bluuebunny/crossref_metadata_2025 huggingface dataset:
The P5A ATPase Spf1p is stimulated by phosphatidylinositol 4-phosphate and influences cellular sterol homeostasis
Authors: Sørensen Danny Mollerup , Holen Henrik Waldal , Pedersen Jesper Torbøl , Martens Helle Juel , Silvestro Daniele , Stanchev Lyubomir Dimitrov , Costa Sara Rute , Günther Pomorski Thomas , López-Marqués Rosa Laura , Palmgren Michael
Published: February 2019

P5A ATPases are expressed in the endoplasmic reticulum (ER) of all eukaryotic cells, and their disruption results in severe ER stress. However, the function of these ubiquitous membrane proteins, which belong to the P-type ATPase superfamily, is unknown. We purified a functional tagged version of the Saccharomyces cerevisiae P5A ATPase Spf1p and observed that the ATP hydrolytic activity of the protein is stimulated by phosphatidylinositol 4-phosphate (PI4P). Furthermore, SPF1 exhibited negative genetic interactions with SAC1, encoding a PI4P phosphatase, and with OSH1 to OSH6, encoding Osh proteins, which, when energized by a PI4P gradient, drive export of sterols and lipids from the ER. Deletion of SPF1 resulted in increased sensitivity to inhibitors of sterol production, a marked change in the ergosterol/lanosterol ratio, accumulation of sterols in the plasma membrane, and cytosolic accumulation of lipid bodies. We propose that Spf1p maintains cellular sterol homeostasis by influencing the PI4P-induced and Osh-mediated export of sterols from the ER.
Choice between 1- and 2-furrow cytokinesis inCaenorhabditis elegansembryos with tripolar spindles
Authors: Kondo Tomo , Kimura Akatsuki
Published: February 2019

Excessive centrosomes often lead to multipolar spindles, and thus probably to multipolar mitosis and aneuploidy. In Caenorhabditis elegans, ∼70% of the paternal emb-27APC6mutant embryonic cells contained more than two centrosomes and formed multipolar spindles. However, only ~30% of the cells with tripolar spindles formed two cytokinetic furrows. The rest formed one furrow, similar to normal cells. To investigate the mechanism via which cells avoid forming two cytokinetic furrows even with a tripolar spindle, we conducted live-cell imaging in emb-27APC6mutant cells. We observed that the chromatids were aligned on only two of the three sides of the tripolar spindle, and the angle of the tripolar spindle relative to the long axis of the cell correlated with the number of cytokinetic furrows. Our numerical modeling showed that the combination of cell shape, cortical pulling forces, and heterogeneity of centrosome size determines whether cells with a tripolar spindle form one or two cytokinetic furrows.
The TMCrys server for supporting crystallization of transmembrane proteins
Authors: Varga Julia K , Tusnády Gábor E
Published: February 2019

Motivation

Due to their special properties, the structures of transmembrane proteins are extremely hard to determine. Several methods exist to predict the propensity of successful completion of the structure determination process. However, available predictors incorporate data of any kind of proteins, hence they can hardly differentiate between crystallizable and non-crystallizable membrane proteins.

Results

We implemented a web server to simplify running TMCrys prediction method that was developed specifically to separate crystallizable and non-crystallizable membrane proteins.

Availability and implementation

http://tmcrys.enzim.ttk.mta.hu

Supplementary information

Supplementary data are available at Bioinformatics online.
Brain annotation toolbox: exploring the functional and genetic associations of neuroimaging results
Authors: Liu Zhaowen , Rolls Edmund T , Liu Zhi , Zhang Kai , Yang Ming , Du Jingnan , Gong Weikang , Cheng Wei , Dai Fei , Wang He , Ugurbil Kamil , Zhang Jie , Feng Jianfeng
Published: February 2019

Motivation

Advances in neuroimaging and sequencing techniques provide an unprecedented opportunity to map the function of brain regions and identify the roots of psychiatric diseases. However, the results from most neuroimaging studies, i.e. activated clusters/regions or functional connectivities between brain regions, frequently cannot be conveniently and systematically interpreted, rendering the biological meaning unclear.

Results

We describe a brain annotation toolbox that generates functional and genetic annotations for neuroimaging results. The voxel-level functional description from the Neurosynth database and gene expression profile from the Allen Human Brain Atlas are used to generate functional/genetic information for region-level neuroimaging results. The validity of the approach is demonstrated by showing that the functional and genetic annotations for specific brain regions are consistent with each other; and further the region by region functional similarity network and genetic similarity network are highly correlated for major brain atlases. One application of brain annotation toolbox is to help provide functional/genetic annotations for newly discovered regions with unknown functions, e.g. the 97 new regions identified in the Human Connectome Project. Importantly, this toolbox can help understand differences between psychiatric patients and controls, and this is demonstrated using schizophrenia and autism data, for which the functional and genetic annotations for the neuroimaging changes in patients are consistent with each other and help interpret the results.

Availability and implementation

BAT is implemented as a free and open-source MATLAB toolbox and is publicly available at http://123.56.224.61:1313/post/bat.

