bluuebunny/crossref_metadata_2025 huggingface dataset:
Social value orientation and attachment: a replication and extension of Van Langeet al. (1997)
Authors: IJzerman Hans , Denissen Jaap J. A.
Published: April 2019

We report a replication and extension of a finding from Studies 1 and 2 of Van Langeet al.'s influential paper (Van Langeet al.1997J. Pers. Soc. Psychol.73, 733–746. (doi:10.1037/0022-3514.73.4.733)), which showed an association between Social Value Orientation (SVO) and attachment security. We report a close replication but with measures of attachment that are considered superior in comparison to measures used by Van Langeet al., due to subsequent psychometric improvements. Psychometric analyses indeed showed that our attachment measures were reliable and valid, demonstrating theoretically predicted associations with other outcomes. With a sample (N= 879) sufficiently large to detectd= 0.19 (and larger than the originalN= 573), we failed to replicate the effect. Based on the available evidence, we interpret as there being no evidence for the link between attachment security and Social Value Orientation, but further replication research that uses solid measures and large samples can provide more definite conclusions about the association between attachment and SVO.
Dynamical modelling of secondary metabolism and metabolic switches in
Streptomyces xiamenensis
318
Authors: Zhu Xiao-Mei , Zhang Xing-Xing , Cheng Run-Tan , Yu He-Lin , Yuan Ruo-Shi , Bu Xu-Liang , Xu Jun , Ao Ping , Chen Yong-Cong , Xu Min-Juan
Published: April 2019

The production of secondary metabolites, while important for bioengineering purposes, presents a paradox in itself. Though widely existing in plants and bacteria, they have no definite physiological roles. Yet in both native habitats and laboratories, their production appears robust and follows apparent metabolic switches. We show in this work that the enzyme-catalysed process may improve the metabolic stability of the cells. The latter can be responsible for the overall metabolic behaviours such as dynamic metabolic landscape, metabolic switches and robustness, which can in turn affect the genetic formation of the organism in question. Mangrove-derived
Streptomyces xiamenensis
318, with a relatively compact genome for secondary metabolism, is used as a model organism in our investigation. Integrated studies via kinetic metabolic modelling, transcriptase measurements and metabolic profiling were performed on this strain. Our results demonstrate that the secondary metabolites increase the metabolic fitness of the organism via stabilizing the underlying metabolic network. And the fluxes directing to NADH, NADPH, acetyl-CoA and glutamate provide the key switches for the overall and secondary metabolism. The information may be helpful for improving the xiamenmycin production on the strain.
The controlled synthesis of complex hollow nanostructures and prospective applications
Authors: Soares Sofia F. , Fernandes Tiago , Daniel-da-Silva Ana L. , Trindade Tito
Published: April 2019

Functionality in nanoengineered materials has been usually explored on structural and chemical compositional aspects of matter that exist in such solid materials. It is well known that the absence of solid matter is also relevant and the existence of voids confined in the nanostructure of certain particles is no exception. Indeed, over the past decades, there has been great interest in exploring hollow nanostructured materials that besides the properties recognized in the dense particles also provide empty spaces, in the sense of condensed matter absence, as an additional functionality to be explored. As such, the chemical synthesis of hollow nanostructures has been driven not only for tailoring the size and shape of particles with well-defined chemical composition, but also to achieve control on the type of hollowness that characterize such materials. This review describes the state of the art on late developments concerning the chemical synthesis of hollow nanostructures, providing a number of examples of materials obtained by distinct strategies. It will be apparent by reading this progress report that the absence of solid matter determines the functionality of hollow nanomaterials for several technological applications.
Evidence of a tunable biological spring: elastic energy storage in aponeuroses varies with transverse strain
in vivo
Authors: Arellano Christopher J. , Konow Nicolai , Gidmark Nicholas J. , Roberts Thomas J.
Published: April 2019

Tendinous structures are generally thought of as biological springs that operate with a fixed stiffness, yet recent observations on the mechanical behaviour of aponeuroses (broad, sheet-like tendons) have challenged this general assumption. During
in situ
contractions, aponeuroses undergo changes in both length and width and changes in aponeuroses width can drive changes in longitudinal stiffness. Here, we explore if changes in aponeuroses width can modulate elastic energy (EE) storage in the longitudinal direction. We tested this idea
in vivo
by quantifying muscle and aponeuroses mechanical behaviour in the turkey lateral gastrocnemius during landing and jumping, activities that require rapid rates of energy dissipation and generation, respectively. We discovered that when aponeurosis width increased (as opposed to decreased), apparent longitudinal stiffness was 34% higher and the capacity of aponeuroses to store EE when stretched in the longitudinal direction was 15% lower. These data reveal that biaxial loading of aponeuroses allows for variation in tendon stiffness and energy storage for different locomotor behaviours.
A new ophiocistioid with soft-tissue preservation from the Silurian Herefordshire Lagerstätte, and the evolution of the holothurian body plan
Authors: Rahman Imran A. , Thompson Jeffrey R. , Briggs Derek E. G. , Siveter David J. , Siveter Derek J. , Sutton Mark D.
Published: April 2019

