bluuebunny/crossref_metadata_2025 huggingface dataset:
Preparation of high-performance polyethylene tubes under the coexistence of silicone cross-linked polyethylene and rotation extrusion
Authors: Sun Fasen , Guo Jia , Li Yijun , Bai Shibing , Wang Qi
Published: May 2019

In this study, the silicone cross-linked polyethylene (Si-XLPE) powder with better thermoplastic performance and abundant cross-linked network points was attained by using solid-state shear mechanochemical (S
3
M) technology and it was added into high-density polyethylene (HDPE) matrix to prepare Si-XLPE/HDPE tubes by a rotation extrusion rheometer. SEM and 2D-SAXS experiments showed that the presence of Si-XLPE and rotation extrusion facilitated the formation of stable shish-kebabs which deviated from the axial direction in polyethylene (PE) tubes. This result was interpreted that introduction of Si-XLPE in PE tubes provided abundant molecular cross-linked network structures, which suppressed the thermal movement and relaxation of oriented molecular chains owing to intermolecular interaction. Moreover, the axial and hoop flow field further promoted orientation of the permanent cross-linked network entanglement points and formation of more stable cluster-like shish structures in the off-axial direction during the rotation extrusion process. Besides, our experimental results had also ascertained that molecular orientation and shish-kebabs in off-axial direction should be the primary responsibility for the remarkable enhancement of hoop torsional strength in PE tubes. Hoop torsional strength of PE tubes adding Si-XLPE reached 19.58 MPa when the mandrel rotation rate was 30 r.p.m., while that of conventional extruded PE tubes was only 9.83 MPa. As a consequence, PE tubes with excellent performance were prepared under the combined effect of Si-XLPE and rotation extrusion.
Dynamical decoration of stabilized-microtubules by tau-proteins
Authors: Hervy Jordan , Bicout Dominique J.
Published: May 2019

Tau is a microtubule-associated protein that regulates axonal transport, stabilizes and spatially organizes microtubules in parallel networks. The Tau-microtubule pair is crucial for maintaining the architecture and integrity of axons. Therefore, it is essential to understand how these two entities interact to ensure and modulate the normal axonal functions. Based on evidence from several published experiments, we have developed a two-dimensional model that describes the interaction between a population of Tau proteins and a stabilized microtubule at the scale of the tubulin dimers (binding sites) as an adsorption-desorption dynamical process in which Tau can bind on the microtubule outer surface via two distinct modes: a longitudinal (along a protofilament) and lateral (across adjacent protofilaments) modes. Such a process yields a dynamical distribution of Tau molecules on the microtubule surface referred to asmicrotubule decorationthat we have characterized at the equilibrium using two observables: the total microtubule coverage (density of the Taus on the microtubule surface) and the nearest neighbor distribution of Tau. Using both analytical and numerical approaches, we have derived expressions and computed these observables as a function of key parameters controlling the binding reaction: the stoichiometries of the Taus in the two binding modes, the binding equilibrium constants and the ratio of the Tau concentration to that of microtubule tubulin dimers.
Time elapsed between choices in a probabilistic task correlates with repeating the same decision
Authors: Jabłońska Judyta , Szumiec Łukasz , Zieliński Piotr , Parkitna Jan Rodriguez
Published: May 2019

Reinforcement learning causes an action that yields a positive outcome more likely to be taken in the future. Here, we investigate how the time elapsed from an action affects subsequent decisions. Groups of C57BL6/J mice were housed in IntelliCages with access to water and chowad libitum; they also had access to bottles with a reward: saccharin solution, alcohol or a mixture of the two. The probability of receiving a reward in two of the cage corners changed between 0.9 and 0.3 every 48 h over a period of ~33 days. As expected, in most animals, the odds of repeating a corner choice were increased if that choice was previously rewarded. Interestingly, the time elapsed from the previous choice also influenced the probability of repeating the choice, and this effect was independent of previous outcome. Behavioral data were fitted to a series of reinforcement learning models. Best fits were achieved when the reward prediction update was coupled with separate learning rates from positive and negative outcomes and additionally a “fictitious” update of the expected value of the nonselected choice. Additional inclusion of a time-dependent decay of the expected values improved the fit marginally in some cases.
FGTpartitioner: A rapid method for parsimonious delimitation of ancestry breakpoints in large genome-wide SNP datasets
Authors: Chafin Tyler K
Published: May 2019