Supplementary information

Supplementary data are available at Bioinformatics online.
Use of avoidance behaviours to reduce the economic impacts of the EU Landing Obligation: the case study of a mixed trawl fishery
Authors: Pointin Fabien , Daurès Fabienne , Rochet Marie-Joëlle
Published: February 2019

The EU Landing Obligation (LO) is designed to reduce bycatch (i.e. unwanted catch) through more selective fishing practices, such as avoidance behaviours which consist in allocating fishing effort to other species, fishing grounds or seasons. Incentives for fishers to change their behaviours depend on their economic performances as well as their ability to avoid bycatch. Changes in economic performances under the LO are evaluated based on cost and revenue equations. The nested grid method is then used to explore the spatial and temporal distribution of landings and discards, and to suggest alternative effort allocation to avoid bycatch. This article is focussed specifically on the French otter trawl fishery in the eastern English Channel and southern North Sea. Results suggest that under the LO the choke species problem will curtail fishing activities earlier in the year, leading to significant economic losses. In the absence of significant quota top-ups (at least 75%), a change in fishing practices consisting in reducing overall bycatch by 30% is insufficient to reduce losses. With a particular attention to choke species, more economically efficient avoidance strategies can be found thanks to the nested grid method.
Mechanistic Interplay Between Autophagy and Apoptotic Signaling in Endosulfan-Induced Dopaminergic Neurotoxicity: Relevance to the Adverse Outcome Pathway in Pesticide Neurotoxicity
Authors: Song Chunjuan , Charli Adhithiya , Luo Jie , Riaz Zainab , Jin Huajun , Anantharam Vellareddy , Kanthasamy Arthi , Kanthasamy Anumantha G
Published: February 2019

Chronic exposure to pesticides is implicated in the etiopathogenesis of Parkinson’s disease (PD). Previously, we showed that dieldrin induces dopaminergic neurotoxicity by activating a cascade of apoptotic signaling pathways in experimental models of PD. Here, we systematically investigated endosulfan’s effect on the interplay between apoptosis and autophagy in dopaminergic neuronal cell models of PD. Exposing N27 dopaminergic neuronal cells to endosulfan rapidly induced autophagy, indicated by an increased number of autophagosomes and LC3-II accumulation. Prolonged endosulfan exposure (>9 h) triggered apoptotic signaling, including caspase-2 and -3 activation and protein kinase C delta (PKCδ) proteolytic activation, ultimately leading to cell death, thus demonstrating that autophagy precedes apoptosis during endosulfan neurotoxicity. Furthermore, inhibiting autophagy with wortmannin, a phosphoinositide 3-kinase inhibitor, potentiated endosulfan-induced apoptosis, suggesting that autophagy is an early protective response against endosulfan. Additionally, Beclin-1, a major regulator of autophagy, was cleaved during the initiation of apoptotic cell death, and the cleavage was predominantly mediated by caspase-2. Also, caspase-2 and caspase-3 inhibitors effectively blocked endosulfan-induced apoptotic cell death. CRISPR/Cas9-based stable knockdown of PKCδ significantly attenuated endosulfan-induced caspase-3 activation, indicating that the kinase serves as a regulatory switch for apoptosis. Additional studies in primary mesencephalic neuronal cultures confirmed endosulfan’s effect on autophagy and neuronal degeneration. Collectively, our results demonstrate that a functional interplay between autophagy and apoptosis dictate pesticide-induced neurodegenerative processes in dopaminergic neuronal cells. Our study provides insight into cell death mechanisms in environmentally linked neurodegenerative diseases.
SANTA-SIM: simulating viral sequence evolution dynamics under selection and recombination
Authors: Jariani Abbas , Warth Christopher , Deforche Koen , Libin Pieter , Drummond Alexei J , Rambaut Andrew , Matsen IV Frederick A , Theys Kristof
Published: February 2019

Simulations are widely used to provide expectations and predictive distributions under known conditions against which to compare empirical data. Such simulations are also invaluable for testing and comparing the behaviour and power of inference methods. We describe SANTA-SIM, a software package to simulate the evolution of a population of gene sequences forwards through time. It models the underlying biological processes as discrete components: replication, recombination, point mutations, insertion–deletions, and selection under various fitness models and population size dynamics. The software is designed to be intuitive to work with for a wide range of users and executable in a cross-platform manner.
Genetic Diversity and Structure in RegionalCercospora beticolaPopulations fromBeta vulgarissubsp.vulgarisSuggest Two Clusters of Separate Origin
Authors: Knight Noel L. , Vaghefi Niloofar , Kikkert Julie R. , Bolton Melvin D. , Secor Gary A. , Rivera Viviana V. , Hanson Linda E. , Nelson Scot C. , Pethybridge Sarah J.
Published: February 2019

