bluuebunny/crossref_metadata_2025 huggingface dataset:
Liraglutide improves hepatic steatosis and metabolic dysfunctions in a 3-week dietary mouse model of non-alcoholic steatohepatitis
Authors: Duparc Thibaut , Briand François , Trenteseaux Charlotte , Mérian Jules , Combes Guillaume , Najib Souad , Sulpice Thierry , Martinez Laurent O.
Published: May 2019

Aim

Non-alcoholic steatohepatitis (NASH) is an emerging health problem worldwide. However, efficacious pharmacological treatment for NASH is lacking. A major issue for preclinical evaluation of potential therapeutics for NASH is the limited number of appropriate animal models, i.e., models that do not require long-term dietary intervention and adequately mimic disease progression in humans. The present study aimed to evaluate a 3-week dietary mouse model of NASH and to validate it by studying the effects of liraglutide, a compound in advanced clinical development for NASH.

Methods

C57BL6/J mice were fed a diet high in fat (60%), cholesterol (1.25%) and cholic acid (0.5%) along with 2% hydroxypropyl-β-cyclodextrin in drinking water (HFCC-CDX diet). Histological and biological parameters were measured at 1 and 3 weeks. Following 1-week diet induction, liraglutide was administrated daily for 2 weeks, and then NASH-associated phenotypic aspects were evaluated in comparison with control mice.

Results

Prior to treatment with liraglutide, mice fed the HFCC-CDX diet for 1 week developed liver steatosis and had increased levels of oxidative-stress markers and hepatic and systemic inflammation. For mice not treated with liraglutide, these aspects were even more pronounced after 3 weeks of the dietary period, with additional liver insulin resistance and fibrosis. Liraglutide treatment corrected the diet-induced alterations in glucose metabolism and significantly reduced hepatic steatosis and inflammation.

Conclusion

This study provides a novel 3-week dietary model of mice that rapidly develop NASH features, and this model will be suitable for evaluating the therapeutic efficacy of compounds in preclinical drug development for NASH.
Increasing cerebral blood flow improves cognition into late stages in Alzheimer’s disease mice
Authors: Bracko Oliver , Njiru Brendah N. , Swallow Madisen , Ali Muhammad , Schaffer Chris B.
Published: May 2019

Alzheimer’s disease (AD) is associated with a 20-30% reduction in cerebral blood flow. In the APP/PS1 mouse model of AD, inhibiting neutrophil adhesion using an antibody against the neutrophil specific protein Ly6G was recently shown to drive rapid improvements in cerebral blood flow that was accompanied by an improvement in performance on short-term memory tasks. Here, in a longitudinal aging study, we assessed how far into disease development a single injection of anti-Ly6G can acutely improve memory function. We found that APP/PS1 mice as old as 15-16 months had improved performance on the object replacement and Y-maze tests of short-term memory, measured at one day after anti-Ly6G treatment. APP/PS1 mice 17-18 months of age or older did not show acute improvements in cognitive performance, although we did find that cerebral blood flow was still increased by 17% in 21-22 months old APP/PS1 mice given anti-Ly6G. These data add to the growing body of evidence suggesting that cerebral blood flow reductions are an important contributing factor to the cognitive dysfunction associated with neurodegenerative disease.
Shift in bacterial taxa precedes morphological plasticity in a larval echinoid
Authors: Carrier Tyler J. , Reitzel Adam M.
Published: May 2019

Morphological plasticity is an adaptive response to heterogenous environments when a fitness advantage is conferred. Larval sea urchins, for example, increase individual fitness in dilute feeding environments by elongating their feeding structure. Morphological plasticity for larval sea urchins is also coupled with significant shifts in the associated bacterial community, but whether this response occurs before, during, or following the expression of plasticity is unclear. Using the sea urchinLytechinus variegatus, we define the temporal pattern of the associated bacterial community throughout the expression of morphological plasticity. From prefeeding through plasticity, we observed thatL. variegatuslarvae exhibit a four-stage successional pattern and the relatedness of the larval-associated bacterial community directly reflects morphological plasticity and does so prior to expression of the environmental-specific morphology. Based on the structure of the larval-associated bacterial communities, the expression of morphological plasticity correlates short-arm larvae deviating from the microbial trajectory of pre-plastic siblings. Taken together, these data suggest that a holobiont may exhibit shifts in the associated bacterial community corresponding with the environmental variation in absence or anticipation of morphological plasticity.
Individual differences in stereotypy and neuron subtype translatome with TrkB deletion
Authors: Engeln Michel , Song Yang , Chandra Ramesh , La Ashley , Evans Brianna , Fox Megan E. , Thomas Shavin , Francis T. Chase , Hertzano Ronna , Lobo Mary Kay
Published: May 2019