Reconstructing the evolutionary assembly of animal body plans is challenging when there are large morphological gaps between extant sister taxa, as in the case of echinozoans (echinoids and holothurians). However, the inclusion of extinct taxa can help bridge these gaps. Here we describe a new species of echinozoan,
Sollasina cthulhu
, from the Silurian Herefordshire Lagerstätte, UK.
Sollasina cthulhu
belongs to the ophiocistioids, an extinct group that shares characters with both echinoids and holothurians. Using physical–optical tomography and computer reconstruction, we visualize the internal anatomy of
S. cthulhu
in three dimensions, revealing inner soft tissues that we interpret as the ring canal, a key part of the water vascular system that was previously unknown in fossil echinozoans. Phylogenetic analyses strongly suggest that
Sollasina
and other ophiocistioids represent a paraphyletic group of stem holothurians, as previously hypothesized. This allows us to reconstruct the stepwise reduction of the skeleton during the assembly of the holothurian body plan, which may have been controlled by changes in the expression of biomineralization genes.
Morphological evolution in therocephalians breaks the hypercarnivore ratchet
Authors: Brocklehurst Neil
Published: April 2019

Large carnivorous mammals have been suggested to show a ratchet-like mode of morphological evolution. A limited number of specializations for hypercarnivory evolve repeatedly in multiple clades, with those lineages evolving such specialities being unable to retreat back along their evolutionary trajectory or jump between adaptive peaks. While it has been hypothesized that such mechanisms should have applied to the evolution of other terrestrial carnivores, the non-mammalian synapsid clade Therocephalia appears to defy this expectation. The earliest, basalmost members of this clade are large macropredators, and it is later that small carnivores appear, seemingly evolving from top-predator ancestors. In order to test this reading of therocephalian evolution, variation in rates of body size evolution were tested for and incorporated into an ancestral reconstruction. Similar studies were made of the evolution of discrete characters related to carnivory. All analyses indicate the ancestral therocephalian was a large macro-predator, with serrated teeth, elongated canines and robust lower jaws. Small sizes apparently evolve later. It is therefore suggested that the hypercarnivore ratchet is a feature of mammalian evolution.
Simulation of model overfit in variance explained with genetic data
Authors: Derringer Jaime
Published: April 2019

Two recent papers, and an author response to prior commentary, addressing the genetic architecture of human temperament and character claimed that “The identified SNPs explained nearly all the heritability expected”. The authors’ method for estimating heritability may be summarized as: Step 1: Pre-select SNPs on the basis of GWAS p<0.01 in the target sample. Step 2: Enter target sample genotypes (the pre-selected SNPs from Step 1) and phenotypes into an unsupervised machine learning algorithm (Phenotype-Genotype Many-to-Many Relations Analysis, PGMRA) for further reduction of the set of SNPs. Step 3: Test the sum score of the SNPs identified from Step 2, weighted by the GWAS regression weights estimated in Step 1, within the same target sample. The authors interpreted the linear regression model R2 obtained from Step 3 as a measure of successfully identified heritability. Regardless of the method applied to select SNPs in Step 2, the combination of Steps 1 and 3, as described, causes inflation of the estimated effect size. The extent of this inflation is demonstrated here, where random SNP selection and polygenic scoring from simulated random data recovered effect sizes similar to those reported in the original empirical papers.
Systematically understanding the key roles of microglia in AD development
Authors: Ji Zhiwei , Liu Changan , Zhao Weiling , Soto Claudio , Zhou Xiaobo
Published: April 2019

Alzheimer’s disease (AD) is the leading cause of age-related dementia, affecting over 5 million people in the United States. Unfortunately, current therapies are largely palliative and several potential drug candidates have failed in late-stage clinical trials. Studies suggest that microglia-mediated neuroinflammation might be responsible for the failures of various therapies. Microglia contribute to Aβ clearance in the early stage of neurodegeneration and may contribute to AD development at the late stage by releasing pro-inflammatory cytokines. However, the activation profile and phenotypic changes of microglia during the development of AD are poorly understood. To systematically understand the key role of microglia in AD progression and predict the optimal therapeutic strategyin silico, we developed a 3D multi-scale model of AD (MSMAD) by integrating multi-level experimental data, to manipulate the neurodegeneration in a simulated system. Based on our analysis, we revealed how TREM2-related signal transduction leads to an imbalance in the activation of different microglia phenotypes, thereby promoting AD development. Our MSMAD model also provides an optimal treatment strategy for improving the outcome of AD treatment.
Role of host genetic diversity for susceptibility-to-infection in the evolution of virulence of a plant virus
Authors: González Rubén , Butković Anamarija , Elena Santiago F.
Published: April 2019