Cercospora leaf spot, caused by Cercospora beticola, is a highly destructive disease of Beta vulgaris subsp. vulgaris worldwide. C. beticola populations are usually characterized by high genetic diversity, but little is known of the relationships among populations from different production regions around the world. This information would be informative of population origin and potential pathways for pathogen movement. For the current study, the genetic diversity, differentiation, and relationships among 948 C. beticola isolates in 28 populations across eight geographic regions were investigated using 12 microsatellite markers. Genotypic diversity, as measured by Simpson’s complement index, ranged from 0.18 to 1.00, while pairwise index of differentiation values ranged from 0.02 to 0.42, with the greatest differentiation detected between two New York populations. In these populations, evidence for recent expansion was detected. Assessment of population structure identified two major clusters: the first associated with New York, and the second with Canada, Chile, Eurasia, Hawaii, Michigan, North Dakota, and one population from New York. Inferences of gene flow among these regions suggested that the source for one cluster likely is Eurasia, whereas the source for the other cluster is not known. These results suggest a shared origin of C. beticola populations across regions, except for part of New York, where population divergence has occurred. These findings support the hypothesis that dispersal of C. beticola occurs over long distances.
Social information and spontaneous emergence of leaders in human groups
Authors: Nakayama Shinnosuke , Krasner Elizabeth , Zino Lorenzo , Porfiri Maurizio
Published: February 2019

Understanding the dynamics of social networks is the objective of interdisciplinary research ranging from animal collective behaviour to epidemiology, political science and marketing. Social influence is key to comprehending emergent group behaviour, but we know little about how inter-individual relationships emerge in the first place. We conducted an experiment where participants repeatedly performed a cognitive test in a small group. In each round, they were allowed to change their answers upon seeing the current answers of other members and their past performance in selecting correct answers. Rather than following a simple majority rule, participants granularly processed the performance of others in deciding how to change their answers. Toward a network model of the experiment, we associated a directed link of a time-varying network with every change in a participant's answer that mirrored the answer of another group member. The rate of growth of the network was not constant in time, whereby links were found to emerge faster as time progressed. Further, repeated interactions reinforced relationships between individuals' performance and their network centrality. Our results provide empirical evidence that inter-individual relationships spontaneously emerge in an adaptive way, where good performers rise as group leaders over time.
Temporal inactivation enhances robustness in an evolving system
Authors: Ogushi Fumiko , Kertész János , Kaski Kimmo , Shimada Takashi
Published: February 2019

We study the robustness of an evolving system that is driven by successive inclusions of new elements or constituents with
m
random interactions to older ones. Each constitutive element in the model stays either active or is temporarily inactivated depending upon the influence of the other active elements. If the time spent by an element in the inactivated state reaches
T

W

, it gets extinct. The phase diagram of this dynamic model as a function of
m
and
T

W

is investigated by numerical and analytical methods and as a result both growing (robust) as well as non-growing (volatile) phases are identified. It is also found that larger time limit
T

W

enhances the system’s robustness against the inclusion of new elements, mainly due to the system’s increased ability to reject ‘falling-together’ type attacks. Our results suggest that the ability of an element to survive in an unfavourable situation for a while, either as a minority or in a dormant state, could improve the robustness of the entire system.
A four-questions perspective on public information use in sticklebacks (Gasterosteidae)
Authors: Webster Mike M. , Chouinard-Thuly Laura , Herczeg Gabor , Kitano Jun , Riley Riva , Rogers Sean , Shapiro Michael D. , Shikano Takahito , Laland Kevin N.
Published: February 2019

Whether learning primarily reflects general processes or species-specific challenges is a long-standing matter of dispute. Here, we present a comprehensive analysis of public information use (PI-use) in sticklebacks (Gasterosteidae). PI-use is a form of social learning by which animals are able to assess the relative quality of resources, here prey patches, by observing the behaviour of others. PI-use was highly specific with only
Pungitius
and their closest relative
Culaea inconstans
showing evidence of PI-use. We saw no effects of ontogenetic experience upon PI-use in
Pungitius pungitius
. Experiments with live demonstrators and animated fish revealed that heightened activity and feeding strikes by foraging conspecifics are important cues in the transmission of PI. Finally, PI-use was the only form of learning in which
P. pungitius
and another stickleback,
Gasterosteus aculeatus
differed. PI-use in sticklebacks is species-specific and may represent an ‘ecological specialization’ for social foraging. Whether this reflects selection on perception, attentional or cognitive processes remains to be determined.
Dung beetle–mammal associations: methods, research trends and future directions
Authors: Raine Elizabeth H. , Slade Eleanor M.
Published: February 2019

Dung beetles are increasingly used as a study taxon—both as bioindicators of environmental change, and as a model system for exploring ecosystem functioning. The advantages of this focal taxon approach are many; dung beetles are abundant in a wide range of terrestrial ecosystems, speciose, straightforward to sample, respond to environmental gradients and can be easily manipulated to explore species-functioning relationships. However, there remain large gaps in our understanding of the relationship between dung beetles and the mammals they rely on for dung. Here we review the literature, showing that despite an increase in the study of dung beetles linked to ecosystem functioning and to habitat and land use change, there has been little research into their associations with mammals. We summarize the methods and findings from dung beetle–mammal association studies to date, revealing that although empirical field studies of dung beetles rarely include mammal data, those that do, indicate mammal species presence and composition has a large impact on dung beetle species richness and abundance. We then review the methods used to carry out diet preference and ecosystem functioning studies, finding that despite the assumption that dung beetles are generalist feeders, there are few quantitative studies that directly address this. Together this suggests that conclusions about the effects of habitat change on dung beetles are based on incomplete knowledge. We provide recommendations for future work to identify the importance of considering mammal data for dung beetle distributions, composition and their contributions to ecosystem functioning; a critical step if dung beetles are to be used as a reliable bioindicator taxon.
Functional crosstalk across IMD and Toll pathways: insight into the evolution of incomplete immune cascades
Authors: Nishide Yudai , Kageyama Daisuke , Yokoi Kakeru , Jouraku Akiya , Tanaka Hiromitsu , Futahashi Ryo , Fukatsu Takema
Published: February 2019