Motor stereotypies occurring in early-onset neuropsychiatric diseases are associated with dysregulated basal ganglia direct-pathway activity. Disruptions in network connectivity through impaired neuronal structure have been implicated in both rodents and humans. However, the neurobiological mechanisms leading to direct-pathway neuron disconnectivity in stereotypy remain poorly understood. We have a mouse line with Tropomyosin receptor kinase B (TrkB) receptor deletion from D1-expressing cells (D1-Cre-flTrkB) in which a subset of animals shows repetitive rotations and head tics with juvenile onset. Here we demonstrate these behaviors may be associated with abnormal direct-pathway activity by reducing rotations using chemogenetic inhibition of dorsal striatum D1-medium spiny neurons (D1-MSNs) in both juvenile and young adult mice. Taking advantage of phenotypical differences in animals with similar genotype, we then interrogated the D1-MSN specific translatome associated with repetitive behavior by using RNA-sequencing of ribosome-associated mRNA. Detailed translatome analysis followed by multiplexed gene expression assessment revealed profound alterations in neuronal projection and synaptic structure related genes in stereotypy mice. Examination of neuronal morphology demonstrated dendritic atrophy and dendritic spine loss in dorsal striatum D1-MSNs from mice with repetitive behavior. Together, our results uncover phenotype-specific molecular alterations in D1-MSNs that relate to morphological adaptations in mice displaying stereotypy behavior.
Identification of pathogenic variant enriched regions across genes and gene families
Authors: Pérez-Palma Eduardo , May Patrick , Iqbal Sumaiya , Niestroj Lisa-Marie , Du Juanjiangmeng , Heyne Henrike , Castrillon Jessica , O’Donnell-Luria Anne , Nürnberg Peter , Palotie Aarno , Daly Mark , Lal Dennis
Published: May 2019

Missense variant interpretation is challenging. Essential regions for protein function are conserved among gene family members, and genetic variants within these regions are potentially more likely to confer risk to disease. Here, we generated 2,871 gene family protein sequence alignments involving 9,990 genes and performed missense variant burden analyses to identify novel essential protein regions. We mapped 2,219,811 variants from the general population into these alignments and compared their distribution with 65,034 missense variants from patients. With this gene family approach, we identified 398 regions enriched for patient variants spanning 33,887 amino acids in 1,058 genes. As a comparison, testing the same genes individually we identified less patient variant enriched regions involving only 2,167 amino acids and 180 genes. Next, we selectedde novovariants from 6,753 patients with neurodevelopmental disorders and 1,911 unaffected siblings, and observed a 5.56-fold enrichment of patient variants in our identified regions (95% C.I. =2.76-Inf, p-value = 6.66×10−8). Using an independent ClinVar variant set, we found missense variants inside the identified regions are 111-fold more likely to be classified as pathogenic in comparison to benign classification (OR = 111.48, 95% C.I = 68.09-195.58, p-value < 2.2e−16). All patient variant enriched regions identified (PERs) are available online through a user-friendly platform for interactive data mining, visualization and download athttp://per.broadinstitute.org. In summary, our gene family burden analysis approach identified novel patient variant enriched regions in protein sequences. This annotation can empower variant interpretation.
A cytomegalovirus immunevasin triggers integrated stress response-dependent reorganization of the endoplasmic reticulum
Authors: Zhang Hongbo , Read Clarissa , Nguyen Christopher C. , Siddiquey Mohammed N.A. , Shang Chaowei , Hall Cameron M. , von Einem Jens , Kamil Jeremy P.
Published: May 2019

Human cytomegalovirus (HCMV) encodes an ER-resident glycoprotein, UL148, which activates the unfolded protein response (UPR) but is fully dispensable for viral replication in cultured cells. Hence, its previously ascribed roles in immune evasion and modulation of viral cell tropism are hypothesized to cause ER stress. Here, we show that UL148 is necessary and sufficient to drive the formation of large ER-derived structures that occupy up to 7% of the infected cell cytosol. The structures are found to be sites where UL148 coalesces with cellular proteins involved in ER quality control, such as Hrd1 and EDEM1. Transmission electron microscopy analyses reveal the structures to be comprised of tortuous, densely packed and apparently collapsed ER membranes that connect to distended cisternae. During induced ectopic expression of UL148-GFP fusion protein, punctate signals traffic to accumulate at prominent structures that exhibit poor recovery of fluorescence after photobleaching. Small molecule blockade of the integrated stress response (ISR) prevents the formation of puncta, leading to a uniform reticular fluorescent signal. Accordingly, ISR inhibition during HCMV infection abolishes the coalescence of UL148 and Hrd1 into discrete structures, which argues that UL148 requires the ISR to cause ER reorganization. Given that UL148 stabilizes immature forms of a receptor binding subunit for a viral envelope glycoprotein complex important for HCMV infectivity, our results imply that stress-dependent ER remodeling contributes to viral cell tropism.