Partitioning large (e.g. chromosomal) alignments into ancestry blocks is a common step in phylogenomic analyses. However, current solutions require complicated analytical assumptions, or are difficult to implement due to excessive runtimes and unintuitive documentation. Additionally, most methods require haplotype phasing, which is often intractable for non-model studies. Here, I present an efficient and rapid solution for partitioning large genome alignments into ancestry blocks, which better accommodates non-model diploid organisms in that phasing information is not required a priori. FGTpartitioner processes a full-chromosome alignment orders of magnitude faster than alternative solutions, while recovering identical results, both via algorithmic improvements and the use of native parallelization. FGTpartitioner provides a means for simple and rapid block delimitation in genome-wide datasets as a pretext for phylogenomic analysis. It thus widens the potential uses for researchers studying phylogenetic processes across large, non-model genomes. Complete code and documentation for FGTpartitioner are available as an open-source repository on GitHub: https://github.com/tkchafin/FGTpartitioner
Three-dimensional connectivity and chromatin environment mediate the activation efficiency of mammalian DNA replication origins
Authors: Jodkowska Karolina , Pancaldi Vera , Almeida Ricardo , Rigau Maria , Graña-Castro Osvaldo , Fernández-Justel José M. , Rodríguez-Acebes Sara , Rubio-Camarillo Miriam , Carrillo-de Santa Pau Enrique , Pisano David , Al-Shahrour Fátima , Valencia Alfonso , Gómez María , Méndez Juan
Published: May 2019

In mammalian cells, chromosomal replication starts at thousands of origins at which replisomes are assembled and bidirectional DNA synthesis is established. The slowdown of DNA polymerases at endogenous or exogenous obstacles triggers the activation of additional ‘dormant’ origins whose genomic positions and regulation are not well understood. Here we report a comparative study of origin activity in mouse embryonic stem cells growing in control conditions or in the presence of mild replication stress. While stress-responsive origins can be identified, we find that the majority of them are also active, albeit with lower frequency, in the control population. To gain insights into the molecular and structural determinants of origin efficiency, we have analyzed the genetic and epigenetic features of origins stratified according to their frequency of activation. We have also integrated the linear origin maps into three-dimensional (3D) chromatin interaction networks, revealing a hierarchical organization in which clusters of connected origins are brought together by longer-range chromatin contacts. Origin efficiency is proportional to the number of connections established with other origin-containing fragments. Interacting origins tend to be activated with similar efficiency and share their timing of replication even when located in different topologically associated domains. Our results are consistent with a model in which clusters of origins are arranged in 3D in replication factories. Within each factory, ‘main’ and ‘dormant’ origins are functionally defined by a combination of chromatin environment and 3D connectivity.
Emergence of an invariant representation of texture in primate somatosensory cortex
Authors: Lieber Justin D. , Bensmaia Sliman J.
Published: May 2019

A major function of sensory processing is to achieve neural representations of objects that are stable across changes in context and perspective. Small changes in exploratory behavior can lead to large changes in signals at the sensory periphery, thus resulting in ambiguous neural representations of objects. Overcoming this ambiguity is a hallmark of human object recognition across sensory modalities. Here, we investigate how the perception of tactile texture remains stable across exploratory movements of the hand, including changes in scanning speed, despite the concomitant changes in afferent responses. To this end, we scanned a wide range of everyday textures across the fingertips of Rhesus macaques at multiple speeds and recorded the responses evoked in tactile nerve fibers and somatosensory cortical neurons. We found that individual cortical neurons exhibit a wider range of speed-sensitivities than do nerve fibers. The resulting representations of speed and texture in cortex are more independent than are their counterparts in the nerve and account for speed-invariant perception of texture. We demonstrate that this separation of speed and texture information is a natural consequence of previously described cortical computations.
Epigenetic regulation underlying Plasmodium berghei gene expression during its developmental transition from host to vector
Authors: Witmer Kathrin , Fraschka Sabine AK , Vlachou Dina , Bártfai Richárd , Christophides George K
Published: May 2019

Epigenetic regulation of gene expression is an important attribute in the survival and adaptation of the malaria parasite Plasmodium in its human host. Our understanding of epigenetic regulation of gene expression in Plasmodium developmental stages beyond asexual replication in the mammalian host is sparse. We used chromatin immune-precipitation (ChIP) and RNA sequencing to create an epigenetic and transcriptomic map of the murine parasite Plasmodium berghei development from asexual blood stages to male and female gametocytes, and finally, to ookinetes. We show that heterochromatin 1 (HP1) almost exclusively associates with variantly expressed gene families at subtelomeric regions and remains stable across stages and various parasite lines. Variant expression based on heterochromatic silencing is observed only in very few genes. In contrast, the active histone mark histone 3 Lysine 9 acetylation (H3K9ac) is found between heterochromatin boundaries and occurs as a sharp peak around the start codon for ribosomal protein genes. H3K9ac occupancy positively correlates with gene transcripts in asexual blood stages, male gametocytes and ookinetes. Interestingly, H3K9ac occupancy does not correlate with transcript abundance in female gametocytes. Finally, we identify novel DNA motifs upstream of ookinete-specific genes thought to be involved in transcriptional activation upon fertilization.
Frontal eye field inactivation alters the readout of superior colliculus activity for saccade generation in a task-dependent manner
Authors: Peel Tyler R. , Dash Suryadeep , Lomber Stephen G. , Corneil Brian D.
Published: May 2019