In insects, antimicrobial humoral immunity is governed by two distinct gene cascades, IMD pathway mainly targeting Gram-negative bacteria and Toll pathway preferentially targeting Gram-positive bacteria, which are widely conserved among diverse metazoans. However, recent genomic studies uncovered that IMD pathway is exceptionally absent in some hemipteran lineages like aphids and assassin bugs. How the apparently incomplete immune pathways have evolved with functionality is of interest. Here we report the discovery that, in the hemipteran stinkbug
Plautia stali
, both IMD and Toll pathways are present but their functional differentiation is blurred. Injection of Gram-negative bacteria and Gram-positive bacteria upregulated effector genes of both pathways. Notably, RNAi experiments unveiled significant functional permeation and crosstalk between IMD and Toll pathways: RNAi of IMD pathway genes suppressed upregulation of effector molecules of both pathways, where the suppression was more remarkable for IMD effectors; and RNAi of Toll pathway genes reduced upregulation of effector molecules of both pathways, where the suppression was more conspicuous for Toll effectors. These results suggest the possibility that, in hemipterans and other arthropods, IMD and Toll pathways are intertwined to target wider and overlapping arrays of microbes, which might have predisposed and facilitated the evolution of incomplete immune pathways.
Heterochronic shifts and conserved embryonic shape underlie crocodylian craniofacial disparity and convergence
Authors: Morris Zachary S. , Vliet Kent A. , Abzhanov Arhat , Pierce Stephanie E.
Published: February 2019

The distinctive anatomy of the crocodylian skull is intimately linked with dietary ecology, resulting in repeated convergence on blunt- and slender-snouted ecomorphs. These evolutionary shifts depend upon modifications of the developmental processes which direct growth and morphogenesis. Here we examine the evolution of cranial ontogenetic trajectories to shed light on the mechanisms underlying convergent snout evolution. We use geometric morphometrics to quantify skeletogenesis in an evolutionary context and reconstruct ancestral patterns of ontogenetic allometry to understand the developmental drivers of craniofacial diversity within Crocodylia. Our analyses uncovered a conserved embryonic region of morphospace (CER) shared by all non-gavialid crocodylians regardless of their eventual adult ecomorph. This observation suggests the presence of conserved developmental processes during early development (before Ferguson stage 20) across most of Crocodylia. Ancestral state reconstruction of ontogenetic trajectories revealed heterochrony, developmental constraint, and developmental systems drift have all played essential roles in the evolution of ecomorphs. Based on these observations, we conclude that two separate, but interconnected, developmental programmes controlling craniofacial morphogenesis and growth enabled the evolutionary plasticity of skull shape in crocodylians.
Global predictors of alien plant establishment success: combining niche and trait proxies
Authors: Gallien Laure , Thornhill Andrew H. , Zurell Damaris , Miller Joseph T. , Richardson David M.
Published: February 2019

Biological invasions are on the rise globally. To reduce future invasions, it is imperative to determine the naturalization potential of species. Until now, screening approaches have relied largely on species-specific functional feature data. Such information is, however, time-consuming and expensive to collect, thwarting the screening of large numbers of potential invaders. We propose to resolve such data limitations by developing indicators of establishment success of alien species that can be readily derived from open-access databases. These indicators describe key features of successfully established aliens, including estimates of potential range size, niche overlap with human-disturbed environments, and proxies of species traits related to their palaeoinvasions and local dominance capacities. We demonstrate the utility of this new approach by applying it to two large and highly invasive plant groups: Australian acacias and eucalypts. Our results show that these indicators robustly predict establishment successes and failures in each clade independently, and that they can cross-predict establishment in these two clades. Interestingly, the indicator identified as most important was species potential range size on Earth, a variable too rarely considered as a predictor. By successfully identifying key features that predispose Australian plants to naturalize, we provide an objective and cost-effective protocol for flagging high-risk introductions.
Loss of top-down biotic interactions changes the relative benefits for obligate mutualists
Authors: Wang Rong , Chen Xiao-Yong , Chen Yan , Wang Gang , Dunn Derek W. , Quinnell Rupert J. , Compton Stephen G.
Published: February 2019

The collapse of mutualisms owing to anthropogenic changes is contributing to losses of biodiversity. Top predators can regulate biotic interactions between species at lower trophic levels and may contribute to the stability of such mutualisms, but they are particularly likely to be lost after disturbance of communities. We focused on the mutualism between the fig treeFicus microcarpaand its host-specific pollinator fig wasp and compared the benefits accrued by the mutualists in natural and translocated areas of distribution. Parasitoids of the pollinator were rare or absent outside the natural range of the mutualists, where the relative benefits the mutualists gained from their interaction were changed significantly away from the plant's natural range owing to reduced seed production rather than increased numbers of pollinator offspring. Furthermore, in the absence of the negative effects of its parasitoids, we detected an oviposition range expansion by the pollinator, with the use of a wider range of ovules that could otherwise have generated seeds. Loss of top-down control has therefore resulted in a change in the balance of reciprocal benefits that underpins this obligate mutualism, emphasizing the value of maintaining food web complexity in the Anthropocene.
On the architecture of mate choice decisions: preference functions and choosiness are distinct traits
Authors: Neelon Daniel P. , Rodríguez Rafael L. , Höbel Gerlinde
Published: February 2019