IMPORTANCE

Perturbations to ER morphology occur during infection with various intracellular pathogens and in certain genetic disorders. We identify that an HCMV gene product, UL148, profoundly reorganizes the ER during infection, and is sufficient to do so when expressed on its own. Our results reveal that UL148-dependent reorganization of the ER is a prominent feature of HCMV infected cells. Moreover, we find that this example of virally induced organelle remodeling requires the integrated stress response (ISR), a stress adaptation pathway that contributes to a number of disease states. Since ER reorganization accompanies the roles of UL148 in HCMV cell tropism and intracellular retention of the immune cell co-stimulatory ligand CD58, our results may have implications for understanding the mechanisms involved. Furthermore, our findings provide a basis to utilize UL148 as a tool to investigate organelle responses to stress and to identify novel drugs targeting the ISR.
Accuracy, Robustness and Scalability of Dimensionality Reduction Methods for Single Cell RNAseq Analysis
Authors: Sun Shiquan , Zhu Jiaqiang , Ma Ying , Zhou Xiang
Published: May 2019

Background

Dimensionality reduction (DR) is an indispensable analytic component for many areas of single cell RNA sequencing (scRNAseq) data analysis. Proper DR can allow for effective noise removal and facilitate many downstream analyses that include cell clustering and lineage reconstruction. Unfortunately, despite the critical importance of DR in scRNAseq analysis and the vast number of DR methods developed for scRNAseq studies, however, few comprehensive comparison studies have been performed to evaluate the effectiveness of different DR methods in scRNAseq.

Results

Here, we aim to fill this critical knowledge gap by providing a comparative evaluation of a variety of commonly used DR methods for scRNAseq studies. Specifically, we compared 18 different DR methods on 30 publicly available scRNAseq data sets that cover a range of sequencing techniques and sample sizes. We evaluated the performance of different DR methods for neighborhood preserving in terms of their ability to recover features of the original expression matrix, and for cell clustering and lineage reconstruction in terms of their accuracy and robustness. We also evaluated the computational scalability of different DR methods by recording their computational cost.

Conclusions

Based on the comprehensive evaluation results, we provide important guidelines for choosing DR methods for scRNAseq data analysis. We also provide all analysis scripts used in the present study atwww.xzlab.org/reproduce.html. Together, we hope that our results will serve as an important practical reference for practitioners to choose DR methods in the field of scRNAseq analysis.
Rotational Dynamics Reduce Interference Between Sensory and Memory Representations
Authors: Libby Alexandra , Buschman Timothy J.
Published: May 2019

Sensory stimuli arrive in a continuous stream. By learning statistical regularities in the sequence of stimuli, the brain can predict future stimuli (Xu et al. 2012; Gavornik and Bear 2014; Maniscalco et al. 2018; J. Fiser and Aslin 2002). Such learning requires associating immediate sensory information with the memory of recently encountered stimuli (Ostojic and Fusi 2013; Kiyonaga et al. 2017). However, new sensory information can also interfere with short-term memories (Parthasarathy et al. 2017). How the brain prevents such interference is unknown. Here, we show that sensory representations rotate in neural space over time, to form an independent memory representation, thus reducing interference with future sensory inputs. We used an implicit learning paradigm in mice to study how statistical regularities in a sequence of stimuli are learned and represented in primary auditory cortex. Mice experienced both common sequences of stimuli (e.g. ABCD) and uncommon sequences (e.g. XYCD). Over four days of learning, the neural population representation of commonly associated stimuli (e.g. A and C) converged. This facilitated the prediction of upcoming stimuli, but also led unexpected sensory inputs to overwrite the sensory representation of previous stimuli (postdiction). Surprisingly, we found the memory of previous stimuli persisted in a second, orthogonal dimension. Unsupervised clustering of functional cell types revealed that the emergence of this second memory dimension is supported by two separate types of neurons; a ‘stable’ population that maintained its selectivity throughout the sequence and a ‘switching’ population that dynamically inverted its selectivity. This combination of sustained and dynamic representations produces a rotation of the encoding dimension in the neural population. This rotational dynamic may be a general principle, by which the cortex protects memories of prior events from interference by incoming stimuli.
Antibiotic interactions shape short-term evolution of resistance in E. faecalis
Authors: Dean Ziah , Maltas Jeff , Wood Kevin B.
Published: May 2019

Antibiotic combinations are increasingly used to combat bacterial infections. Multidrug therapies are a particularly important treatment option for E. faecalis, an opportunistic pathogen that contributes to high-inoculum infections such as infective endocarditis. While numerous synergistic drug combinations for E. faecalis have been identified, much less is known about how different combinations impact the rate of resistance evolution. In this work, we use high-throughput laboratory evolution experiments to quantify adaptation in growth rate and drug resistance of E. faecalis exposed to drug combinations exhibiting different classes of interactions, ranging from synergistic to suppressive. We identify a wide range of evolutionary behavior, including both increased and decreased rates of growth adaptation, depending on the specific interplay between drug interaction and cross resistance. For example, selection in a dual-lactam combination leads to accelerated growth adaptation compared to selection with the individual drugs, even though the resulting resistance profiles are nearly identical. On the other hand, populations evolved in an aminoglycoside and -lactam combination exhibit decreased growth adaptation and resistant profiles that depend on the specific drug concentrations. We show that the main qualitative features of these evolutionary trajectories can be explained by simple rescaling arguments that correspond to geometric transformations of the two-drug growth response surfaces measured in ancestral cells. The analysis also reveals multiple examples where resistance profiles selected by drug combinations correspond to (nearly) optimized linear combinations of those selected by the component drugs. Our results highlight trade-offs between drug interactions and collateral effects during the evolution of multi-drug resistance and emphasize evolutionary benefits and disadvantages of particular drug pairs targeting enterococci.
Tracking of quiescence inLeishmaniaby quantifying the expression of GFP in the ribosomal DNA locus
Authors: Jara Marlene , Maes Ilse , Imamura Hideo , Domagalska Malgorzata A. , Claude Dujardin Jean , Arevalo Jorge
Published: May 2019