Predicting viral emergence is difficult due to the stochastic nature of the underlying processes and the many factors that govern pathogen evolution. Environmental factors affecting the host, the pathogen and the interaction between both are key in emergence. In particular, infectious disease dynamics are affected by spatiotemporal heterogeneity in their environments. A broad knowledge of these factors will allow better estimating where and when viral emergence is more likely to occur. Here we investigate how the population structure for susceptibility-to-infection genes of the plantArabidopsis thalianashapes the evolution ofTurnip mosaic virus(TuMV). For doing so we have evolved TuMV lineages in two radically different host population structures: (i) multiple genetically homogeneousA. thalianasubpopulations and (ii) a single maximally genetically heterogeneous population. We found faster adaptation of TuMV to homogeneous than to heterogeneous host populations. However, viruses evolved in heterogeneous host populations were more pathogenic and infectious than viruses evolved in the homogeneous population. Furthermore, the viruses evolved in homogeneous populations showed stronger signatures of local specialization than viruses evolved in heterogeneous populations. These results illustrate how the genetic diversity of hosts in an experimental ecosystem favors the evolution of virulence of a pathogen.
Integrative taxonomy confirms the species status of the Himalayan langurs, Semnopithecus schistaceus Hodgson 1840
Authors: Arekar Kunal , Sathyakumar S. , Karanth K. Praveen
Published: April 2019

Taxonomy is replete with groups where the species identity and classification remain unresolved. One such group is the widely distributed Hanuman langur (Colobinae: Semnopithecus). For most part of the last century, Hanuman langur was considered to be a single species with multiple subspecies. Nevertheless, recent studies using an integrative taxonomy approach suggested that this taxon is a complex, with at least three species. However, these studies did not include the Himalayan population of the Hanuman langur whose taxonomic status remains unresolved. The Himalayan population of Hanuman langurs have been classified as a distinct species with multiple subspecies or have been subsumed into other species. These classification schemes are wholly based on morphological characters and which are sometimes insufficient to delimit different species. Here, we have integrated data from multiple sources viz. morphology, DNA, and ecology to resolve the taxonomy of the Himalayan langur and to understand its distribution limit. Our results with three lines of evidence corresponding to three different species concepts show that Himalayan langur is a distinct species from S. entellus of the plains. Additionally, these results did not show any support for splitting of the Himalayan langur into multiple subspecies. Our study supports the classification proposed by Hill (1939) and we recommend Semnopithecus schistaceus, Hodgson 1840 as species name for the Himalayan langur and subsume all the known subspecies into it.
Evaluating the quorum quenching potential of bacteria associated toAurelia auritaandMnemiopsis leidyi
Authors: Prasse Daniela , Weiland-Bräuer Nancy , Jaspers Cornelia , Reusch Thorsten B.H. , Schmitz Ruth A.
Published: April 2019

The associated microbiota of marine invertebrates plays an important role to the host in relation to fitness, health and homeostasis of the metaorganism. As one key chemically-mediated interaction, Quorum sensing (QS) and interference with QS among colonizing bacteria ultimately affects the establishment and dynamics of the microbial community on the host. Aiming to address interspecies competition of cultivable microbes associated to merging model species of the basal animal phyla Cnidaria (Aurelia aurita) and Ctenophora (Mnemiopsis leidyi) as well as to evaluate their potential to shape the associated community by interfering with QS, we performed a classical isolation approach. Overall, 84 bacteria were isolated fromA. auritamedusae and polyps, 64 bacteria fromM. leidyi, and 83 bacteria from the ambient seawater, followed by taxonomically classification by full length 16S rRNA gene analysis. The results show that the moon jellyfishA. auritaand the comb jellyM. leidyiharbor a cultivable core microbiota consisting of typical marine and ubiquitously found bacteria (e.g.Chryseobacter, Microbacterium, Micrococcus, Olleya, Phaeobacter, Pseudoalteromonas, Pseudomonas, Rhodococcus, Shewanella, Staphylococcus, andVibrio) which can also be found in the ambient seawater. However, several bacteria were restricted to one host (e.g. forA. aurita: Bacillus, Glaciecola, Ruegeria, Luteococcus;forM. leidyi: Acinetobacter, Aeromonas, Colwellia, Exiguobacterium, Marinomonas, Pseudoclavibacter, Psychrobacter, Sagittula, Thalassomonas) suggesting host-specific microbial community patterns. Evaluating QQ activities, out of 231 isolates, 121 showed QS-interfering activity. They mainly interfered with the acyl homoserine lactone (AHL) based communication, whereas 21 showed simultaneous quorum quenching activities against AHL and autoinducer-2. Overall, this study provides insights into the cultivable part of the microbiota associated to two environmentally important marine non-model organisms and discloses their potential in synthesizing QS interfering compounds, potentially important in shaping a healthy and resilient microbiota.
Transcriptional response ofStreptomyces coelicolorto rapid chromosome relaxation or long-term supercoiling imbalance
Authors: Szafran MJ , Gongerowska M , Małecki T , Elliot MA , Jakimowicz D
Published: April 2019