Mate choice is an important cause of sexual selection; it can drive the evolution of extravagant ornaments and displays, and promote speciation through the reproductive isolation generated by rapid divergence of sexual traits. Understanding mate choice requires knowledge of the traits involved in generating mate-choice decisions, and how those traits may interact with each other. It has been proposed that mate-choice decisions are the outcome of two components that vary independently: thepreference function(the ranking of the attractiveness of prospective mates) andchoosiness(the effort invested in mate assessment). Here we test this hypothesis by examining individual variation in female preference functions and choosiness in green treefrogs (Hyla cinerea). We show that measures describing preference functions and choosiness are not correlated. We also show that both components are influenced differently by variation in female body size, and that preference function shape (closed and preferring intermediate values or open-ended and preferring extremes) has a strong influence on this relationship: function traits are positively correlated with body size only for individuals with closed functions, while choosiness is positively correlated with body size for individuals with open functions, but negatively for those with closed functions.
Non-native honey bees disproportionately dominate the most abundant floral resources in a biodiversity hotspot
Authors: Hung Keng-Lou James , Kingston Jennifer M. , Lee Adrienne , Holway David A. , Kohn Joshua R.
Published: February 2019

Most plant–pollinator mutualisms are generalized. As such, they are susceptible to perturbation by abundant, generalist, non-native pollinators such as the western honey bee (
Apis mellifera
), which can reach high abundances and visit flowers of many plant species in their expansive introduced range. Despite the prevalence of non-native honey bees, their effects on pollination mutualisms in natural ecosystems remain incompletely understood. Here, we contrast community-level patterns of floral visitation by honey bees with that of the diverse native pollinator fauna of southern California, USA. We show that the number of honey bees visiting plant species increases much more rapidly with flower abundance than does that of non-honey bee insects, such that the percentage of all visitors represented by honey bees increases with flower abundance. Thus, honey bees could disproportionately impact the most abundantly blooming plant species and the large numbers of both specialized and generalized pollinator species that they sustain. Honey bees may preferentially exploit high-abundance floral resources because of their ability to recruit nest-mates; these foraging patterns may cause native insect species to forage on lower-abundance resources to avoid competition. Our results illustrate the importance of understanding foraging patterns of introduced pollinators in order to reveal their ecological impacts.
The pursuit strategy of predatory bluefish (Pomatomus saltatrix)
Authors: McHenry Matthew J. , Johansen Jacob L. , Soto Alberto P. , Free Brian A. , Paley Derek A. , Liao James C.
Published: February 2019

A predator’s ability to capture prey depends critically on how it coordinates its approach in response to a prey’s motion. Flying insects, bats and raptors are capable of capturing prey with a strategy known as parallel navigation, which allows a predator to move directly towards the anticipated point of interception. It is unclear if predators using other modes of locomotion are employing this strategy when pursuing evasive prey. Using kinematic measurements and mathematical modelling, we tested whether bluefish (Pomatomus saltatrix) pursue prey fish (Fundulus heteroclitus) with parallel navigation. We found that the directional changes of bluefish were not consistent with this strategy, but rather were predicted by a strategy known as deviated pursuit. Although deviated pursuit requires few sensory cues and relatively modest motor coordination, a comparison of mathematical models suggested negligible differences in path length from parallel navigation, largely owing to the acceleration exhibited by bluefish near the end of a pursuit. Therefore, the strategy of bluefish is unlike flying predators, but offers comparable performance with potentially more robust control that may be well suited to the visual system and habitat of fishes. These findings offer a foundation for understanding the sensing and locomotor control of predatory fishes.
Recombinant production and purification of the human protein Tau
Authors: Ferrari Luca , Rüdiger Stefan G.D.
Published: February 2019

Tau protein is a microtubule-stabilizing protein whose aggregation is linked to Alzheimer’s Disease and other forms of dementia. Tau biology is at the heart of cytoskeletal dynamics and neurodegenerative mechanisms, making it a crucial protein to study. Tau purification, however, is challenging as Tau is disordered, which makes it difficult to produce in recombinant system and is degradation-prone. It is thus challenging to obtain pure and stable preparations of Tau. Here, we present a fast and robust protocol to purify Tau recombinantly in Escherichia coli. Our protocol allows purifyig Tau either tag-less free or FLAG-tagged at its N-terminus. By exploiting a cleavable affinity tag and two anion exchange columns, we obtained Tau is of high purity, stable and suitable for in vitro studies, including aggregation experiments that resemble neurodegenerative processes.
Computational tool to study perturbations in muscle regulation and its application to heart disease
Authors: Barrick Samantha K. , Clippinger Sarah R. , Greenberg Lina , Greenberg Michael J.
Published: February 2019