Under stressful conditions some microorganisms adopt a reversible non or slow proliferative quiescent stage that allows their survival. Although quiescence has been described broadly in bacteria, this phenotype has been only recently discovered inLeishmania. In the present work we developed a biosensor of quiescence that allows to monitor the physiological stage of the parasite at population and single cell levels. We inserted a GFP gene into the ribosomal DNA locus and followed the expression of this reporter gene, driven by the ribosomal promotor (rGFP expression). We showed that rGFP expression decreased significantly and rapidly during thein vitrotransition from extracellular promastigotes to intracellular amastigotes ofL. mexicanaanL. braziliensisand that the decrease in rGFP expression was coupledin vitrowith a decrease in replication as measured by BrdU incorporation. Quiescence was not only observed in reference laboratory strains, but also among clinical isolates. We found that quiescence was reversible as the parasites could rapidly resume their metabolically active and proliferative stage when they were put back in an optimal environment for growth. We demonstrated for the first time in live cells that amastigotes are a heterogeneous population in which shallow and deep quiescent stages may coexist. Finally, we showed that rGFP expression could be monitoredin vivoand that quiescent amastigotes could reside in tissues of animals with latent infections ofL. braziliensisorL. mexicana. We propose rGFP expression as a simple parameter to define quiescent cells and further characterize them.

IMPORTANCE

Quiescence is a physiological diversification that allows pathogens to overcome chemotherapy without the development of drug resistance and to be invisible to the immune system of their host. Quiescent pathogens can cause latent infections and (re-) emerge in an unpredictable time during the lifetime of the individual. The phenomenon was recently described inLeishmaniain which it could explain several clinical and sub-clinical features, like therapeutic failure, reactivation of the disease and asymptomatic infections. However, a simple biosensor of quiescence forLeishmaniais not yet available. We show for the first time that the integration of GFP within the rDNA locus and the subsequent quantification of its expression can be used as a biosensor to distinguish quiescent subpopulations among live amastigotes. Moreover, we show quiescence is quickly reversible bothin vivoandin vitro. We offer a tool that will allow the further molecular characterization of quiescent parasites.
CCMetagen: comprehensive and accurate identification of eukaryotes and prokaryotes in metagenomic data
Authors: Marcelino Vanessa R. , Clausen Philip T.L.C. , Buchmann Jan P. , Wille Michelle , Iredell Jonathan R. , Meyer Wieland , Lund Ole , Sorrell Tania C. , Holmes Edward C.
Published: May 2019

High-throughput sequencing of DNA and RNA from environmental and host-associated samples (metagenomics and metatranscriptomics) is a powerful tool to assess which organisms are present in a sample. Taxonomic identification software usually align individual short sequence reads to a reference database, sometimes containing taxa with complete genomes only. This is a challenging task given that different species can share identical sequence regions and complete genome sequences are only available for a fraction of organisms. A recently developed approach to map sequence reads to reference databases involves weighing all high scoring read-mappings to the data base as a whole to produce better-informed alignments. We used this novel concept in read mapping to develop a highly accurate metagenomic classification pipeline named CCMetagen. Using simulated fungal and bacterial metagenomes, we demonstrate that CCMetagen substantially outperforms other commonly used metagenome classifiers, attaining a 3 – 1580 fold increase in precision and a 2 – 922 fold increase in F1 scores for species-level classifications when compared to Kraken2, Centrifuge and KrakenUniq. CCMetagen is sufficiently fast and memory efficient to use the entire NCBI nucleotide collection (nt) as reference, enabling the assessment of species with incomplete genome sequence data from all biological kingdoms. Our pipeline efficiently produced a comprehensive overview of the microbiome of two biological data sets, including both eukaryotes and prokaryotes. CCMetagen is user-friendly and the results can be easily integrated into microbial community analysis software for streamlined and automated microbiome studies.
Chromatin structure-dependent histone incorporation revealed by a genome-wide deposition assay
Authors: Tachiwana Hiroaki , Dacher Mariko , Maehara Kazumitsu , Harada Akihito , Ohkawa Yasuyuki , Kimura Hiroshi , Kurumizaka Hitoshi , Saitoh Noriko
Published: May 2019

In eukaryotes, histone variant distribution within the genome is the key epigenetic feature. To understand how each histone variant is targeted to the genome, we developed a new method, in which epitope-tagged histone complexes are introduced into permeabilized cells and incorporated into their chromatin. We found that the incorporation of histones H2A and H2A.Z mainly occurred at less condensed chromatin (open), suggesting that the condensed chromatin (closed) is a barrier for histone incorporation. To overcome this barrier, H2A, but not H2A.Z, uses a replication-coupled deposition mechanism. This led to the recapitulation of the pre-existing chromatin structure: the genome-wide even distribution of H2A and the exclusion of H2A.Z from the closed chromatin. Intriguingly, an H2A.Z mutant with mutations in the developmentally essential region was incorporated into closed chromatin. Our study revealed that the combination of chromatin structure and DNA replication dictates the differential histone deposition for maintaining the epigenetic chromatin states.
Structural and functional characterisation of SiiA, an auxiliary protein from the SPI4-encoded type 1 secretion system fromSalmonella enterica
Authors: Kirchweger Peter , Weiler Sigrid , Egerer-Sieber Claudia , Blasl Anna-Theresa , Hoffmann Stefanie , Schmidt Christiane , Sander Nathalie , Merker Dorothee , Gerlach Roman G. , Hensel Michael , Muller Yves A.
Published: May 2019