Negative DNA supercoiling allows chromosome condensation within a cell and facilitates DNA unwinding, which is required for the occurrence of DNA transaction processes, i.e., DNA replication, transcription and recombination. In bacteria, changes in chromosome supercoiling impact global gene expression; however, the limited studies on the global transcriptional response have focused mostly on pathogenic species and have reported various fractions of affected genes. Furthermore, the transcriptional response to long-term supercoiling imbalance is still poorly understood. Here, we address the transcriptional response to both novobiocin-induced rapid chromosome relaxation or long-term topological imbalance, both increased and decreased supercoiling, in environmental antibiotic-producing bacteria belonging to theStreptomycesgenus. During theStreptomycescomplex developmental cycle, multiple copies of GC-rich linear chromosomes present in hyphal cells undergo profound topological changes, from being loosely condensed in vegetative hyphae, to being highly compacted in spores. InStreptomyces, chromosomal supercoiling changes may also be triggered by environmental stressors and have been suggested to be associated with the control of antibiotic production. Remarkably, inS. coelicolor, one of modelStreptomycesspecies, topoisomerase I (TopA) is solely responsible for the removal of negative DNA supercoils. Using aS. coelicolorstrain in whichtopAtranscription is under the control of an inducible promoter, we generated a long-term supercoiling imbalance, enabling us to identify genes involved in the supercoiling-sensitive transcriptional response. We observed that affected genes are preferentially organized in clusters, and among them, we identified a supercoiling-hypersensitive cluster (SHC) located in the core of theS. coelicolorchromosome. Moreover, using a gyrase inhibitor, we identified the directly affected novobiocin-sensitive genes and established that the AT content in their promoter regions was increased. Notably, genes whose expression was immediately impacted by gyrase inhibition encoded products associated with membrane transport or secondary metabolite synthesis. In contrast to the novobiocin-sensitive genes, the transcripts affected by long-term topological imbalance encompassed genes encoding nucleoid-associated proteins, DNA repair proteins and transcriptional regulators, including multiple developmental regulators. Collectively, our results show that long-term supercoiling imbalance globally regulates gene transcription and has the potential to impact development, secondary metabolism and DNA repair, amongst others.
High Throughput PET/CT Imaging Using a Multiple Mouse Imaging System
Authors: Greenwood Hannah E. , Nyitrai Zoltan , Mocsai Gabor , Hobor Sandor , Witney Timothy H.
Published: April 2019

A considerable limitation of current small animal positron emission tomography/computed tomography (PET/CT) imaging is the low throughput of image acquisitions. Subsequently, to design sufficiently-powered studies, high costs accumulate. Together with Mediso Medical Imaging Systems, a four-bed mouse ‘hotel’ was developed to simultaneously image up to four mice, thereby reducing the cost and maximising radiotracer usage when compared to scans performed with a single mouse bed.

Methods

For physiological evaluation of the four-bed mouse hotel, temperature and anaesthesia were tested for uniformity, followed by [18F]fluorodeoxyglucose (FDG) PET/CT imaging of ‘mini’ image quality (IQ) phantoms specifically designed to fit the new imaging system. Post-reconstruction, National Electrical Manufacturers Association (NEMA) NU-4 tests examined uniformity, recovery coefficients (RCs) and spill-over ratios (SORs). To evaluate the bed under standard in vivo imaging conditions, four mice were simultaneously scanned by dynamic [18F]FDG PET/CT over 60 minutes using the four-bed mouse hotel, with quantified images compared to those acquired using a single mouse bed.

Results

The bed maintained a constant temperature of 36.8°C ± 0.4°C (n = 4), with anaesthesia distributed evenly to each nose cone (2.9 ± 0.1 L/min, n = 4). The NEMA tests performed on reconstructed mini IQ phantom images acquired using the four-bed mouse hotel revealed values within the tolerable limits for uniformity, RC values in >2mm rods, and SORs in the non-radioactive water- and air-filled chambers. There was low variability in radiotracer uptake in all major organs of mice scanned using the four-animal bed versus those imaged using a single bed imaging platform.

Conclusion

Analysis of images acquired using the four-bed mouse hotel confirmed its utility to increase the throughput of small animal PET imaging without considerable loss of image quality and quantitative precision. In comparison to a single mouse bed, the cost and time associated with each scan were substantially reduced.
Evolved resistance to GAPDH inhibition results in loss of the Warburg Effect but retains a different state of glycolysis
Authors: Liberti Maria V. , Allen Annamarie E. , Ramesh Vijyendra , Dai Ziwei , Singleton Katherine R. , Guo Zufeng , Liu Jun O. , Wood Kris C. , Locasale Jason W.
Published: April 2019

Aerobic glycolysis or the Warburg Effect (WE) is characterized by increased glucose uptake and incomplete oxidation to lactate. Although ubiquitous, the biological role of the WE remains controversial and whether glucose metabolism is functionally different during fully oxidative glycolysis or during the WE is unknown. To investigate this question, we evolved resistance to koningic acid (KA), a natural product shown to be a specific inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-controlling glycolytic enzyme during the WE. We find that KA-resistant cells lose the WE but conduct glycolysis and surprisingly remain dependent on glucose and central carbon metabolism. Consequentially this altered state of glycolysis leads to differential metabolic activity and requirements including emergent activities in and dependencies on fatty acid metabolism. Together, these findings reveal that, contrary to some recent reports, aerobic glycolysis is a functionally distinct entity from conventional glucose metabolism and leads to distinct metabolic requirements and biological functions.
Mapping numerical perception and operations in relation to functional and anatomical landmarks of human parietal cortex
Authors: Castaldi Elisa , Vignaud Alexandre , Eger Evelyn
Published: April 2019