Striated muscle contraction occurs when myosin thick filaments bind to thin filaments in the sarcomere and generate pulling forces. This process is regulated by calcium, and it can be perturbed by pathological conditions (e.g., myopathies), physiological adaptations (e.g., β-adrenergic stimulation), and pharmacological interventions. Therefore, it is important to have a methodology to robustly determine the mechanism of these perturbations and statistically evaluate their effects. Here, we present an approach to measure the equilibrium constants that govern muscle activation, estimate uncertainty in these parameters, and statistically test the effects of perturbations. We provide a MATLAB-based computational tool for these analyses, along with easy-to-follow tutorials that make this approach accessible. The hypothesis testing and error estimation approaches described here are broadly applicable, and the provided tools work with other types of data, including cellular measurements. To demonstrate the utility of the approach, we apply it to determine the biophysical mechanism of a mutation that causes familial hypertrophic cardiomyopathy. This approach is generally useful for studying the mechanisms of muscle diseases and therapeutic interventions that target muscle contraction.
Nonlinear diversification rates of linguistic phylogenies over the Holocene
Authors: Hamilton Marcus J , Walker Robert S.
Published: February 2019

The expansion of the human species out of Africa in the Pleistocene, and the subsequent development of agriculture in the Holocene resulted in waves of linguistic diversification and replacement across the planet. Analogous to the growth of populations or the speciation of biological organisms, languages diversify over time to form phylogenies of language families. However, the dynamics of this diversification process are unclear. Bayesian methods applied to lexical and phonetic data have created dated linguistic phylogenies for 18 language families encompassing ∼3,000 of the world’s ∼7,000 extant languages. In this paper we use these phylogenies to quantify how fast languages expand and diversify through time both within and across language families. The overall diversification rate of languages in our sample is ∼0.001 yr-1(or a doubling time of ∼700 yr) over the last 6,000 years with evidence for nonlinear dynamics in language diversification rates over time, where both within and across language families, diversity initially increases rapidly and then slows. The large-scale replacement of the world’s hunter-gatherer languages by agricultural languages over the Holocene was a non-constant process.
Possible co-option of a VEGF-driven tubulogenesis program for biomineralization in echinoderms
Authors: Morgulis Miri , Gildor Tsvia , Roopin Modi , Sher Noa , Malik Assaf , Lalzar Maya , Dines Monica , Khalaily Lama , de-Leon Smadar Ben-Tabou
Published: February 2019

Biomineralization is the process in which living organisms use minerals to form hard structures that protect and support them. Biomineralization is believed to have evolved rapidly and independently in different phyla utilizing existing components used for other purposes. The mechanistic understanding of the regulatory networks that drive biomineralization and their evolution is far from clear. The sea urchin skeletogenesis is an excellent model system for studying both gene regulation and mineral uptake and deposition. The sea urchin calcite spicules are formed within a tubular cavity generated by the skeletogenic cells under the control the vascular endothelial growth factor (VEGF) signaling. The VEGF pathway controls tubulogenesis and vascularization across metazoans while its regulation of biomineralization was only observed in echinoderms. Despite the critical role of VEGF signaling in sea urchin spiculogenesis, the downstream program it activates was largely unknown. Here we study the cellular and molecular machinery activated by the VEGF pathway during sea urchin spiculogenesis and reveal multiple parallels to the regulation of tubulogenesis during vertebrate vascularization. Human VEGF rescues sea urchin VEGF knock-down; VEGF-dependent vesicle deposition plays a significant role in both systems and sea urchin VEGF signaling activates hundreds of genes including biomineralization and vascularization genes. Five upstream transcription factors and three signaling genes active in spiculogenesis are homologous to vertebrate factors that regulate vascularization. Overall, our findings suggest that sea urchin spiculogenesis and vertebrate vascularization diverged from a common ancestral tubulogenesis program, broadly adapted for vascularization and specifically co-opted for biomineralization in the echinoderm phylum.

Significance statement

The sea urchin calcite spicules and vertebrate blood vessels are quite distinct in their function, yet both have a tubular structure and are controlled by the vascular endothelial growth factor (VEGF) pathway. Here we study the downstream program by which VEGF pathway drives sea urchin spiculogenesis and find remarkable similarities to the control of vertebrate vascularization. The similarities are observed both in the upstream gene regulatory network, in the downstream effector genes and the cellular processes that VEGF signaling controls at the site of the calcite spicule formation. We speculate that sea urchin spiculogenesis and vertebrate vascularization diverged from a common ancestral tubulogenesis program that was co-opted for biomineralization in the echinoderm phylum.
Notch signalling mediates secondary senescence
Authors: Teo Yee Voan , Rattanavirotkul Nattaphong , Salzano Angela , Quintanilla Andrea , Tarrats Nuria , Kiourtis Christos , Mueller Miryam , Green Anthony R. , Adams Peter D. , Acosta Juan-Carlos , Bird Thomas G. , Kirschner Kristina , Neretti Nicola , Chandra Tamir
Published: February 2019

Oncogene induced senescence (OIS) is a tumour suppressive response to oncogene activation that can be transmitted to neighbouring cells through secreted factors of the senescence associated secretory phenotype (SASP). Using single-cell transcriptomics we observed two distinct endpoints, a primary marked by Ras and a secondary by Notch. We find that secondary senescence in vitro and in vivo requires Notch, rather than SASP alone as previously thought. Currently, primary and secondary senescent cells are not thought of as functionally distinct endpoints. A blunted SASP response and the induction of fibrillar collagens in secondary senescence compared to OIS point towards a functional diversification.