Salmonellainvasion is mediated by a concerted action of theSalmonellapathogenicity island 4 (SPI4)-encoded type one secretion system (T1SS) and the SPIl-encoded type three secretion system (T3SS-1). The SPI4-encoded T1SS establishes the first contact to the host membrane. It consists of five proteins (SiiABCDF) that secrete the giant adhesin SiiE. The exact mechanism by which the T1SS enables host cell recognition remains unclear. Here, we investigated structure-function relationships in SiiA, a non-canonical T1SS subunit located at the inner membrane (IM). We observe that SiiA consists of a membrane domain, an intrinsically disordered periplasmic linker region and a folded globular periplasmic domain (SiiA-PD). The crystal structure of SiiA-PD shows homology to that of MotB-PD and other peptidoglycan (PG)-binding domains. Indeed, SiiA-PD binds PGin vitroalbeit at an acidic pH, only, whereas MotB-PD binds PG from pH 5.8 to 8. Mutation of Arg162 in SiiA impedes PG binding and reducesSalmonellainvasion efficacy of polarized epithelial cells. SiiA forms a complex with SiiB at the IM, and the SiiA-MotB homology is likely paralleled by a SiiB-MotA homology. We show that, in addition to PG binding, the SiiAB complex translocates protons across the IM. Substituting Asp13 in SiiA impairs proton translocation. Overall, SiiA displays many properties previously observed in MotB. However, whereas the MotAB complex uses the proton motif force (PMF) to energize the bacterial flagellum, it remains to be shown how the use of the PMF by SiiAB assists T1SS function and ultimatelySalmonellainvasion.
PhenoGMM: Gaussian mixture modelling of microbial cytometry data enables efficient predictions of biodiversity
Authors: Rubbens Peter , Props Ruben , Kerckhof Frederiek-Maarten , Boon Nico , Waegeman Willem
Published: May 2019

Microbial flow cytometry allows to rapidly characterize microbial communities. Recent research has demonstrated a moderate to strong connection between the cytometric diversity and taxonomic diversity based on 16S rRNA gene amplicon sequencing data. This creates the opportunity to integrate both types of data to study and predict the microbial community diversity in an automated and efficient way. However, microbial flow cytometry data results in a number of unique challenges that need to be addressed. The results of our work are threefold: i) We expand current microbial cytometry fingerprinting approaches by proposing and validating a model-based fingerprinting approach based upon Gaussian Mixture Models, which we calledPhenoGMM. ii) We show that microbial diversity can be rapidly estimated byPhenoGMM. In combination with a supervised machine learning model, diversity estimations based on 16S rRNA gene amplicon sequencing data can be predicted. iii) We evaluate our method extensively by using multiple datasets from different ecosystems and compare its predictive power with a generic binning fingerprinting approach that is commonly used in microbial flow cytometry. These results demonstrate the strong connection between the genetic make-up of a microbial community and its phenotypic properties as measured by flow cytometry. Our workflow facilitates the study of microbial diversity and community dynamics using flow cytometry in a fast and quantitative way.

Importance

Microorganisms are vital components in various ecoystems on Earth. In order to investigate the microbial diversity, researchers have largely relied on the analysis of 16S rRNA gene sequences from DNA. Flow cytometry has been proposed as an alternative technique to characterize microbial community diversity and dynamics. It is an optical technique, able to rapidly characterize a number of phenotypic properties of individual cells. So-called fingerprinting techniques are needed in order to describe microbial community diversity and dynamics based on flow cytometry data. In this work, we propose a more advanced fingerprinting strategy based on Gaussian Mixture Models. When samples have been analyzed by both flow cytometry and 16S rRNA gene amplicon sequencing, we show that supervised machine learning models can be used to find the relationship between the two types of data. We evaluate our workflow on datasets from different ecosystems, illustrating its general applicability for the analysisof microbial flow cytometry data.PhenoGMMfacilitates the rapid characterization and predictive modelling of microbial diversity using flow cytometry.
Effects of mid-frontal brain stimulation on sustained attention
Authors: van Schouwenburg Martine R. , Sligte Ilja G. , Giffin Michael R. , Günther Franziska , Koster Dirk , Spronkers Floortje S. , Vos Anna , Slagter Heleen A.
Published: May 2019

