were measured by Western blot and anaerobic performance by the Wingate test. Results: Percent type I myosin heavy chain (MHC I) was lower in men (37.1 ± 10.4 vs. 58.5 ± 12.5, P < .01). Total, free testosterone and free androgen index were higher in men (11.5, 36.6 and 40.6 fold, respectively, P < .01). AMPKα phosphorylation was 2.2‐fold higher in men compared to women (P < .01). Total Ser221ACCβ and Thr286CaMKII fractional phosphorylation tended to be higher in men (P = .1). PGC1‐α and SIRT1 total protein expression was similar in men and women, whereas CnA tended to be higher in men (P = .1). Basal AMPKα phosphorylation was linearly related to the percentage of MHC I in men (r = 0.56; P < .01), but not in women. No association was observed between anaerobic performance and basal phosphorylations in men and women, analysed separately. Conclusion: In summary, skeletal muscle basal AMPKα phosphorylation is higher in men compared to women, with no apparent effect on anaerobic performance.
An occlusion paradigm to assess the importance of the timing of the quiet eye fixation
Authors: Vine Samuel J. , Lee Don Hyung , Walters‐Symons Rosanna , Wilson Mark R.
Published: August 2015

The aim of the study was to explore the significance of the ‘timing’ of the quiet eye (QE), and the relative importance of late (online control) or early (pre‐programming) visual information for accuracy. Twenty‐seven skilled golfers completed a putting task using an occlusion paradigm with three conditions: early (prior to backswing), late (during putter stroke), and no (control) occlusion of vision. Performance, QE, and kinematic variables relating to the swing were measured. Results revealed that providing only early visual information (occluding late visual information) had a significant detrimental effect on performance and kinematic measures, compared to the control condition (no occlusion), despite QE durations being maintained. Conversely, providing only late visual information (occluding early visual information) was not significantly detrimental to performance or kinematics, with results similar to those in the control condition. These findings imply that the visual information extracted during movement execution – the late proportion of the QE – is critical when golf putting. The results challenge the predominant view that the QE serves only a pre‐programming function. We propose that the different proportions of the QE (before and during movement) may serve different functions in supporting accuracy in golf putting.
APC is required for muscle stem cell proliferation and skeletal muscle tissue repair
Authors: Parisi Alice , Lacour Floriane , Giordani Lorenzo , Colnot Sabine , Maire Pascal , Le Grand Fabien
Published: August 2015

The tumor suppressor adenomatous polyposis coli (APC) is a crucial regulator of many stem cell types. In constantly cycling stem cells of fast turnover tissues, APC loss results in the constitutive activation of a Wnt target gene program that massively increases proliferation and leads to malignant transformation. However, APC function in skeletal muscle, a tissue with a low turnover rate, has never been investigated. Here we show that conditional genetic disruption of APC in adult muscle stem cells results in the abrogation of adult muscle regenerative potential. We demonstrate that APC removal in adult muscle stem cells abolishes cell cycle entry and leads to cell death. By using double knockout strategies, we further prove that this phenotype is attributable to overactivation of β-catenin signaling. Our results demonstrate that in muscle stem cells, APC dampens canonical Wnt signaling to allow cell cycle progression and radically diverge from previous observations concerning stem cells in actively self-renewing tissues.
Protein kinase D promotes plasticity-induced F-actin stabilization in dendritic spines and regulates memory formation
Authors: Bencsik Norbert , Szíber Zsófia , Liliom Hanna , Tárnok Krisztián , Borbély Sándor , Gulyás Márton , Rátkai Anikó , Szűcs Attila , Hazai-Novák Diána , Ellwanger Kornelia , Rácz Bence , Pfizenmaier Klaus , Hausser Angelika , Schlett Katalin
Published: August 2015