One Sentence Summary

Notch signalling is an essential driver of secondary senescence with primary and secondary senescence being distinct molecular endpoints.
Immune-informed mucin hydrogels evade fibrotic foreign body response in vivo
Authors: Yan Hongji , Seignez Cédric , Hjorth Morgan , Winkeljann Benjamin , Lieleg Oliver , Phillipson Mia , Crouzier Thomas
Published: February 2019

The immune-mediated foreign body response to biomaterial implants can trigger the formation of insulating fibrotic capsules that can compromise implant function. To address this challenge, we leverage the intrinsic bioactivity of the mucin biopolymer, a heavily glycosylated protein that forms the protective mucus gel covering mucosal epithelia. By using a bioorthogonal inverse electron demand Diels-Alder reaction, we crosslink mucins into implantable hydrogels. We show that mucin hydrogels (Muc-gels) modulate the immune response driving biomaterial-induced fibrosis. Muc-gels did not elicit fibrosis 21 days after implantation in the peritoneal cavity of C57Bl/6 mice, whereas medical-grade alginate hydrogels (Alg-gels) were covered by fibrous tissues. Further, Muc-gels dampened the recruitment of innate and adaptive immune cells to the gel and triggered a pattern of very mild activation marked by a noticeably low expression of the fibrosis-stimulating TGF-β1 cytokine. With this advance in mucin materials, we provide an essential tool to better understand mucin bioactivities and to initiate the development of new mucin-based and mucin-inspired ‘immune-informed’ materials for implantable devices subject to fibrotic encapsulation.
Raman Spectroscopic Study of the Influence of Oxytocin and Uvariodendron anisatum Verdeck (Annonaceae) Freeze-dried Extracts on Diet Induced Obesity in Sprague Dawley Rats
Authors: Birech Zephania , Sehmi Prabjot K. , Mwangi Peter W. , Nyaga Nelly M.
Published: February 2019

Obesity is a condition affecting many people in the world. Obese people have increased risks of developing chronic metabolic diseases such as type II diabetes, hypertension, cancer among others. Early and rapid diagnosis of the condition together with effective treatment is therefore necessary. This work investigated, first, Raman spectroscopic similarities between oxytocin and a freeze-dried extract of a local herbal plant exhibiting oxytocin-like properties called Uvariodendron anisatum Verdeck (Annonaceae) (UAV). Secondly, whether Raman spectroscopy could be used for comparative studies of the influence of oxytocin and UAV on diet induced obesity in Sprague Dawley (SD) rat models. We also sought for obesity or metabolic syndrome biomarker Raman spectral bands. Both oxytocin and extract samples together with blood extracted from the rats were excited using a 785 nm laser with conductive silver paste smeared glass slides as Raman sample substrates. It was found that Raman spectral profiles of oxytocin solution and UAV freeze dried extract’s powder were identical with a cosine similarity value of 0.95 implying presence of similar Raman active molecules. The prominent peaks were those assigned to disulphide S-S stretching mode at 508 cm−1 and to tyrosine at 645 cm−1, 846 cm−1 and 1617 cm−1. Raman spectra of blood from oxytocin- and UAV-treated rats displayed similar profiles which were different from those of obese and non-obese (normal controls) animals. A prominent peak in spectra of treated rats centred at 401 cm−1 could be used as oxytocin biomarker band in blood. Comparison of average intensity trend of fructose bands at around 638 cm−1 and 812 cm−1 between prepared fructose solution and blood of treated rats, revealed elevated levels of fructose in blood of rats intraperitoneally injected oxytocin and UAV extracts. The result implied upregulation of fructose in oxytocin and UAV treated animals. Principal component analysis (PCA) showed that the Raman spectral profiles from blood of obese rats were different from those of non-obese rats. It also showed that spectra from oxytocin treated and UAV treated rat’s blood were similar indicating identical influence. The study shows the potential of Raman spectroscopy as tool for quick obesity (metabolic syndrome) screening with intensity of Raman bands associated with fructose acting as biomarkers. The same bands can also be used in comparative efficacy studies of anti-obesity drugs. Further studies are needed to validate these Raman spectroscopic results since, to the best of our knowledge, this was the first such investigation regarding comparison of UAV and conventional oxytocin together with their influence on obese SD rats. Weather human subjects exhibits similar results are also not known.
Metabolic Reprogramming: Short-term Western Diet Exposure Induces Sustained Changes in Plasma Metabolites
Authors: Misra Biswapriya B. , Upadhayay Ram P. , Mattern Vicki , Parks John S. , Cox Laura A. , Comuzzie Anthony G. , Olivier Michael
Published: February 2019