Human functional imaging has identified the middle part of the intraparietal sulcus (IPS) as an important brain substrate for different types of numerical tasks. This area is often equated with the macaque ventral intraparietal area (VIP) where neuronal selectivity for non-symbolic numbers is found. However, the low spatial resolution and whole-brain averaging analysis performed in most fMRI studies limit the extent to which an exact correspondence of activation in different numerical tasks with specific sub-regions of the IPS can be established. Here we disentangled the functional neuroanatomy of numerical perception and operations (comparison and calculation) by acquiring high-resolution 7T fMRI data in a group of human adults, and relating the activations in different numerical contrasts to anatomical and functional landmarks on the cortical surface. Our results reveal a functional heterogeneity within human intraparietal cortex where the visual field map representations in superior/medial parts of IPS and superior parietal gyrus are involved predominantly in numerosity perception, whereas numerical operations predominantly recruit lateral/inferior parts of IPS. Since calculation and comparison-related activity fell mainly outside the field map representations considered the functional equivalent of the monkey VIP/LIP complex, the areas most activated during such numerical operations in humans are likely different from VIP.
Fidelity of Prespacer Capture and Processing is Governed by the PAM Mediated Interaction of Cas1-2 Adaptation complex in Escherichia coli
Authors: Yoganand K.N.R. , Muralidharan Manasasri , Anand B.
Published: April 2019

During CRISPR adaptation, short sections of invader derived DNA of defined length are specifically integrated at the leader-repeat junction as spacers by Cas1-2 integrase complex. While several variants of CRISPR systems utilise Cas4 as an indispensible nuclease for processing the PAM containing prespacers to a defined length for integration– surprisingly– a few CRISPR systems such as type I-E are bereft of Cas4. Therefore, how the prespacers show impeccable conservation for length and PAM selection in type I-E remains intriguing. In Escherichia coli, we show that Cas1-2/I-E– via the type I-E specific extended C-terminal tail of Cas1 –displays intrinsic affinity for PAM containing prespacers of variable length and its binding protects the prespacer boundaries of defined length from the exonuclease action that ensues the pruning of aptly sized substrates for integration. This suggests that cooperation between Cas1-2 and cellular exonucleases drives the Cas4 independent prespacer capture and processing in type I-E.
Precise timing is ubiquitous, consistent and coordinated across a comprehensive, spike-resolved flight motor program
Authors: Putney Joy , Conn Rachel , Sponberg Simon
Published: April 2019

Sequences of action potentials, or spikes, carry information in the number of spikes and their timing. Spike timing codes are critical in many sensory systems, but there is now growing evidence that millisecond-scale changes in timing also carry information in motor brain regions, descending decision-making circuits, and individual motor units. Across all the many signals that control a behavior how ubiquitous, consistent, and coordinated are spike timing codes? Assessing these open questions ideally involves recording across the whole motor program with spike-level resolution. To do this, we took advantage of the relatively few motor units controlling the wings of a hawk moth,Manduca sexta. We simultaneously recorded nearly every action potential from all major wing muscles and the resulting forces in tethered flight. We found that timing encodes more information about turning behavior than spike count in every motor unit, even though there is sufficient variation in count alone. Flight muscles vary broadly in function as well as in the number and timing of spikes. Nonetheless, each muscle with multiple spikes consistently blends spike timing and count information in a 3:1 ratio. Coding strategies are consistent. Finally, we assess the coordination of muscles using pairwise redundancy measured through interaction information. Surprisingly, not only are all muscle pairs coordinated, but all coordination is accomplished almost exclusively through spike timing, not spike count. Spike timing codes are ubiquitous, consistent, and essential for coordination.

Significance Statement

Brains can encode precise sensory stimuli and specific motor systems also appear to be precise, but how important are millisecond changes in timing of neural spikes across the whole motor program for a behavior? We record every spike that the hawk moth’s nervous system sends to its wing muscles. We show that all muscles convey the majority of their information in spike timing. The number of spikes does play a role, but not in a coordinated way across muscles. Instead, all coordination is done using in the millisecond timing of in spikes. The importance and prevalence of timing across the motor program pose new questions for how nervous systems create precise, coordinated motor commands.
Assessment and representation of variability in ecological niche model predictions
Authors: Cobos Marlon E. , Osorio-Olvera Luis , Peterson A. Townsend
Published: April 2019