Saccades require a spatiotemporal transformation of activity between the intermediate layers of the superior colliculus (iSC) and downstream brainstem burst generator. The dynamic linear ensemble-coding model (Goossens and Van Opstal, 2006) proposes that each iSC spike contributes a fixed mini-vector to saccade displacement. Although biologically-plausible, this model assumes cortical areas like the frontal eye fields (FEF) simply provide the saccadic goal to be executed by the iSC and brainstem burst generator. However, the FEF and iSC operate in unison during saccades, and a pathway from the FEF to the brainstem burst generator that bypasses the iSC exists. Here, we investigate the impact of large yet reversible inactivation of the FEF on iSC activity in the context of the model across four saccade tasks. We exploit the overlap of saccade vectors generated when the FEF is inactivated or not, comparing the number of iSC spikes for metrically-matched saccades. We found that the iSC emits fewer spikes for metrically-matched saccades during FEF inactivation. The decrease in spike count is task-dependent, with a greater decrease accompanying more cognitively-demanding saccades. Our results show that FEF integrity influences the readout of iSC activity in a task-dependent manner. We propose that the dynamic linear ensemble-coding model be modified so that FEF inactivation increases the gain of a readout parameter, effectively increasing the influence of a single iSC spike. We speculate that this modification could be instantiated by a direct pathway from the FEF to the omnipause region that modulates the excitability of the brainstem burst generator.

Significance statement

One of the enduring puzzles in the oculomotor system is how it achieves the spatiotemporal transformation, converting spatial activity within the intermediate layers of the superior colliculus (iSC) into a rate code within the brainstem burst generator. The spatiotemporal transformation has traditionally been viewed as the purview of the oculomotor brainstem. Here, within the context of testing a biologically-plausible model of the spatiotemporal transformation, we show that reversible inactivation of the frontal eye fields (FEF) decreases the number of spikes issued by the iSC for metrically-matched saccades, with greater decreases accompanying more cognitively-demanding tasks. These results show that signals from the FEF influence the spatiotemporal transformation.
Age-dependent sexual dimorphism in the adult human gut microbiota
Authors: Zhang Xiuying , Zhong Huanzi , Li Yufeng , Shi Zhun , Zhang Zhe , Zhou Xianghai , Ren Huahui , Tang Shanmei , Han Xueyao , Lin Yuxiang , Wang Dan , Yang Fangming , Fang Chao , Fu Zuodi , Wang Lianying , Zhu Shida , Hou Yong , Xu Xun , Yang Huanming , Wang Jian , Kristiansen Karsten , Li Junhua , Ji Linong
Published: May 2019

A decade of studies has established the importance of the gut microbiome in human health. In spite of sex differences in the physiology, lifespan, and prevalence of many age-associated diseases, sex and age disparities in the gut microbiota have been little studied. Here we show age-related sex differences in the adult gut microbial composition and functionality in two community-based cohorts from Northern China and the Netherlands. Consistently, women harbour a more diverse and stable microbial community across broad age ranges, whereas men exhibit a more variable gut microbiota strongly correlated with age. Reflecting the sex-biased age-gut microbiota interaction patterns, sex differences observed in younger adults are considerably reduced in the elderly population. Our findings highlight the age- and sex-biased differences in the adult gut microbiota across two ethnic population and emphasize the need for considering age and sex in studies of the human gut microbiota.
Behaviour, biology, and evolution of vocal learning in bats
Authors: Vernes Sonja C. , Wilkinson Gerald S.
Published: May 2019

The comparative approach can provide insight into the evolution of human speech, language, and social communication by studying relevant traits in animal systems. Bats are emerging as a model system with great potential to shed light on these processes given their learned vocalisations, close social interactions, and mammalian brains and physiology. A recent framework outlined the multiple levels of investigation needed to understand vocal learning across a broad range of non-human species including cetaceans, pinnipeds, elephants, birds and bats. Herein we apply this framework to the current state of the art in bat research. This encompasses our understanding of the abilities bats have displayed for vocal learning, what is known about the timing and social structure needed for such learning, and current knowledge about the prevalence of the trait across the order. It also addresses the biology (vocal tract morphology, neurobiology, and genetics) and phylogenetics of this trait. We conclude by highlighting some key questions that should be answered to advance our understanding of the biological encoding and evolution of speech and spoken communication.
Microclimatic effects on alpine plant and flower visitor communities and their interactions
Authors: Ohler Lisa-Maria , Lechleitner Martin , Junker Robert R.
Published: May 2019

High-alpine ecosystems are commonly assumed to be particularly endangered by climate warming. Recent research, however, suggests that the heterogeneous topography of alpine landscapes provide microclimatic niches for alpine plants, which may buffer negative effects. Whether the microclimatic heterogeneity also affects higher trophic levels remains unknown. This study shows that the variation in mean seasonal soil temperature within a single alpine pasture is within the same range as in plots differing in nearly 500 m in elevation. This pronounced heterogeneity affected the spatial distribution of plant cover, richness of flowering plant species and plant species composition. These microclimatic effects on plant communities also affected richness of flower visiting insects and the frequency and structure of plant-insect interactions suggesting an effect of microclimate also on higher trophic levels. Our results may stimulate a re-evaluation of the consequences of climate warming on ecosystems that may compensate warming by microclimatic refuges.
Phasic Dopamine Release Magnitude Tracks Individual Differences in Sensitization of Locomotor Response following a History of Nicotine Exposure
Authors: Fennell Ashley M. , Pitts Elizabeth G. , Sexton Lacey L. , Ferris Mark J.
Published: May 2019