Dietary patterns are well known to contribute to the metabolic syndrome and related disorders. We evaluated the impact of a short-term Westernized diet (WD) exposure on systemic plasma metabolomic changes in a cohort of adult male baboons. In this pilot study, five male baboons (n=5) raised and maintained on a standard monkey chow diet (high complex carbohydrates, low fat) were exposed to a challenge WD (high in saturated fats and simple carbohydrates) for 7 weeks (49 d), followed by a 57-day washout period on monkey chow (106 d). In addition to monitoring clinical measures, we used a comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (2D GC-ToF-MS) platform to assess the metabolomic changes in plasma at three time points. Twenty-three metabolites were changed in response to the WD (49 d), but the response across the animals was highly variable. All animals presented a very different metabolic profile than at baseline (0 d), and the washout period resulted in a relatively homogenous metabolic state across all animals. A short-term exposure to a WD led to long-term changes in the metabolic profile, suggesting a “reset” of the metabolic program.
A CyclinB2-Cas9 fusion promotes the homology-directed repair of double-strand breaks
Authors: Vicente Manuel M. , Mendes Afonso , Cruz Margarida , Vicente José R. , Barreto Vasco M.
Published: February 2019

The discovery of clustered regularly interspaced palindromic repeats (CRISPR), a defense system against viruses found in bacteria, launched a new era in gene targeting. The key feature of this technique is the guiding of the endonuclease Cas9 by single guide RNAs (sgRNA) to specific sequences, where a DNA lesion is introduced to trigger DNA repair. The CRISPR/Cas9 system may be extremely relevant for gene therapy, but the technique needs improvement to become a safe and fully effective tool. The Cas9-induced double-strand break (DSB) is repaired by one of two pathways, the error-prone Non-homologous end joining (NHEJ) or the high-fidelity Homology Direct Repair (HDR). Shifting the repair of the DSB to HDR is challenging, given the efficiency of NHEJ. Here we describe an engineered protein approach to increase knock-in efficiency by promoting the relative increase in Cas9 activity in G2, the phase of the cell cycle where HDR is more active. Cas9 was fused to the degradation domain of proteins known to be degraded in G1. The activity of two chimeric proteins, Geminin-Cas9 and CyclinB2-Cas9, is demonstrated, as well as their cell-cycle-dependent degradation. The chimeras shifted the repair of the DSBs to the HDR repair pathway compared to the commonly used Cas9. The application of cell cycle specific degradation tags could pave the way for more efficient and secure gene editing applications of the CRISPR/Cas9 system.
Metagenomic dynamics in Olea europaea after root damage and Verticillium dahliae infection
Authors: Martí Jose Manuel , Arias Luis F. , Díaz Wladimiro , Arnau Vicente , Rodriguez-Franco Antonio , Garay Carlos P.
Published: February 2019

The olive tree is of particular economic interest in the Mediterranean basin. Researchers have conducted several studies on one of the most devastating disorders affecting this tree, the Verticillium wilt of olive, which causes significant economic damage in numerous areas of this crop. We have analyzed the temporal metagenomic samples of a transcriptomic study in Olea europaea roots and leaves after root-damage and after a root Verticillium dahliae infection (Jimenez-Ruiz et al. 2017). Our results indicate that this infection, although led by Verticillium, is driven not by a single species but by a polymicrobial community, including their natural endophytes, which acts as a consortium in the attack to the host plant. This community includes both biotrophic and necrotrophic organisms that alternate and live together during the infection. Our results not only describe how the microbial community progresses along these processes, but also explain the high complexity of these systems, that in turn, could justify at least in part the occasional changes and disparity found at the time of classifying the kind of parasitism of a determined organism.
Genome-wide estimates of heritability and genetic correlations in Essential Tremor
Authors: Diez-Fairen Monica , Bandres-Ciga Sara , Houle Gabrielle , Nalls Mike A. , Girard Simon L. , Dion Patrick A. , Blauwendraat Cornelis , Singleton Andrew B. , Rouleau Guy A. , Pastor Pau
Published: February 2019

Despite considerable efforts to identify disease-causing and risk factors contributing to essential tremor (ET), no comprehensive assessment of heritable risk has been performed to date. We use GREML-LDMS to estimate narrow-sense heritability due to additive effects (h2) and GREMLd to calculate non-additive heritability due to dominance variance (δ2) using data from 1,748 ET cases and 5,302 controls. We evaluate heritability per 10Mb segments across the genome and assess the impact of Parkinson’s disease (PD) misdiagnosis on heritability estimates. We apply genetic risk score (GRS) from PD and restless legs syndrome (RLS) to explore its contribution to ET risk and further assess genetic correlations with 832 traits by Linkage disequilibrium score regression. Our results show for the first time that ET is a highly heritable condition (h2=0.755, s.e=0.075) in which additive common variability plays a prominent role. In contrast, dominance variance shows insignificant effect on the overall estimates. Heritability split by 10Mb regions revealed increased estimates at chromosomes 6 and 21 suggesting that these may contain causative risk variants influencing susceptibility to ET. The proportion of genetic variance due to PD misdiagnosed cases was estimated to be 5.33%. PD and RLS GRS were not significantly predictive of ET case-control status demonstrating that despite overlapping symptomatology, ET does not seem to share genetic etiologies with PD or RLS. Our study suggests that most of ET genetic component is yet to be discovered and future GWAS will reveal additional risk factors that will improve our understanding of this disabling disorder.