Actin turnover in dendritic spines influences spine development, morphology, and plasticity, with functional consequences on learning and memory formation. In nonneuronal cells, protein kinase D (PKD) has an important role in stabilizing F-actin via multiple molecular pathways. Using in vitro models of neuronal plasticity, such as glycine-induced chemical long-term potentiation (LTP), known to evoke synaptic plasticity, or long-term depolarization block by KCl, leading to homeostatic morphological changes, we show that actin stabilization needed for the enlargement of dendritic spines is dependent on PKD activity. Consequently, impaired PKD functions attenuate activity-dependent changes in hippocampal dendritic spines, including LTP formation, cause morphological alterations in vivo, and have deleterious consequences on spatial memory formation. We thus provide compelling evidence that PKD controls synaptic plasticity and learning by regulating actin stability in dendritic spines.
Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome
Authors: Kreins Alexandra Y. , Ciancanelli Michael J. , Okada Satoshi , Kong Xiao-Fei , Ramírez-Alejo Noé , Kilic Sara Sebnem , El Baghdadi Jamila , Nonoyama Shigeaki , Mahdaviani Seyed Alireza , Ailal Fatima , Bousfiha Aziz , Mansouri Davood , Nievas Elma , Ma Cindy S. , Rao Geetha , Bernasconi Andrea , Sun Kuehn Hye , Niemela Julie , Stoddard Jennifer , Deveau Paul , Cobat Aurelie , El Azbaoui Safa , Sabri Ayoub , Lim Che Kang , Sundin Mikael , Avery Danielle T. , Halwani Rabih , Grant Audrey V. , Boisson Bertrand , Bogunovic Dusan , Itan Yuval , Moncada-Velez Marcela , Martinez-Barricarte Ruben , Migaud Melanie , Deswarte Caroline , Alsina Laia , Kotlarz Daniel , Klein Christoph , Muller-Fleckenstein Ingrid , Fleckenstein Bernhard , Cormier-Daire Valerie , Rose-John Stefan , Picard Capucine , Hammarstrom Lennart , Puel Anne , Al-Muhsen Saleh , Abel Laurent , Chaussabel Damien , Rosenzweig Sergio D. , Minegishi Yoshiyuki , Tangye Stuart G. , Bustamante Jacinta , Casanova Jean-Laurent , Boisson-Dupuis Stéphanie
Published: August 2015

Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17+ T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.
Lu Yu: the past and future of condensed matter physics
Authors: Poo Mu-ming , Wang Ling
Published: August 2015

Lu Yu, a distinguished theoretical physicist at the Institute of Physics (IOP) of Chinese Academy of Sciences (CAS), has witnessed the development of Chinese physics over the past five decades, from the difficult period of 1960s when physicists worked in a ‘half-fed’ state to the present flowering springtime of Chinese physics in which many breakthroughs at the frontier of physics are attracting international recognition. He considers these achievements to be not merely ‘intermittent bubbles’, but the cumulative result of sustained governmental support of basic research over the past decades. In his area of condensed-matter physics, Yu sees ‘a big deep-rooted tree with many branches—some old branches have withered away, but new shoots continue to appear’. In a recent interview with NSR, Yu reflected upon the recent history of condensed-matter physics in China—what has been accomplished and what lies ahead—and his view on the development of physics in general.
Combating H7N9: an interview with Lanjuan Li and Yi Shi
Authors: Xu Xiuling
Published: August 2015

On March 31, 2013, the Chinese government reported that three persons from Shanghai and Anhui had died from a novel avian influenza virus, known as H7N9. This avian flu is unique in that it has a high human mortality rate, while fatality in poultry remains low. In other words, this virus can circulate ‘silently’ among poultry, but be a very possible cause of the next flu pandemic. Since 2013, human cases of H7N9 infection have been reported continuously, posing a potential threat to public health in China and attracting global attention. Will H7N9 be the next flu pandemic? With this question, NSR spoke to clinical expert, Professor Lanjuan Li from Zhejiang University, and the virologist, Dr. Shi Yi, from the Beijing Institutes of Life Science, Chinese Academy of Sciences and Shenzhen Third People's Hospital. In this interview, they share with us the biological information of H7N9, its clinical manifestation and treatment, and its future pandemic potential.
The landscape of nonlinear structural dynamics: an introduction
Authors: Butlin T. , Woodhouse J. , Champneys A. R.
Published: August 2015

Nonlinear behaviour is ever-present in vibrations and other dynamical motions of engineering structures. Manifestations of nonlinearity include amplitude-dependent natural frequencies, buzz, squeak and rattle, self-excited oscillation and non-repeatability. This article primarily serves as an extended introduction to a theme issue in which such nonlinear phenomena are highlighted through diverse case studies. More ambitiously though, there is another goal. Both the engineering context and the mathematical techniques that can be used to identify, analyse, control or exploit these phenomena in practice are placed in the context of a mind-map, which has been created through expert elicitation. This map, which is available in software through the electronic supplementary material, attempts to provide a practitioner’s guide to what hitherto might seem like a vast and complex research landscape.
The use of normal forms for analysing nonlinear mechanical vibrations
Authors: Neild Simon A. , Champneys Alan R. , Wagg David J. , Hill Thomas L. , Cammarano Andrea
Published: August 2015

A historical introduction is given of the theory of
normal forms
for simplifying nonlinear dynamical systems close to resonances or bifurcation points. The specific focus is on mechanical vibration problems, described by finite degree-of-freedom second-order-in-time differential equations. A recent variant of the normal form method, that respects the specific structure of such models, is recalled. It is shown how this method can be placed within the context of the general theory of normal forms provided the damping and forcing terms are treated as unfolding parameters. The approach is contrasted to the alternative theory of nonlinear normal modes (NNMs) which is argued to be problematic in the presence of damping. The efficacy of the normal form method is illustrated on a model of the vibration of a taut cable, which is geometrically nonlinear. It is shown how the method is able to accurately predict NNM shapes and their bifurcations.
On the bistable zone of milling processes
Authors: Dombovari Zoltan , Stepan Gabor
Published: August 2015

A modal-based model of milling machine tools subjected to time-periodic nonlinear cutting forces is introduced. The model describes the phenomenon of bistability for certain cutting parameters. In engineering, these parameter domains are referred to as unsafe zones, where steady-state milling may switch to chatter for certain perturbations. In mathematical terms, these are the parameter domains where the periodic solution of the corresponding nonlinear, time-periodic delay differential equation is linearly stable, but its domain of attraction is limited due to the existence of an unstable quasi-periodic solution emerging from a secondary Hopf bifurcation. A semi-numerical method is presented to identify the borders of these bistable zones by tracking the motion of the milling tool edges as they might leave the surface of the workpiece during the cutting operation. This requires the tracking of unstable quasi-periodic solutions and the checking of their grazing to a time-periodic switching surface in the infinite-dimensional phase space. As the parameters of the linear structural behaviour of the tool/machine tool system can be obtained by means of standard modal testing, the developed numerical algorithm provides efficient support for the design of milling processes with quick estimates of those parameter domains where chatter can still appear in spite of setting the parameters into linearly stable domains.
On the nonlinear dynamics of a rotor in autorotation: a combined experimental and numerical approach
Authors: Rezgui D. , Lowenberg M. H.
Published: August 2015

This article presents a systematic assessment of the use of numerical continuation and bifurcation techniques in investigating the nonlinear periodic behaviour of a teetering rotor operating in forward autorotation. The aim is to illustrate the potential of these tools in revealing complex blade dynamics, when used in combination (not necessarily at the same time) with physical testing. We show a simple procedure to promote understanding of an existing but not fully understood engineering instability problem, when uncertainties in the numerical modelling and constraints in the experimental testing are present. It is proposed that continuation and bifurcation methods can play a significant role in developing numerical and experimental techniques for studying the nonlinear dynamics not only for rotating blades but also for other engineering systems with uncertainties and constraints.
Control of sensory ectopic spike initiation by descending modulatory projection neurons
Authors: Städele Carola , Stein Wolfgang
Published: August 2015

Abstract

Descending pathways are important modulators of motor networks and allow the dynamic adjustment of behaviors to changing internal and external conditions. Central pattern generating networks (CPG) have been particularly amenable to study the modulation of motor networks and demonstrated that virtually all levels of information processing are controlled by descending projections. CPGs receive sensory feedback and while it is known that sensory activity can be gated by central pathways, we here present for the first time that descending projection neurons modulate action potential initiation in sensory neurons.

We used the fact that the anterior gastric receptor neuron (AGR), a single-cell bipolar muscle tendon organ in the crustacean stomatogastric nervous system, generates spontaneous ectopic action potentials in its axon. We found that axonal spike initiation is under direct neuromodulatory control by a pair of descending projection neurons. These IV (inferior ventricular) neurons descend from the brain and are known to control CPGs in the stomatogastric ganglion (STG). Activation of the IV neurons elicited a long-lasting decrease in AGR ectopic spike activity. This decrease was only observed when spikes were generated ectopically in the central portion of the axon, i.e. the modulation was specific to the site of spontaneous spike initiation. The decrease could be mimicked by focal application of the IV neuron co-transmitter histamine and IV neuron actions were diminished after blocking H2receptors, indicating a direct descending modulation of the axonal spike initiation site. In contrast, the propagation dynamics of en-passant action potentials were not affected. Descending modulatory projection neurons therefore control axonal spike initiation in sensory neurons without affecting afferent spike propagation to increase the physiological activity repertoire of sensory pathways.
Construction of relatedness matrices using genotyping-by-sequencing data
Authors: Dodds Ken G , McEwan John C , Brauning Rudiger , Anderson Rayna M , van Stijn Tracey C , Kristjánsson Theodor , Clarke Shannon M
Published: August 2015

Background

Genotyping-by-sequencing (GBS) is becoming an attractive alternative to array-based methods for genotyping individuals for a large number of single nucleotide polymorphisms (SNPs). Costs can be lowered by reducing the mean sequencing depth, but this results in genotype calls of lower quality. A common analysis strategy is to filter SNPs to just those with sufficient depth, thereby greatly reducing the number of SNPs available. We investigate methods for estimating relatedness using GBS data, including results of low depth, using theoretical calculation, simulation and application to a real data set.

Results

We show that unbiased estimates of relatedness can be obtained by using only those SNPs with genotype calls in both individuals. The expected value of this estimator is independent of the SNP depth in each individual, under a model of genotype calling that includes the special case of the two alleles being read at random. In contrast, the estimator of self-relatedness does depend on the SNP depth, and we provide a modification to provide unbiased estimates of self-relatedness. We refer to these methods of estimation as kinship using GBS with depth adjustment (KGD). The estimators can be calculated using matrix methods, which allow efficient computation. Simulation results were consistent with the methods being unbiased, and suggest that the optimal sequencing depth is around 2-4 for relatedness between individuals and 5-10 for self-relatedness. Application to a real data set revealed that some SNP filtering may still be necessary, for the exclusion of SNPs which did not behave in a Mendelian fashion. A simple graphical method (a ‘fin plot’) is given to illustrate this issue and to guide filtering parameters.

Conclusion

We provide a method which gives unbiased estimates of relatedness, based on SNPs assayed by GBS, which accounts for the depth (including zero depth) of the genotype calls. This allows GBS to be applied at read depths which can be chosen to optimise the information obtained. SNPs with excess heterozygosity, often due to (partial) polyploidy or other duplications can be filtered based on a simple graphical method.
Differential transcript usage from RNA-seq data: isoform pre-filtering improves performance of count-based methods
Authors: Soneson Charlotte , Matthes Katarina L. , Nowicka Malgorzata , Law Charity W. , Robinson Mark D.
Published: August 2015

Large-scale sequencing of cDNA (RNA-seq) has been a boon to the quantitative analysis of transcriptomes. A notable application is the detection of changes in transcript usage between experimental conditions. For example, discovery of pathological alternative splicing may allow the development of new treatments or better management of patients. From an analysis perspective, there are several ways to approach RNA-seq data to unravel differential transcript usage, such as annotation-based exon-level counting, differential analysis of the ‘percent spliced in’ measure or quantitative analysis of assembled transcripts. The goal of this research is to compare and contrast current state-of-the-art methods, as well as to suggest improvements to commonly used workflows.

We assess the performance of representative workflows using synthetic data and explore the effect of using non-standard counting bin definitions as input to a state-of-the-art inference engine (DEXSeq). Although the canonical counting provided the best results overall, several non-canonical approaches were as good or better in specific aspects and most counting approaches outperformed the evaluated event- and assembly-based methods. We show that an incomplete annotation catalog can have a detrimental effect on the ability to detect differential transcript usage in transcriptomes with few isoforms per gene and that isoform-level pre-filtering can considerably improve false discovery rate (FDR) control.

Count-based methods generally perform well in detection of differential transcript usage. Controlling the FDR at the imposed threshold is difficult, mainly in complex organisms, but can be improved by pre-filtering of the annotation catalog.
ARCIMBOLDO_LITE: single-workstation implementation and use
Authors: Sammito Massimo , Millán Claudia , Frieske Dawid , Rodríguez-Freire Eloy , Borges Rafael J. , Usón Isabel
Published: August 2015

ARCIMBOLDOsolves the phase problem at resolutions of around 2 Å or better through massive combination of small fragments and density modification. For complex structures, this imposes a need for a powerful grid where calculations can be distributed, but for structures with up to 200 amino acids in the asymmetric unit a single workstation may suffice. The use and performance of the single-workstation implementation,ARCIMBOLDO_LITE, on a pool of test structures with 40–120 amino acids and resolutions between 0.54 and 2.2 Å is described. Inbuilt polyalanine helices and iron cofactors are used as search fragments.ARCIMBOLDO_BORGEScan also run on a single workstation to solve structures in this test set using precomputed libraries of local folds. The results of this study have been incorporated into an automated, resolution- and hardware-dependent parameterization.ARCIMBOLDOhas been thoroughly rewritten and three binaries are now available:ARCIMBOLDO_LITE,ARCIMBOLDO_SHREDDERandARCIMBOLDO_BORGES. The programs and libraries can be downloaded from http://chango.ibmb.csic.es/ARCIMBOLDO_LITE.
A conformational change in the peripheral anionic site ofTorpedo californicaacetylcholinesterase induced by a bis-imidazolium oxime
Authors: Legler Patricia M. , Soojhawon Iswarduth , Millard Charles B.
Published: August 2015

As part of ongoing efforts to design improved nerve agent antidotes, two X-ray crystal structures ofTorpedo californicaacetylcholinesterase (TcAChE) bound to the bis-pyridinium oxime, Ortho-7, or its experimental bis-imidazolium analogue, 2BIM-7, were determined. Bis-oximes contain two oxime groups connected by a hydrophobic linker. One oxime group of Ortho-7 binds at the entrance to the active-site gorge near Trp279, and the second binds at the bottom near Trp84 and Phe330. In the Ortho-7–TcAChE complex the oxime at the bottom of the gorge was directed towards the nucleophilic Ser200. In contrast, the oxime group of 2BIM-7 was rotated away from Ser200 and the oxime at the entrance induced a significant conformational change in the peripheral anionic site (PAS) residue Trp279. The conformational change alters the surface of the PAS and positions the imidazolium oxime of 2BIM-7 further from Ser200. The relatively weaker binding and poorer reactivation of VX-inhibited, tabun-inhibited or sarin-inhibited human acetylcholinesterase by 2BIM-7 compared with Ortho-7 may in part be owing to the unproductively bound states caughtin crystallo. Overall, the reactivation efficiency of 2BIM-7 was comparable to that of 2-pyridine aldoxime methyl chloride (2-PAM), but unlike 2-PAM the bis-imidazolium oxime lacks a fixed charge, which may affect its membrane permeability.
Accounting for partiality in serial crystallography using ray-tracing principles
Authors: Kroon-Batenburg Loes M. J. , Schreurs Antoine M. M. , Ravelli Raimond B. G. , Gros Piet
Published: August 2015

Serial crystallography generates `still' diffraction data sets that are composed of single diffraction images obtained from a large number of crystals arbitrarily oriented in the X-ray beam. Estimation of the reflection partialities, which accounts for the expected observed fractions of diffraction intensities, has so far been problematic. In this paper, a method is derived for modelling the partialities by making use of the ray-tracing diffraction-integration methodEVAL. The method estimates partialities based on crystal mosaicity, beam divergence, wavelength dispersion, crystal size and the interference function, accounting for crystallite size. It is shown that modelling of each reflection by a distribution of interference-function weighted rays yields a `still' Lorentz factor. Still data are compared with a conventional rotation data set collected from a single lysozyme crystal. Overall, the presented still integration method improves the data quality markedly. TheRfactor of the still data compared with the rotation data decreases from 26% using a Monte Carlo approach to 12% after applying the Lorentz correction, to 5.3% when estimating partialities byEVALand finally to 4.7% after post-refinement. The mergingRintfactor of the still data improves from 105 to 56% but remains high. This suggests that the accuracy of the model parameters could be further improved. However, with a multiplicity of around 40 and anRintof ∼50% the merged still data approximate the quality of the rotation data. The presented integration method suitably accounts for the partiality of the observed intensities in still diffraction data, which is a critical step to improve data quality in serial crystallography.
Structural insights into the novel inhibition mechanism ofTrypanosoma cruzispermidine synthase
Authors: Amano Yasushi , Namatame Ichiji , Tateishi Yukihiro , Honboh Kazuya , Tanabe Eiki , Niimi Tatsuya , Sakashita Hitoshi
Published: August 2015

Trypanosoma cruzicauses Chagas disease, a severe disease affecting 8–10 million people in Latin America. While nifurtimox and benznidazole are used to treat this disease, their efficacy is limited and adverse effects are observed. New therapeutic targets and novel drugs are therefore urgently required. Enzymes in the polyamine–trypanothione pathway are promising targets for the treatment of Chagas disease. Spermidine synthase is a key enzyme in this pathway that catalyzes the transfer of an aminopropyl group from decarboxylatedS-adenosylmethionine (dcSAM) to putrescine. Fragment-based drug discovery was therefore conducted to identify novel, potent inhibitors of spermidine synthase fromT. cruzi(TcSpdSyn). Here, crystal structures of TcSpdSyn in complex with dcSAM,trans-4-methylcyclohexylamine and hit compounds from fragment screening are reported. The structure of dcSAM complexed with TcSpdSyn indicates that dcSAM stabilizes the conformation of the `gatekeeping' loop to form the putrescine-binding pocket. The structures of fragments bound to TcSpdSyn revealed two fragment-binding sites: the putrescine-binding pocket and the dimer interface. The putrescine-binding pocket was extended by an induced-fit mechanism. The crystal structures indicate that the conformation of the dimer interface is required to stabilize the gatekeeping loop and that fragments binding to this interface inhibit TcSpdSyn by disrupting its conformation. These results suggest that utilizing the dynamic structural changes in TcSpdSyn that occur upon inhibitor binding will facilitate the development of more selective and potent inhibitors.
Iron binding to human heavy-chain ferritin
Authors: Pozzi Cecilia , Di Pisa Flavio , Bernacchioni Caterina , Ciambellotti Silvia , Turano Paola , Mangani Stefano
Published: August 2015

Maxi-ferritins are ubiquitous iron-storage proteins with a common cage architecture made up of 24 identical subunits of five α-helices that drive iron biomineralization through catalytic iron(II) oxidation occurring at oxidoreductase sites (OS). Structures of iron-bound human H ferritin were solved at high resolution by freezing ferritin crystals at different time intervals after exposure to a ferrous salt. Multiple binding sites were identified that define the iron path from the entry ion channels to the oxidoreductase sites. Similar data are available for another vertebrate ferritin: the M protein fromRana catesbeiana. A comparative analysis of the iron sites in the two proteins identifies new reaction intermediates and underlines clear differences in the pattern of ligands that define the additional iron sites that precede the oxidoreductase binding sites along this path. Stopped-flow kinetics assays revealed that human H ferritin has different levels of activity compared with itsR. catesbeianacounterpart. The role of the different pattern of transient iron-binding sites in the OS is discussed with respect to the observed differences in activity across the species.