Smoking remains the primary cause of preventable death in the United States and smoking related illness costs more than $300 billion annually. Nicotine (the primary reinforcer in cigarettes) causes changes in behavior and neurochemistry that lead to increased probability of relapse. Given the role of mesolimbic dopamine projections in motivation, substance use disorder, and drug relapse, we examined the effect of repeated nicotine on rapid dopamine signals in the nucleus accumbens (NAc) of rats. Adult, male Sprague-Dawley rats were exposed to nicotine (0.2 or 0.4 mg/kg, subcutaneous) once daily for 7 days. On day 8, dopamine release and uptake dynamics, and their modulation by nicotinic receptor agonists and antagonists, were assessed using fast scan cyclic voltammetry in the NAc core. Nicotine exposure decreased electrically-stimulated dopamine release across a range of stimulation frequencies and decreased α6β2-containing nicotinic receptor control over dopamine release. Additionally, nicotine locomotor sensitization correlated with accumbal dopamine modulation by nicotine and mecamylamine. Taken together, our study suggests that repeated exposure to nicotine blunts dopamine release in the NAc core through changes in α6β2 modulation of dopamine release and individual differences in the sensitivity to this outcome may predict variation in behavioral models of vulnerability to substance use disorder.
Does the margin of stability measure predict stability of gait with a constrained base of support?
Authors: Gill Lakshdeep , Huntley Andrew H. , Mansfield Avril
Published: May 2019

This study aimed to determine the validity of the centre of mass position (COM) position and extrapolated COM (XCOM), relative to the base of support, for predicting stability during a walking task where the base of support is constrained. Nine young healthy participants walked on a narrow beam. Three-dimensional motion capture was used to calculate the COM and XCOM relative to the base of support. Steps were classified as having either the COM or XCOM inside or outside the base of support, and were classified as successful (stable – foot placed on the beam) or failed (unstable – foot stepped off the beam). If the COM or XCOM are valid measures of stability, they should be within the base of support for successful steps and outside the base of support for failed steps. Classifying the COM and XCOM inside or outside the base of support correctly predicted successful or failed steps in 69% and 58% of cases, respectively. When the COM or XCOM were outside the base of support, walking faster seemed to help participants to maintain stability. The further the COM or XCOM were outside the base of support during a successful step, the more likely participants were to fail on a subsequent step. The results of this study suggest that both COM and XCOM are valid measures of stability during a beam walking task, but that classifying COM and XCOM as inside or outside the base of support may be over-simplistic.
Parallel and nonparallel genomic responses contribute to herbicide resistance inIpomoea purpurea, a common agricultural weed
Authors: Van Etten Megan , Lee Kristin M. , Chang Shu-Mei , Baucom Regina S.
Published: May 2019

The repeated evolution of herbicide resistance has been cited as an example of genetic parallelism, wherein separate species or genetic lineages utilize the same genetic solution in response to selection. However, most studies that investigate the genetic basis of herbicide resistance examine the potential for changes in the protein targeted by the herbicide rather than considering genome-wide changes. We used a population genomics screen and targeted exome re-sequencing to uncover the potential genetic basis of glyphosate resistance in the common morning glory,Ipomoea purpurea, and to determine if genetic parallelism underlies the repeated evolution of resistance across replicate resistant populations. We found no evidence for changes in 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), glyphosate’s target protein, that were associated with resistance, and instead identified five genomic regions that show evidence of selection. Within these regions, genes involved in herbicide detoxification--cytochrome P450s, ABC transporters, and glycosyltransferases--are enriched and exhibit signs of selective sweeps. One region under selection shows parallel changes across all assayed resistant populations whereas other regions exhibit signs of divergence. Thus, while it appears likely that the physiological mechanism of resistance in this species is likely the same among resistant populations, we find patterns of both similar and divergent selection across separate resistant populations at particular loci.
Modification of primary amines to higher order amines reduces in vivo hematological and immunotoxicity of cationic nanocarriers through TLR4 and complement pathways
Authors: Toy Randall , Pradhan Pallab , Ramesh Vijayeetha , Di Paolo Nelson C. , Lash Blake , Liu Jiaying , Blanchard Emmeline L. , Santangelo Philip J. , Shayakhmetov Dmitry M. , Roy Krishnendu
Published: May 2019

For decades, cationic polymer nanoparticles have been investigated for nucleic acid delivery. Despite promising in vitro transfection results, most formulations have failed to translate into the clinic due to significantin vivotoxicity – especially when delivered intravenously. To address this significant problem, we investigated the detailed mechanisms that govern the complexin vivosystemic toxicity response to common polymeric nanoparticles. We determined that the toxicity response is material dependent. For branched polyethylenimine (bPEI) nanoparticles – toxicity is a function of multiple pathophysiological responses – triggering of innate immune sensors, induction of hepatic toxicity, and significant alteration of hematological properties. In contrast, for chitosan-based nanoparticles – systemic toxicity is primarily driven through innate immune activation. We further identified that modification of primary amines to secondary and tertiary amines using the small molecule imidazole-acetic-acid (IAA) amelioratesin vivotoxicity from both nanocarriers by different, material-specific mechanisms related to Toll-like receptor 4 activation (for bPEI) and complement activation driven neutrophil infiltration (for chitosan), respectively. Our results provide a detailed roadmap for evaluatingin vivotoxicity of nanocarriers and identifies potential opportunities to reduce toxicity for eventual clinical translation.

Graphical Abstract
Manual stabilization reveals a transient role for balance control during locomotor adaptation
Authors: Park Sungwoo , Finley James M.
Published: May 2019

A fundamental feature of human locomotor control is the need to adapt our walking pattern in response to changes in the environment. For example, when people walk on a split-belt treadmill which has belts that move at different speeds, they adapt to the asymmetric speed constraints by reducing their spatiotemporal asymmetry. Here, we aim to understand the role of stability as a potential factor driving this adaptation process. We recruited 24 healthy, young adults to adapt to walking on a split-belt treadmill while either holding on to a handrail or walking with free arm swing. We measured whole-body angular momentum and step length asymmetry as measures of dynamic balance and spatiotemporal asymmetry, respectively. To understand how changes in intersegmental coordination influenced measures of dynamic balance, we also measured segmental angular momenta and the coefficient of limb cancellation. When participants were initially exposed to the asymmetry in belt speeds, we observed an increase in whole-body angular momentum that was due to both an increase in the momentum of individual limb segments and a reduction in limb cancellation. Holding on to a handrail reduced the perturbation to asymmetry during the early phase of adaptation and resulted in a smaller after-effect during post-adaptation. In addition, the stabilization provided by holding on to a handrail led to reductions in the coupling between angular momentum and asymmetry. These results suggest that regulation of dynamic balance is most important during the initial, transient phase of adaptation to walking on a split-belt treadmill.

Summary Statement

Regulation of balance exhibits a transient effect on adaptation to imposed asymmetries during bipedal walking. External stabilization attenuates initial deviations in spatiotemporal asymmetry but has no effect on subsequent adaptation.
Consistent metagenome-derived metrics verify and define bacterial species boundaries
Authors: Olm Matthew R. , Crits-Christoph Alexander , Diamond Spencer , Lavy Adi , Matheus Carnevali Paula B. , Banfield Jillian F.
Published: May 2019

Longstanding questions relate to the existence of naturally distinct bacterial species and genetic approaches to distinguish them. Bacterial genomes in public databases form distinct groups, but these databases are subject to isolation and deposition biases. We compared 5,203 bacterial genomes from 1,457 environmental metagenomic samples to test for distinct clouds of diversity, and evaluated metrics that could be used to define the species boundary. Bacterial genomes from the human gut, soil, and the ocean all exhibited gaps in whole-genome average nucleotide identities (ANI) near the previously suggested species threshold of 95% ANI. While genome-wide ratios of non-synonymous and synonymous nucleotide differences (dN/dS) decrease until ANI values approach ∼98%, estimates for homologous recombination approached zero at ∼95% ANI, supporting breakdown of recombination due to sequence divergence as a species-forming force. We evaluated 107 genome-based metrics for their ability to distinguish species when full genomes are not recovered. Full length 16S rRNA genes were least useful because they were under-recovered from metagenomes, but many ribosomal proteins displayed both high metagenomic recoverability and species-discrimination power. Taken together, our results verify the existence of sequence-discrete microbial species in metagenome-derived genomes and highlight the usefulness of ribosomal genes for gene-level species discrimination.
Novel Cyclic Peptides in Seed of Annona muricata are Ribosomally Synthesized
Authors: Fisher Mark F. , Zhang Jingjing , Berkowitz Oliver , Whelan James , Mylne Joshua S.
Published: May 2019

Small, cyclic peptides are reported to have many bioactivities. In bacteria and fungi they can be made by non-ribosomal peptide synthetases, but in plants they are exclusively ribosomal. Cyclic peptides from the Annona genus possess cytotoxic and anti-inflammatory activities, but their biosynthesis is unknown. The medicinal soursop plant, Annona muricata, contains annomuricatins A (cyclo-PGFVSA) and B (cyclo-PNAWLGT). Here, using de novo transcriptomics and tandem mass spectrometry, we identify a suite of short transcripts for precursor proteins for ten validated annomuricatins, nine of which are novel. In their precursors, annomuricatins are preceded by an absolutely conserved Glu and each peptide sequence has a conserved proto-C-terminal Pro, revealing parallels with the segetalin orbitides from the seed of Vaccaria hispanica, which are processed through ligation by a prolyl oligopeptidase in a transpeptidation reaction.
A role for Toxoplasma gondii chloroquine resistance transporter in bradyzoite viability and digestive vacuole maintenance
Authors: Kannan Geetha , Di Cristina Manlio , Schultz Aric J. , Huynh My-Hang , Wang Fengrong , Schultz Tracey L. , Lunghi Matteo , Coppens Isabelle , Carruthers Vern B.
Published: May 2019

Toxoplasma gondii is a ubiquitous pathogen that can cause encephalitis, congenital defects, and ocular disease. T. gondii has also been implicated as a risk factor for mental illness in humans. The parasite persists in the brain as slow growing bradyzoites contained within intracellular cysts. No treatments exist to eliminate this form of parasite. Although proteolytic degradation within the parasite lysosomal-like vacuolar compartment (VAC) is critical for bradyzoite viability, whether other aspects of the VAC are important for parasite persistence remains unknown. An ortholog of Plasmodium falciparum CRT has previously been identified in T. gondii (TgCRT). To interrogate the function of TgCRT in chronic stage bradyzoites and its role in persistence, we knocked out TgCRT in a cystogenic strain and assessed VAC size, VAC digestion of host-derived proteins and parasite autophagosomes, and viability of in vitro and in vivo bradyzoites. We found that whereas parasites deficient in TgCRT exhibit normal digestion within the VAC, they display a markedly distended VAC and their viability is compromised both in vitro and in vivo. Interestingly, impairing VAC proteolysis in TgCRT deficient bradyzoites restored VAC size, consistent with a role for TgCRT as a transporter of products of digestion from the VAC. In conjunction with earlier studies, our current findings suggest a functional link between TgCRT and VAC proteolysis. This work provides further evidence of a crucial role for the VAC in bradyzoite persistence and a new potential VAC target to abate chronic Toxoplasma infection.

IMPORTANCE

Individuals chronically infected with the intracellular parasite Toxoplasma gondii are at risk of experiencing reactivated disease that can result in progressive loss of vision. No effective treatments exist for chronic toxoplasmosis due in part to a poor understanding of the biology underlying chronic infection and a lack of well validated potential targets. Here we show that a T. gondii transporter is functionally linked to protein digestion within the parasite lysosome-like organelle and that this transporter is necessary to sustain chronic infection in culture and in experimentally infected mice. Ablating the transporter results in severe bloating of the lysosome-like organelle. Together with earlier work, this study suggests the parasite’s lysosome-like organelle is vital for parasite survival, thus rendering it a potential target for diminishing infection and reducing the risk of reactivated disease.
Microbial composition of the human nasopharynx varies according to influenza virus type and vaccination status
Authors: Ding Tao , Song Timothy , Zhou Bin , Geber Adam , Ma Yixuan , Zhang Lingdi , Volk Michelle , Kapadia Shashi N. , Jenkins Stephen G. , Salvatore Mirella , Ghedin Elodie
Published: May 2019

Factors that contribute to enhanced susceptibility to severe bacterial disease after influenza infection are not well defined, but likely include the microbiome of the respiratory tract. Vaccination against influenza, while having variable effectiveness, could also play a role in microbial community stability. We collected nasopharyngeal samples from 215 individuals infected with influenza A/H3N2 or influenza B and profiled the microbiota by target sequencing of the 16S rRNA gene. We identified signature taxonomic groups by performing linear discriminant analysis and effective size comparisons (LEfSe) and defined bacterial community types using Dirichlet Multinomial Mixture (DMM) models. Influenza infection was shown to be significantly associated with microbial composition of the nasopharynx according to the virus type and the vaccination status of the patient. We identified 4 microbial community types across the combined cohort of influenza patients and healthy individuals with one community type most representative of the influenza-infected group. We also identified microbial taxa for which relative abundance was significantly higher in the unvaccinated elderly group; these taxa include species known to be associated with pneumonia.

Importance

Our results suggest that there is a significant association between the composition of the microbiota in the nasopharynx and the influenza virus type causing the infection. We observe that vaccination status, especially in more senior individuals, also has an association with the microbial community profile. This indicates that vaccination against influenza, even when ineffective to prevent disease, could play a role in controlling secondary bacterial complications.
Revealing The Colourful Side of Birds: Spatial Distribution of Conspicuous Plumage Colours on The Body of Australian Birds
Authors: Delhey Kaspar
Published: May 2019

In many species of birds, different body parts often display very different colours. This spatial distribution of coloured plumage patches may be determined by the balance between being cryptic to predators, and conspicuous to intended receivers. If this is the case, ventral and anterior body parts in birds–which are less visible to predators but more prominent to conspecifics– should present more conspicuous and sexually dichromatic plumage colours. Here I test these predictions using reflectance spectrometric measurements of standardised plumage patches across males and females for nearly an entire avifauna (Australian landbirds, N = 538 species). My data show that, as predicted, conspicuous colours are mainly located near the head, while the plumage of the back is the most cryptic. However, there is considerable variation across species, and this makes position on the body a relatively modest predictor of plumage elaboration (R2= 0.15-0.19). One clear exception to this pattern is the conspicuous rump coloration. In many species, this patch can be concealed by wings, and therefore exposed only when necessary. In addition, conspicuous rump coloration could deflect or confuse predators in case of attack. Finally, patterns for sexual dichromatism were much weaker (R2= 0.02), whereby wing and tail showed lower levels of dichromatism than the rest of the body.
Source-Sink Modifications Affect Leaf Senescence and Grain Mass in Wheat
Authors: Lv Xuemei , Zhang Yan , Zhang Yunxiu , Fan Shoujin , Kong Lingan
Published: May 2019

A field experiment was performed in wheat to investigate the responses of flag leaf and grain to sink/source manipulations. The results showed that half-degraining delayed but defoliation (only flag leaf left) enhanced the leaf senescence. Sink/source manipulations influenced the content of reactive oxygen species of flag leaf and the content of phytohormones including cytokinins, indoleacetic 3-acid, gibberellin 3, salicylic acid and jasmonic acid in the defoliated flag leaf (DL) and grain (DG), half-degrained flag leaf (HL) and grain (HG). An iTRAQ based quantitative proteomic analysis indicated that at 16 days after manipulation a total of 97 and 59 differentially expressed proteins (DEPs) from various functional categories were observed in HL and DL groups, respectively, compared with control and 115 and 121 DEPs were observed in HG and DG groups, respectively. GO annotation terms of DEPs mainly included carbon fixation, hydrogen peroxide catabolic process, chloroplast and cytoplasm, oxidoreductase activity and glutamate synthase activity in flag leaf of manipulated plants; organonitrogen compound metabolic process, cytoplasm, vacuolar membrane, CoA carboxylase activity, starch synthase activity and nutrient reservoir activity in grain of manipulated plants. KEGG pathway enrichment analysis revealed that photosynthesis, carbon, nitrogen and pyruvate metabolisms and glycolysis/gluconeogenesis were the most remarkable processes for sink/source manipulations. Sink/source manipulations affected the activities of α- and β- amylases and proteinases. Ultimately, manipulations changed the mass per grain. In conclusion, manipulations to change the sink/source ratio affect the levels of hormones, activities of hydrolytic enzymes, metabolisms of carbon, nitrogen and other main compounds, stress resistance, the leaf senescence, and ultimately influence the grain mass.
Design principles of ROS dynamic networks relevant to precision therapies for age-related diseases
Authors: Kolodkin Alexey , Sharma Raju Prasad , Colangelo Anna Maria , Ignatenko Andrew , Martorana Francesca , Jennen Danyel , Briede Jacco J. , Brady Nathan , Barberis Matteo , Mondeel Thierry D.G.A. , Papa Michele , Kumar Vikas , Peters Bernhard , Skupin Alexander , Alberghina Lilia , Balling Rudi , Westerhoff Hans V.
Published: May 2019

The eminently complex regulatory network protecting the cell against oxidative stress, surfaces in several disease maps, including that of Parkinson’s disease (PD). How this molecular networking achieves its various functionalities and how processes operating at the seconds-minutes time scale cause a disease at a time scale of multiple decennia is enigmatic.

By computational analysis, we here disentangle the reactive oxygen species (ROS) regulatory network into a hierarchy of subnetworks that each correspond to a different functionality. The detailed dynamic model of ROS management obtained integrates these functionalities and fitsin vitrodata sets from two different laboratories.

The model shows effective ROS-management for a century, followed by a sudden system’s collapse due to the loss of p62 protein. PD related conditions such as lack of DJ-1 protein or increased α-synuclein accelerated the system’s collapse. Variousin-silicointerventions (e.g. addition of antioxidants or caffeine) slowed down the collapse of the systemin silico, suggesting the model may help discover new medicinal and nutritional therapies.
Direct Measurement of Synchronous Precursor Selection (SPS) Accuracy in Public Proteomics Datasets
Authors: Jenkins Conor , Rinas Aimee , Orsburn Ben
Published: May 2019

Reporter ion quantification techniques utilizing reagents such as TMT and iTRAQ allow proteomics studies to multiplex up to 11 different samples within a single LC-MS/MS experimental run. In these experiments, peptides derived from different samples are labeled with chemical tags possessing identical mass but differing distributions of heavy isotopes through their structure. Peptides from all samples may then be physically combined prior to LC-MS/MS. Relative quantification of the peptides from each sample is obtained from the liberation of low mass reporter ions alone, as these are the only discernible factor between peptides in the entire LC-MS/MS workflow. When coeluting ions of similar mass to charge ratios are fragmented along with the ions of interest, it is not possible to determine the source of the reporter fragments and quantification is skewed, most often resulting in ratio suppression. One technique for combatting ratio suppression is the selection of MS2 fragment ions that are likely to retain the intact mass tag region by synchronous precursor selection (SPS) and the liberation of the reporter ions from this combination of ions in MS/MS/MS (MS3). In this study we utilize a new post processing tool that can directly assess the accuracy of the SPS system for picking ions for quantification that are truly derived from the peptide of interest. We then apply this tool to the re-analysis of 3 public proteomics datasets. Directly assessing SPS accuracy allows a new measurement of confidence in the quantification values obtained from these reporter ion quantification experiments.

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EpiScanpy: integrated single-cell epigenomic analysis
Authors: Danese Anna , Richter Maria L. , Fischer David S. , Theis Fabian J. , Colomé-Tatché Maria
Published: May 2019

Epigenetic single-cell measurements reveal a layer of regulatory information not accessible to single-cell transcriptomics, however single-cell-omics analysis tools mainly focus on gene expression data. To address this issue, we present epiScanpy, a computational framework for the analysis of single-cell DNA methylation and single-cell ATAC-seq data. EpiScanpy makes the many existing RNA-seq workflows from scanpy available to large-scale single-cell data from other -omics modalities. We introduce and compare multiple feature space constructions for epigenetic data and show the feasibility of common clustering, dimension reduction and trajectory learning techniques. We benchmark epiScanpy by interrogating different single-cell brain mouse atlases of DNA methylation, ATAC-seq and transcriptomics. We find that differentially methylated and differentially open markers between cell clusters enrich transcriptome-based cell type labels by orthogonal epigenetic information.
Uncovering bi-directional causal relationships between plasma proteins and psychiatric disorders: A proteome-wide study and directed network analysis
Authors: Chau Carlos Kwan-long , Lau Alexandria , Sham Pak-Chung , So Hon-Cheong
Published: May 2019

Psychiatric disorders represent a major public health burden yet their etiologies remain poorly understood, and treatment advances are limited. In addition, there are no reliable biomarkers for diagnosis or progress monitoring.

Here we performed a proteome-wide causal association study covering 3522 plasma proteins and 24 psychiatric traits or disorders, based on large-scale GWAS data and the principle of Mendelian randomization (MR). We have conducted ~95,000 MR analyses in total; to our knowledge, this is the most comprehensive study on the causal relationship between plasma proteins and psychiatric traits.

The analysis was bi-directional: we studied how proteins may affect psychiatric disorder risks, but also looked into how psychiatric traits/disorders may be causal risk factors for changes in protein levels. We also performed a variety of additional analysis to prioritize protein-disease associations, including HEIDI test for distinguishing functional association from linkage, analysis restricted to cis- acting variants and replications in independent datasets from the UK Biobank. Based on the MR results, we constructed directed networks linking proteins, drugs and different psychiatric traits, hence shedding light on their complex relationships and drug repositioning opportunities. Interestingly, many top proteins were related to inflammation or immune functioning. The full results were also made available online in searchable databases.

In conclusion, identifying proteins causal to disease development have important implications on drug discovery or repurposing. Findings from this study may also guide the development of blood-based biomarkers for the prediction or diagnosis of psychiatric disorders, as well as assessment of disease progression or recovery.
Widespread microbial mercury methylation genes in the global ocean
Authors: Villar Emilie , Cabrol Lea , Heimbürger-Boavida Lars-Eric
Published: May 2019

Methylmercury is a neurotoxin that bioaccumulates from seawater to high concentrations in marine fish, putting human and ecosystem health at risk. High methylmercury levels have been found in the oxic subsurface waters of all oceans, yet only anaerobic microorganisms have been identified so far as efficient methylmercury producers in anoxic environments. The microaerophilic nitrite oxidizing bacteriaNitrospinahas been previously suggested as a possible mercury methylator in Antarctic sea ice. However, the microorganisms processing inorganic mercury into methylmercury in oxic seawater remain unknown. Here we show metagenomic evidence from open ocean for widespread microbial methylmercury production in oxic subsurface waters. We find high abundances of the key mercury methylating geneshgcABacross all oceans corresponding to taxonomic relatives of known mercury methylators from Deltaproteobacteria, Firmicutes and Chloroflexi. Our results identifyNitrospinaas the predominant and widespread key player for methylmercury production in the oxic subsurface waters of the global ocean.
Antibody cross-reactivity accounts for widespread appearance of m1A in 5’ UTRs
Authors: Grozhik Anya V. , Olarerin-George Anthony O. , Sindelar Miriam , Li Xing , Gross Steven S. , Jaffrey Samie R.
Published: May 2019

N1-methyladenosine (m1A) was recently identified as a new mRNA modification based on its mapping to the 5’ UTRs of thousands of mRNAs with an m1A-binding antibody. More recent studies have confirmed the prevalence of m1A, while others have questioned it. To address this discrepancy, we mapped m1A using ultra-deep RNA-Seq datasets based on m1A-induced misincorporations during reverse transcription. Using this approach, we find m1A only in the mitochondrial MT-ND5 transcript. In contrast, when we mapped m1A antibody-binding sites at single-nucleotide resolution, we found binding to transcription start nucleotides in mRNA 5’ UTRs. Using different biochemical assays, we find that m1A is not present at these sites. Instead, we find that the m1A antibody exhibits m1A-independent binding to mRNA cap structures. We also tested a new and independently derived m1A antibody. We show that this m1A antibody lacks m7G cap-binding cross-reactivity, and notably does not map to 5’ UTRs in the transcriptome. Our data demonstrate that high-stoichiometry m1A sites are rare in the transcriptome and that previous mapping of m1A to mRNA 5’ UTRs are due to unintended binding of the m1A antibody to m7G cap structure in mRNA.