Ecological niche models are popular tools used in fields such as ecology, biogeography, conservation biology, and epidemiology. These models are used commonly to produce representations of species’ potential distributions, which are then used to answer other research questions; for instance, where species richness is highest, where potential impacts of climate change can be anticipated, or where to expect spread of invasive species or disease vectors. Although these representations of potential distributions are variable which contributes to uncertainty in these predictions, model variability is neglected when presenting results of ecological niche model analyses. Here, we present examples of how to quantify and represent variability in models, particularly when models are transferred in space and time. To facilitate implementations of analyses of variability, we developed R functions and made them freely available. We demonstrate means of understanding how much variation exists and where this variation is manifested in geographic space. Representing model variability in geographic space gives a reference of the uncertainty in predictions, so analyzing this aspect of model outcomes must be a priority when policy is to be set or decisions taken based on these models. Our open access tools also facilitate post modeling process that otherwise could take days of manual work.
Pairing interactions between nucleobases and ligands in aptamer:ligand complexes of riboswitches: Crystal structure analysis, classification, optimal structures and accurate interaction energies
Authors: Prabhakar Preethi S. , Sharma Purshotam , Mitra Abhijit
Published: April 2019

In the present work, sixty-seven crystal structures of the aptamer domains of RNA riboswitches, are chosen for analysis of the structure and strength of hydrogen bonding (pairing) interactions between nucleobases constituting the aptamer binding pockets and the bound ligands. A total of eighty unique base:ligand hydrogen-bonded pairs containing at least two hydrogen bonds were identified through visual inspection. Classification of these contacts in terms of the interacting edge of the aptamer nucleobase revealed that interactions involving the Watson-Crick edge are the most common, followed by the sugar edge of purines and the Hoogsteen edge of uracil. Alternatively, classification in terms of the chemical constitution of the ligand yields five unique classes of base:ligand pairs: base:base, base:amino acid, base:sugar, base:phosphate and base:other. Further, quantum mechanical (QM) geometry optimizations revealed that sixty seven out of eighty pairs exhibit stable geometries and optimal deviations from their macromolecular crystal occurrences. This indicates that these contacts are well-defined RNA aptamer:ligand interaction motifs. QM calculated interaction energies of base:ligand pairs reveal rich hydrogen bonding landscape, ranging from weak interactions (base:other, –3 kcal/mol) to strong (base:phosphate, –48 kcal/mol) contacts. The analysis was further extended to study the biological importance of base:ligand interactions in the binding pocket of the tetrahydrofolate riboswitch and thiamine pyrophosphate riboswitch. Overall, our study helps in understanding the structural and energetic features of base:ligand pairs in riboswitches, which could aid in developing meaningful hypotheses in context of RNA:ligand recognition. This can, in turn contribute towards current efforts to develop antimicrobials that target RNAs.
Evolution of Auxin Response Factors in plants characterized by phylogenomic synteny network analyses
Authors: Gao Bei , Wang Liuqiang , Oliver Melvin , Chen Moxian , Zhang Jianhua
Published: April 2019

Auxin response factors (ARFs) have long been a research focus and represent a class of key regulators of plant growth and development. Previous studies focusing genes from limited number of species were unable to uncover the evolutionary trajectory of this family. Here, more than 3,500 ARFs collected from plant genomes and transcriptomes covering major streptophyte lineages were used to reconstruct the broad-scale family phylogeny, where the early origin and diversification ofARFin charophytes was delineated. Based on the family phylogeny, we proposed a unified six-group classification system for angiosperm ARFs. Phylogenomic synteny network analyses revealed the deeply conserved genomic syntenies within each of the six ARF groups and the interlocking syntenic relationships connecting distinct groups. Recurrent duplication events, such as those that occurred in seed plant, angiosperms, core eudicots and grasses contributed the expansion of ARF genes which facilitated functional diversification. Ancestral transposition activities in important plant families, including crucifers, legumes and grasses, were unveiled by synteny network analyses. Ancestral gene duplications along with transpositions have profound evolutionary significance which may have accelerated the functional diversification process of paralogues. Our study provides insights into the evolution of ARFs which will enhance our current understandings for this important transcription factor family.
Nuisance effects in inter-scan functional connectivity estimates before and after nuisance regression
Authors: Nalci Alican , Luo Wenjing , Liu Thomas T.
Published: April 2019

In resting-state functional MRI, the correlation between blood-oxygenation-level-dependent (BOLD) signals across brain regions is used to estimate the functional connectivity (FC) of the brain. FC estimates are prone to the influence of nuisance factors including scanner-related artifacts and physiological modulations of the BOLD signal. Nuisance regression is widely performed to reduce the effect of nuisance factors on FC estimates on a per-scan basis. However, a dedicated analysis of nuisance effects on the variability of FC metrics across a collection of scans has been lacking. This work investigates the effects of nuisance factors on the variability of FC estimates across a collection of scans both before and after nuisance regression. Inter-scan variations in FC estimates are shown to be significantly correlated with the geometric norms of various nuisance terms, including head motion measurements, signals derived from white-matter and cerebrospinal regions, and the whole-brain global signal (GS) both before and after nuisance regression. In addition, it is shown that GS regression (GSR) can introduce GS norm-related fluctuations that are negatively correlated with inter-scan FC estimates. The empirical results are shown to be largely consistent with the predictions of a theoretical framework previously developed for the characterization of dynamic FC measures. This work shows that caution must be exercised when interpreting inter-scan FC measures across scans both before and after nuisance regression.
Positional dynamics and glycosomal recruitment of developmental regulators during trypanosome differentiation
Authors: Szöőr Balázs , Simon Dorina V. , Rojas Federico , Young Julie , Robinson Derrick R. , Krüger Timothy , Engstler Markus , Matthews Keith R.
Published: April 2019