Sustained attention is defined as the ability to maintain attention over longer periods of time, which typically declines with time on task (i.e., the vigilance decrement). Previous studies have suggested an important role for the dorsomedial prefrontal cortex (mPFC) in sustained attention. In two experiments, we aimed to enhance sustained attention by applying transcranial electrical current stimulation over the mPFC during a sustained attention task. In the first experiment, we applied transcranial direct current stimulation (tDCS) in a between-subject design (n=97): participants received either anodal, cathodal, or sham stimulation. Contrary to our prediction, we found no effect of stimulation on the vigilance decrement. In the second experiment, participants received theta and alpha transcranial alternating current stimulation (tACS) in two separate sessions (n=47, within-subject design). Here, we found a frequency-dependent effect on the vigilance decrement, such that contrary to our expectation, participants’ performance over time became worse after theta compared to alpha stimulation. However, this result needs to be interpreted with caution given that this effect could be driven by differential side effects between the two stimulation frequencies. To conclude, across two studies, we were not able to reduce the vigilant decrement using tDCS or theta tACS.
Higher surfaces of a crop in the landscape increase outbreak risks the following growing season
Authors: Delaune T. , Ballot R. , Sausse C. , Felix I. , Chen M. , Maupas F. , Valantin-Morison M. , Makowski D. , Barbu C.
Published: May 2019

The use of fungicides and insecticides by farmers represents a major threat to biodiversity1, endangering agriculture itself2,3. Landscapes could be designed4to take advantage of the dependencies of pests5,6, pathogens7and their natural enemies8on landscape elements. However, the complexity of the interactions makes it difficult to establish general rules. Despite initial enthusiasm9, the many studies opposing cultivated and semi-natural habitats have not revealed a homogeneous response of pests10and pathogens11to semi-natural habitats. In addition, the question of the impact of crop diversity on pests and pathogens remains largely open12. Based on about half a million observations over nine years on 30 major field crop pests and pathogens spread over all latitudes of metropolitan France, we show that the outbreak risk increases with the area of the host crop in the landscape the previous growing season. The impact on the risk of the host crop area the ongoing growing season diverges between animal pests and pathogens. We also confirm that woodlands, scrublands, hedgerows and grasslands do not have a consistent effect over the spectrum of pests. The spatial and temporal distribution of the resource, the host crop, generally prevails over the effects of potential alternative habitats. Territorial and temporal coordination generally promoting crop diversity but excluding a crop at risk a given year may prove to be key levers for reducing pesticide use14.
Follicular regulatory T cells can access the germinal centre independently of CXCR5
Authors: Vanderleyden Ine , Fra-Bido Sigrid C. , Innocentin Silvia , Okkenhaug Hanneke , Evans-Bailey Nicola , Pierson Wim , Linterman Michelle A.
Published: May 2019

The germinal centre (GC) response is critical for generating high-affinity humoral immunity and immunological memory, which forms the basis of successful immunisation. Control of the GC response is thought to require follicular regulatory T (Tfr) cells, a subset of suppressive Foxp3+ Treg cells located within GCs. Relatively little is known about the exact role of Tfr cells within the GC, and the mechanism/s through which they exert their suppressive function. A unique feature of Tfr cells is their reported CXCR5-dependent localisation to the GC. Here we show that the lack of CXCR5 on Foxp3+ regulatory T cells resulted in a reduced frequency, but not an absence of, GC-localised Tfr cells. This demonstrates that additional, CXCR5-independent mechanisms facilitate Treg cell homing to the GC.
Temporal signal-to-noise changes in combined multiband- and slice-accelerated echo-planar imaging with a 20- and 64-channel coil
Authors: Seidel Philipp , Levine Seth M. , Tahedl Marlene , Schwarzbach Jens V.
Published: May 2019

Echo planar imaging (EPI) is the most common method of functional magnetic resonance imaging for acquiring the blood oxygenation level-dependent (BOLD) contrast. One of the primary benefits of using EPI is that an entire volume of the brain can be acquired on the order of two seconds. However, this speed benefit comes with a cost. Because imaging protocols are limited by hardware (e.g., fast gradient switching), researchers are forced to compromise between spatial resolution, temporal resolution, or whole-brain coverage. Earlier attempts to circumvent this problem included developing protocols in which slices of a volume were acquired faster (i.e., slice (S) acceleration), while more recent protocols allow for multiple slices to be acquired simultaneously (i.e., multiband (MB) acceleration). However, applying such acceleration methods can lead to a reduction in the temporal signal-to-noise ratio (tSNR), which is a critical measure of the stability of the signal over time. Here we show, in five healthy subjects, using a 20- and 64-channel receiver coil, that enabling S-acceleration consistently yielded, as expected, a substantial decrease in tSNR, regardless of the receiver coil employed, whereas tSNR decrease resulting from MB acceleration was less pronounced. Specifically, with the 20-channel coil, tSNR of upto 4-fold MB-acceleration is comparable to that of no acceleration, while up to 6-fold MB-acceleration with the 64-channel coil yields comparable tSNR to that of no acceleration. Moreover, observed tSNR losses tended to be localized to temporal, insular, and medial brain regions and were more noticeable in the 20-than in the 64-channel coil. Conversely, with the 64-channel coil, the tSNR in lateral frontoparietal regions remained relatively stable with increasing MB factors. Such methodological explorations can inform researchers and clinicians as to how they can optimize imaging protocols depending on the available hardware and the brain regions they want to investigate.
SYCP2translocation-mediated dysregulation and frameshift variants cause human male infertility
Authors: Schilit Samantha L.P. , Menon Shreya , Friedrich Corinna , Kammin Tammy , Wilch Ellen , Hanscom Carrie , Jiang Sizun , Kliesch Sabine , Talkowski Michael E. , Tüttelmann Frank , MacQueen Amy J. , Morton Cynthia C.
Published: May 2019

Infertility is one of the most common disorders for men of reproductive age. To identify novel genetic etiologies, we studied a male with severe oligozoospermia and 46, XY,t(20;22)(q13.3;q11.2). We identified exclusive overexpression ofSYCP2from the der(20) allele that is hypothesized to result from enhancer adoption. Modeling the dysregulation in budding yeast resulted in disruption of the synaptonemal complex, a common cause of defective spermatogenesis in mammals. Exome sequencing of infertile males revealed three novel heterozygousSYCP2frameshift variants in additional subjects with cryptozoospermia and azoospermia. This study provides the first evidence ofSYCP2-mediated male infertility in humans.
Using citizen science data to define and track restoration targets in urban areas
Authors: Callaghan Corey T. , Major Richard E. , Lyons Mitchell B. , Martin John M. , Wilshire John H. , Kingsford Richard T. , Cornwell William K.
Published: May 2019

Habitat fragmentation and land degradation, directly and indirectly caused by urbanization, are drastically altering the world's ecosystems and are therefore driving an imperative for ecological restoration within the world's cities. Current methods for the implementation and monitoring of restoration are limited. Restoration ecology needs cost‐effective and repeatable tools for tracking changes at global scales, but with local relevance.

We propose the Urban Greenspace Integrity Index—a locally relevant measure of an urban greenspace's response to urbanization, derived from widely accessible citizen science data. Unlike classical measurements of biodiversity (e.g. species richness, species diversity), this index measures species‐specific responses to continuous measures of urbanization.

Increases in this index are evidence of a successful urban restoration project; that is, restoration results in a community shift that favours urban‐sensitive species. Importantly, data for this index are easily and efficiently collected by citizen scientists, providing long‐term repeatable data. This urban index, calculated from greenspace surveys, correlates with and complements traditional biodiversity metrics.

Synthesis and applications. Policymakers and practitioners can use the index—a measure of the urbanness of the local bird community—to define and track restoration of urban ecosystems, effectively measuring changes in biodiversity in response to urbanization: measuring whether the urbanness of the bird community changes through time. Importantly, this index can be calculated using citizen science data, providing a potentially long‐term monitoring effort of restoration projects.
Bird services and disservices to strawberry farming in Californian agricultural landscapes
Authors: Gonthier David J. , Sciligo Amber R. , Karp Daniel S. , Lu Adrian , Garcia Karina , Juarez Gila , Chiba Taiki , Gennet Sasha , Kremen Claire
Published: May 2019

Bird conservation in agricultural settings can be controversial. While some bird species damage some crops, others suppress insect pests. Few studies have simultaneously compared bird services and disservices to assess their net impact.

Using an exclusion experiment in six California strawberry farms, we show that bird suppression of berry damage by insect pests (about 3.8% of berries) is similar in magnitude to the damage birds inflict on strawberries (about 3.2% of berries).

Across 27 farms, we found that bird species richness and the relative abundance of insectivorous birds increased, while the relative abundance of strawberry‐eating birds and bird damage decreased on farms with more semi‐natural land cover in the surrounding landscapes (1000 m radius).

Relative to homogeneous farms, those that implemented diversification practices, such as hedgerows, flower strips or increased crop diversity, had greater bird species richness, total relative abundance, insectivore abundance and strawberry‐eating bird abundance.

Synthesis and applications. Conserving semi‐natural land cover in the surrounding landscape benefits bird species richness locally and aids farmers through reduced abundance of strawberry‐eating birds and bird damage. These results highlight the need to consider both the services and disservices of birds when making management decisions.
Predicting the spatial dynamics of Wolbachia infections in Aedes aegypti arbovirus vector populations in heterogeneous landscapes
Authors: Hancock Penelope A. , Ritchie Scott A. , Koenraadt Constantianus J. M. , Scott Thomas W. , Hoffmann Ary A. , Godfray H. Charles J.
Published: May 2019

A promising strategy for reducing the transmission of dengue and other arboviral human diseases by Aedes aegypti mosquito vector populations involves field introductions of the endosymbiotic bacteria Wolbachia. Wolbachia infections inhibit viral transmission by the mosquito, and can spread between mosquito hosts to reach high frequencies in the vector population. Wolbachia spreads by maternal transmission, and spread dynamics can be variable and highly dependent on natural mosquito population dynamics, population structure and fitness components.

We develop a mathematical model of an A. aegypti metapopulation that incorporates empirically validated relationships describing density‐dependent mosquito fitness components. We assume that density dependent relationships differ across subpopulations, and construct heterogeneous landscapes for which model‐predicted patterns of variation in mosquito abundance and demography approximate those observed in field populations. We then simulate Wolbachia release strategies similar to that used in field trials.

We show that our model can produce rates of spatial spread of Wolbachia similar to those observed following field releases.

We then investigate how different types of spatio‐temporal variation in mosquito habitat, as well as different fitness costs incurred by Wolbachia on the mosquito host, influence predicted spread rates. We find that fitness costs reduce spread rates more strongly when the habitat landscape varies temporally due to stochastic and seasonal processes.

Synthesis and applications: Our empirically based modelling approach represents effects of environmental heterogeneity on the spatial spread of Wolbachia. The models can assist in interpreting observed spread patterns following field releases and in designing suitable release strategies for targeting spatially heterogeneous vector populations.
Ecosystem services and disservices by birds, bats and monkeys change with macadamia landscape heterogeneity
Authors: Linden Valerie M. G. , Grass Ingo , Joubert Elsje , Tscharntke Teja , Weier Sina M. , Taylor Peter J.
Published: May 2019

The relative importance of ecosystem services and disservices can change with landscape structure in a poorly understood way.

We compare the impact of biocontrol, provided by bats and birds, with that of crop raiding by vervet monkeys on yield in South African macadamia orchards. Insectivorous bats and birds are known to feed on macadamia pest insect species, like the macadamia nut borer or the green vegetable bug. Vervet monkeys move into the orchards during the day to feed on premature macadamia nuts. Bats, birds and monkeys benefit from patches of natural vegetation adjacent to orchards.

With exclusion experiments (four treatments: day, night, day and night, control) we quantified the relative importance of biocontrol and crop raiding on yield, comparing two different landscape settings of the orchards, a natural and a human‐modified.

Crop raiding occurred only close to natural vegetation and caused yield losses of about 26%. Biocontrol by bats and birds was higher near natural vegetation, but still significant in human‐modified landscapes, at up to 530 m distance to forest patches. Prevented biocontrol through the exclusion of bats and birds resulted in yield losses of up to 60%.

Effects of biocontrol by bats and birds (USD ~5,000 ha/year) were economically more important than the losses of crop raiding (USD ~1,600 ha/year). As both are linked to the vicinity of forest patches, the removal of natural vegetation to limit monkey abundances would also limit biocontrol service provision.

Synthesis and applications. This study highlights the high economic benefits of biocontrol by bats and birds, which outweighed negative impacts through yield losses caused by crop raiding monkeys. Management practices to prevent crop damage, such as guarding, excluding vertebrates or removal of adjacent natural vegetation, would also limit access for bats and birds and the great economic benefits provided by their biocontrol. Ecosystem services by bats and birds can be promoted by the exposure of artificial roost and nest sites, but research into species‐specific preferences is needed. The education of farmers is crucial, as many are unaware of the benefits from birds and bats and the fact that these benefits can outweigh the disadvantages of the monkeys’ crop raiding.
Cyclo(tetrahydroxybutyrate) production is sufficient to distinguish between Xenorhabdus and Photorhabdus isolates in Thailand
Authors: Tobias Nicholas J. , Parra‐Rojas César , Shi Yan‐Ni , Shi Yi‐Ming , Simonyi Svenja , Thanwisai Aunchalee , Vitta Apichat , Chantratita Narisara , Hernandez‐Vargas Esteban A. , Bode Helge B.
Published: May 2019

Bacteria of the genera Photorhabdus and Xenorhabdus produce a plethora of natural products to support their similar symbiotic life cycles. For many of these compounds, the specific bioactivities are unknown. One common challenge in natural product research when trying to prioritize research efforts is the rediscovery of identical (or highly similar) compounds from different strains. Linking genome sequence to metabolite production can help in overcoming this problem. However, sequences are typically not available for entire collections of organisms. Here, we perform a comprehensive metabolic screening using HPLC‐MS data associated with a 114‐strain collection (58 Photorhabdus and 56 Xenorhabdus) across Thailand and explore the metabolic variation among the strains, matched with several abiotic factors. We utilize machine learning in order to rank the importance of individual metabolites in determining all given metadata. With this approach, we were able to prioritize metabolites in the context of natural product investigations, leading to the identification of previously unknown compounds. The top three highest ranking features were associated with Xenorhabdus and attributed to the same chemical entity, cyclo(tetrahydroxybutyrate). This work also addresses the need for prioritization in high‐throughput metabolomic studies and demonstrates the viability of such an approach in future research.
Jobactive and young job seekers: Strengths, limitations, and suggested improvements to current practices
Authors: Moore Katherine
Published: May 2019

This paper explores the efficacy of current employment services in Australia, jobactive, from the perspectives of young job seekers and their employment officers. As high youth unemployment rates and the efficacy of jobactive employment services are currently areas of priority for the Australian Government, the study offers a timely contribution to the social policy and youth employment literature by exploring the tensions experienced by young job seekers while registered with a jobactive provider, and employment officers when assisting young people to find sustainable employment. The study analyses data from 46 interviews with young job seekers and their employment officers in an outer western Melbourne region. The findings reveal particular concerns about appropriate and adequate service provision for marginalized young job seekers that are similar to those in evaluations of previous marketwise employment service contracts, Job Network and Job Services Australia. Suggestions for tailored employment assistance for young job seekers to gain sustainable employment are offered for future consideration.