Glycosomes are peroxisome-related organelles that compartmentalise the glycolytic enzymes in kinetoplastid parasites. These organelles are developmentally regulated in their number and composition, allowing metabolic adaptation to the parasite’s needs in the blood of mammalian hosts or within their arthropod vector. A protein phosphatase cascade regulates differentiation between parasite developmental forms, comprising a tyrosine phosphatase, TbPTP1, that dephosphorylates and inhibits a serine threonine phosphatase TbPIP39 that promotes differentiation. When TbPTP1 is inactivated, TbPIP39 is activated and during differentiation becomes located in glycosomes. Here we have tracked TbPIP39 recruitment to glycosomes during differentiation from bloodstream stumpy forms to procyclic forms. Detailed microscopy and live cell imaging during the synchronous transition between life cycle stages revealed that in stumpy forms, TbPIP39 is located at a periflagellar pocket site closely associated with TbVAP, that defines the flagellar pocket endoplasmic reticulum. TbPTP1 is also located at the same site in stumpy forms, as is REG9.1, a regulator of stumpy-enriched mRNAs. This site provides a molecular node for the interaction between TbPTP1 and TbPIP39. Within 30 minutes of the initiation of differentiation TbPIP39 relocates to glycosomes whereas TbPTP1 disperses to the cytosol. Overall, the study identifies a ‘stumpy regulatory nexus’ (STuRN) that co-ordinates the molecular components of life cycle signalling and glycosomal development during transmission ofTrypanosoma brucei.

Importance

African trypanosomes are parasites of sub-Saharan Africa responsible for both human and animal disease. The parasites are transmitted by tsetse flies and completion of their life cycle involves progression through several development steps. The initiation of differentiation between blood and tsetse forms is signalled by a phosphatase cascade, ultimately trafficked into peroxisome-related organelles called glycosomes that are unique to this group of organisms. Glycosomes undergo substantial remodelling of their composition and function during the differentiation step but how this is regulated is not understood. Here we identify a cytological site where the signalling molecules controlling differentiation converge before the dispersal of one of them into glycosomes. This coincides with a specialised ER site that may contribute to glycosome developmental biogenesis or regeneration. In combination, the study provides the first insight into the spatial co-ordination of signalling pathway components in trypanosomes as they undergo cell-type differentiation.
DNA barcoding reveals that injected transgenes are predominantly processed by homologous recombination in mouse zygote
Authors: Smirnov Alexander , Yunusova Anastasia , Korablev Alexey , Serova Irina , Fishman Veniamin , Battulin Nariman
Published: April 2019

Mechanisms that ensure repair of double-stranded DNA breaks play a key role in the integration of foreign DNA into the genome of transgenic organisms. After pronuclear microinjection, exogenous DNA is usually found in the form of concatemer consisting of multiple co-integrated transgene copies. Here we investigated contribution of various DSB repair pathways to the concatemer formation. We injected a pool of linear DNA molecules carrying unique barcodes at both ends into mouse zygotes and obtained 10 transgenic embryos with transgene copy number ranging from 1 to 300 copies. Sequencing of the barcodes allowed us to assign relative positions to the copies in concatemers and to detect recombination events that happened during integration. Cumulative analysis of approximately 1000 integrated copies revealed that more than 80% of copies underwent recombination when their linear ends were processed by SDSA or DSBR. We also observed evidence of double Holliday junction (dHJ) formation and crossing-over during the formation of concatemers. Additionally, sequencing of indels between copies showed that at least 10% of the DNA molecules introduced into the zygote are ligated by non-homologous end joining (NHEJ). Our barcoding approach documents high activity of homologous recombination after exogenous DNA injection in mouse zygote.
Intraspecific variation in Artiodactyla social organisation: A Bayesian phylogenetic multilevel analysis of detailed population-level data
Authors: Miles M.I. , Jaeggi A.V. , Festa-Bianchet M. , Schradin C. , Hayes L.D.
Published: April 2019

Understandinginter-specific variation in social systems is a major goal of behavioural ecology. Previous comparative studies of mammalian social organisation produced inconsistent results, possibly because they ignoredintra-specific variation in social organisation (IVSO). The Artiodactyla have been the focus of many comparative studies as they occupy a wide diversity of habitats and exhibit large variation in life history patterns as well as other potential correlates of social organisation. Here we present the first systematic data on IVSO among Artiodactyla, infer their ancestral social organisation, and test whether habitat, sexual dimorphism, seasonal breeding, and body size predict inter- and intraspecific variation in social organisation. We found data on social organisation for 110 of 226 artiodactyl species, of which 74.5% showed IVSO. Using Bayesian phylogenetic multilevel models, the ancestral artiodactyl population was predicted to have a variable social organisation with significantly higher probability (0.77, 95% CI 0.29-1.00) than any non-variable form (i.e. solitary, pair-living, group-living). Greater sexual dimorphism and smaller body size both predicted more IVSO; smaller body size also predicted a higher likelihood of pair-living. Our results challenge the long-held assumption that ancestral Artiodactyla were pair-living and strongly imply that taking IVSO into account is crucial for understanding mammalian social evolution.
Crowder-induced Conformational Ensemble Shift inEscherichia ColiProlyl-tRNA Synthetase
Authors: Adams L. M. , Andrews R. J. , Hu Q. H. , Schmit H. L. , Hati S. , Bhattacharyya S.
Published: April 2019

The effect of macromolecular crowding on the structure and function ofEscherichia coliprolyl-tRNA synthetase (Ec ProRS) has been investigated using a combined experimental and theoretical method. Ec ProRS is a multi-domain enzyme; coupled-domain dynamics is essential for efficient catalysis. To gain an insight into the mechanistic detail of the crowding effect, kinetic studies were conducted with varying concentrations and sizes of crowders. In parallel, spectroscopic and quantum chemical studies were employed to probe the “soft-interactions” between crowders and protein side chains. Finally, the dynamics of the dimeric protein was examined in the presence of crowders using a long-duration (70 ns) classical molecular dynamic simulations. The results of the simulations revealed a significant shift in the conformational ensemble, which is consistent with the “soft-interactions” model of the crowding effect and explained the observed alteration in kinetic parameters. Collectively, the present study demonstrated that the effects of molecular crowding on both conformational dynamics and catalytic function, are correlated. This is the first report where molecular crowding has been found to impact the conformational ensemble in the multi-domain Ec ProRS, a member of aminoacyl-tRNA synthetase family, which is central to protein synthesis in all living cells. The present study affirmed that the effect of crowders should be considered while investigating the structure-dynamics-function relationship in modular enzymes.
Measuring and Mitigating PCR Bias in Microbiome Data
Authors: Silverman Justin D. , Bloom Rachael J. , Jiang Sharon , Durand Heather K. , Mukherjee Sayan , David Lawrence A.
Published: April 2019

PCR amplification plays a central role in the measurement of mixed microbial communities via high-throughput sequencing. Yet PCR is also known to be a common source of bias in microbiome data. Here we present a paired modeling and experimental approach to characterize and mitigate PCR bias in microbiome studies. We use experimental data from mock bacterial communities to validate our approach and human gut microbiota samples to characterize PCR bias under real-world conditions. Our results suggest that PCR can bias estimates of microbial relative abundances by a factor of 2-4 but that this bias can be mitigated using simple Bayesian multinomial logistic-normal linear models.

Author summary

High-throughput sequencing is often used to profile host-associated microbial communities. Many processing steps are required to transform a community of bacteria into a pool of DNA suitable for sequencing. One important step is amplification where, to create enough DNA for sequencing, DNA from many different bacteria are repeatedly copied using a technique called Polymerase Chain Reaction (PCR). However, PCR is known to introduce bias as DNA from some bacteria are more efficiently copied than others. Here we introduce an experimental procedure that allows this bias to be measured and computational techniques that allow this bias to be mitigated in sequencing data.
The Parkinson’s Disease Mendelian Randomization Research Portal
Authors: Noyce Alastair J , Bandres-Ciga Sara , Kim Jonggeol , Heilbron Karl , Kia Demis , Hemani Gibran , Xue Angli , Lawlor Debbie A , Smith George Davey , Duran Raquel , Gan-Or Ziv , Blauwendraat Cornelis , Gibbs J Raphael ,   23andMe Research Team,   International Parkinson’s Disease Genomics Consortium (IPDGC), Hinds David A , Yang Jian , Visscher Peter , Cuzick Jack , Morris Huw , Hardy John , Wood Nicholas W , Nalls Mike A , Singleton Andrew B
Published: April 2019

Background

Mendelian randomization (MR) is a method for exploring observational associations to find evidence of causality.

Objective

To apply MR between multiple risk factors/phenotypic traits (exposures) and Parkinson’s disease (PD) in a large, unbiased manner, and to create a public resource for research.

Methods

We used two-sample MR in which the summary statistics relating to SNPs from genome wide association studies (GWASes) of 5,839 exposures curated on MR Base were used to assess causal relationships with PD. We selected the highest quality exposure GWASes for this report (n=401). For the disease outcome, summary statistics from the largest published PD GWAS were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted (IVW) method, followed by a range of sensitivity analyses. We used a false discovery rate (FDR) corrected p-value of <0.05 from the IVW analysis to prioritize traits of interest.

Results

We observed evidence for causal associations between twelve exposures and risk of PD. Of these, nine were causal effects related to increasing adiposity and decreasing risk of PD. The remaining top exposures that affected PD risk were tea drinking, time spent watching television and forced vital capacity, but the latter two appeared to be biased by violations of underlying MR assumptions.

Discussion

We present a new platform which offers MR analyses for a total of 5,839 GWASes versus the largest PD GWASes available (https://pdgenetics.shinyapps.io/pdgenetics/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD.