bluuebunny/crossref_metadata_2025 huggingface dataset:
Pleiotropic effects of statins on ischemic heart disease: a Mendelian Randomization study in the UK Biobank
Authors: Schooling CM , Zhao JV , Yeung SL Au , Leung GM
Published: January 2020

Objectives

Statins appear to have pleiotropic effects. We examined whether specifically statins, of the major lipid modifiers, operate on ischemic heart disease (IHD) via testosterone. As a validation, we assessed whether a drug that unexpectedly likely increases IHD also operates via testosterone.

Design

A sex-specific univariable and multivariable Mendelian randomization study

Setting

A large, population-based cohort study recruited in the UK from 2006-10, the UK Biobank

Participants

179918 men with 25410 IHD cases and 212080 women with 12511 IHD cases

Main Outcome measures

Testosterone and IHD

Results

Of the three lipid modulations considered, statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe, only genetically predicted statin use in men affected testosterone (−0.15 effect size testosterone per effect size lower (of low-density lipoprotein cholesterol), 95% confidence interval (CI) −0.23 to −0.06). The genetically predicted effect of statin use on IHD in specifically men was partially mediated by testosterone (odds ratio (OR) 0.55 per effect size lower (low-density lipoprotein cholesterol), 95% CI 0.38 to 0.79, compared to OR 0.73, 95% CI 0.46 to 1.11 after allowing for testosterone). The estimate for the effect of genetically predicted statin use, independent of testosterone, was very similar in women, giving overall meta-analyzed OR 0.72, 95% CI 0.57 to 0.90 per effect size lower of low-density lipoprotein cholesterol. The genetically predicted effect of anakinra use also affected testosterone (0.022 per effect size (of IL-1Ra), 95% CI 0.01 to 0.04), and increased IHD in men.

Conclusions

Statins may partially operate via testosterone in men, which may contribute to sex-specific pleiotropic effects. Anakinra operating by testosterone may also explain its unexpected effects. Our findings could facilitate the development of new interventions for cardiovascular diseases as well as highlighting the importance of sex-specific investigations and possibly treatments.

Section 1: What is already known on this topic

Statins appear to have pleiotropic effects on cardiovascular disease. Whether such effects exist and why they should occur is unclear, but could be highly relevant to the prevention and treatment of the leading cause of death.

Section 2: What this study adds

Our study shows that statins have similar protective effects on ischemic heart disease via low-density lipoprotein cholesterol in men and women, but unlike other major lipid modifiers statins have an additional effect specific to men via testosterone, while any harms of anakinra in men may operate by a similar mechanism. Our findings highlighting the possibility of sex-specific causes of cardiovascular disease and the need for sex-specific investigations, prevention and treatment.
Corollary Discharge versus Efference Copy: Distinct Neural Signals in Speech Preparation Differentially Modulate Auditory Responses
Authors: Li Siqi , Zhu Hao , Tian Xing
Published: January 2020

Actions influence sensory processing in a complex way to shape behavior. For example, during actions, a copy of motor signals—termedcorollary discharge(CD) orefference copy(EC)—can be transmitted to sensory regions and modulate perception. However, the sole inhibitory function of the motor copies is challenged by mixed empirical observations as well as multifaceted computational demands for behaviors. We hypothesized that the content in the motor signals available at distinct stages of actions determined the nature of signals (CDvs.EC) and constrained their modulatory functions on perceptual processing. We tested this hypothesis using speech in which we could precisely control and quantify the course of action. In three electroencephalography (EEG) experiments using a novel delayed articulation paradigm, we found that preparation without linguistic contents suppressed auditory responses to all speech sounds, whereas preparing to speak a syllable selectively enhanced the auditory responses to the prepared syllable. A computational model demonstrated that a bifurcation of motor signals could be a potential algorithm and neural implementation to achieve the distinct functions in the motor-to-sensory transformation. These results suggest that distinct motor signals are generated in the motor-to-sensory transformation and integrated with sensory input to modulate perception.
Parallel evolution in the integration of a co-obligate aphid symbiosis
Authors: Monnin David , Jackson Raphaella , Kiers E. Toby , Bunker Marie , Ellers Jacintha , Henry Lee M.
Published: January 2020

Insects evolve dependencies - often extreme - on microbes for nutrition. These include cases where insects harbour multiple endosymbionts that function collectively as a metabolic unit. How do these metabolic co-dependencies originate, and is there a predictable sequence of events leading to the integration of new symbionts? While dependency on multiple nutrient-provisioning symbionts has evolved numerous times across sap-feeding insects, there is only one known case of metabolic co-dependency in aphids, betweenBuchnera aphidicolaandSerratia symbioticain the Lachninae subfamily. Here we identify three additional independent transitions to the same co-obligate symbiosis in different aphids. A comparison of recent and ancient associations allows us to investigate intermediate stages of metabolic and physical integration between the typically facultative symbiont,Serratia, and the ancient obligate symbiontBuchnera. We find that these uniquely replicated evolutionary events support the idea that co-obligate associations initiate in a predictable manner, through parallel evolutionary processes. Specifically, we show (i) how the repeated losses of the riboflavin pathway inBuchneraleads to dependency onSerratia, (ii) evidence of a stepwise process of symbiont integration, whereby dependency evolves first, then essential amino acid pathways are lost (at ~30-60MYA), which coincides with increased physical integration of the companion symbiont; and (iii) dependency can evolve prior to specialised structures (e.g. bacteriocytes), and in one case with no direct nutritional basis. More generally, our results suggest the energetic costs of synthesising nutrients may provide a unified explanation for the sequence of gene loses that occur during the evolution of co-obligate symbiosis.
Quantification of amyloid fibril polymorphism by nano-morphometry reveals the individuality of filament assembly
Authors: Aubrey Liam D. , Blakeman Ben J. F. , Lutter Liisa , Serpell Christopher J. , Tuite Mick F. , Serpell Louise C. , Xue Wei-Feng
Published: January 2020

Amyloid fibrils are highly polymorphic structures formed by many different proteins. They provide biological function but also abnormally accumulate in numerous human diseases. The physicochemical principles of amyloid polymorphism are not understood due to lack of structural insights at the single-fibril level. To identify and classify different fibril polymorphs and to quantify the level of heterogeneity is essential to decipher the precise links between amyloid structures and their functional and disease associated properties such as toxicity, strains, propagation and spreading. Employing gentle, force-curve based AFM, we produce detailed images, from which the 3D reconstruction of individual filaments in heterogeneous amyloid samples is achieved. Distinctive fibril polymorphs are then classified by hierarchical clustering, and sample heterogeneity is objectively quantified. These data demonstrate the polymorphic nature of fibril populations, provide important information regarding the energy landscape of amyloid self-assembly, and offer quantitative insights into the structural basis of polymorphism in amyloid populations.
Distinct signals in medial and lateral VTA dopamine neurons modulate fear extinction at different times
Authors: Cai Lili X. , Pizano Katherine , Gundersen Gregory W. , Hayes Cameron L. , Fleming Weston T. , Witten Ilana B.
Published: January 2020

Dopamine (DA) neurons are known to encode reward prediction error (RPE), in addition to other signals, such as salience. While RPE is known to support learning, the role of salience in supporting learning remains less clear. To address this, we recorded and manipulated VTA DA neurons in mice during fear extinction, a behavior we observed to generate spatially segregated RPE and salience signals. We applied deep learning to classify mouse freezing behavior, eliminating the need for human scoring. Our fiber photometry recordings showed that DA neurons in medial and lateral VTA have distinct activity profiles during fear extinction: medial VTA activity more closely reflected RPE, while lateral VTA activity more closely reflected a salience-like signal. Optogenetic inhibition of DA neurons in either region slowed fear extinction, with the relevant time period for inhibition differing across regions. Our results indicate that salience-like signals can have similar downstream consequences to RPE-like signals, although with different temporal dependencies.
Ignoring fossil age uncertainty leads to inaccurate topology and divergence times in time calibrated tree inference
Authors: Barido-Sottani Joëlle , van Tiel Nina , Hopkins Melanie J. , Wright David F. , Stadler Tanja , Warnock Rachel C. M.
Published: January 2020

Time calibrated trees are challenging to estimate for many extinct groups of species due to the incompleteness of the rock and fossil records. Additionally, the precise age of a sample is typically not known as it may have occurred at any time during the time interval spanned by the rock layer.

Bayesian phylogenetic approaches provide a coherent framework for incorporating multiple sources of evidence and uncertainty. In this study, we simulate datasets with characteristics typical of Palaeozoic marine invertebrates, in terms of character and taxon sampling. We use these datasets to examine the impact of different age handling methods on estimated topologies and divergence times obtained using the fossilized birth-death process. Our results reiterate the importance of modeling fossil age uncertainty, although we find that the overall impact of fossil age uncertainty depends on both fossil taxon sampling and character sampling. When character sampling is low, different approaches to handling fossil age uncertainty make little to no difference in the accuracy and precision of the results. However, when character sampling is high, sampling the fossil ages as part of the inference gives topology and divergence times estimates that are as good as those obtained by fixing ages to the truth, whereas fixing fossil ages to incorrect values results in higher error and lower coverage. Modeling fossil age uncertainty is thus critical, as fixing incorrect fossil ages will negate the benefits of improved fossil and character sampling.
d-PBWT: dynamic positional Burrows-Wheeler transform
Authors: Sanaullah Ahsan , Zhi Degui , Zhang Shaojie
Published: January 2020

Durbin’s PBWT, a scalable data structure for haplotype matching, has been successfully applied to identical by descent (IBD) segment identification and genotype imputation. Once the PBWT of a haplotype panel is constructed, it supports efficient retrieval of all shared long segments among all individuals (long matches) and efficient query between an external haplotype and the panel. However, the standard PBWT is an array-based static data structure and does not support dynamic updates of the panel. Here, we generalize the static PBWT to a dynamic data structure, d-PBWT, where the reverse prefix sorting at each position is represented by linked lists. We developed efficient algorithms for insertion and deletion of individual haplotypes. In addition, we verified that d-PBWT can support all algorithms of PBWT. In doing so, we systematically investigated variations of set maximal match and long match query algorithms: while they all have average case time complexity independent of database size, they have different worst case complexities, linear time complexity with the size of the genome, and dependency on additional data structures.
Development of novel anti-malarial from structurally diverse library of molecules, targeting plant-like Calcium Dependent Protein Kinase 1, a multistage growth regulator ofP. falciparum
Authors: Jain Ravi , Gupta Sakshi , Munde Manoj , Pati Soumya , Singh Shailja
Published: January 2020

UponPlasmodium falciparummerozoites exposure to low [K+] environment in blood plasma, there is escalation of cytosolic [Ca2+] which activates Ca2+-Dependent Protein Kinase 1 (CDPK1), a signaling hub of intra-erythrocytic proliferative stages of parasite. Given its high abundance and multidimensional attributes in parasite life-cycle, this is a lucrative target for desiging antimalarials. Towards this, we have virtually screened MyriaScreenII diversity collection of 10,000 drug-like molecules, which resulted in 18 compounds complementing ATP-binding pocket of CDPK1.In vitroscreening for toxicity in mammalian cells revealed that these compounds are non-toxic in nature. Further, SPR analysis demonstrated differential binding affinity of these compounds towards recombinantly purified CDPK1 protein. Selection of lead compound 1 was performed by evaluating their inhibitory effects on phosphorylation and ATP binding activities of CDPK1. Further,in vitrobiophysical evaluations by ITC and FS revealed that binding of compound 1 is driven by formation of energetically favorable non-covalent interactions, with different binding constants in presence and absence of Ca2+, and TSA authenticated stability of compound 1 bound CDPK1 complex. Finally, compound 1 strongly inhibited intra-erythrocytic growth ofP. falciparum in vitro. Concievably, we propose a novel CDPK1-selective inhibitor, step towards developing pan-CDPK kinase inhibitors, prerequisite for cross-stage anti-malarial protection.
Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease
Authors: Janelidze Shorena , Stomrud Erik , Smith Ruben , Palmqvist Sebastian , Mattsson Niklas , Airey David C. , Proctor Nicholas K. , Chai Xiyun , Shcherbinin Sergey , Sims John R. , Dage Jeffrey L. , Hansson Oskar
Published: January 2020

Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD) reflecting abnormal tau metabolism in the brain. Tau can be phosphorylated at multiple other sites including threonine 217, and here we investigated the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n=194), p-tau217 had stronger correlations with the tau PET tracer [18F]flortaucipir, and more accurately identified individuals with abnormally increased [18F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 were higher compared to p-tau181 and better correlated with [18F]flortaucipir retention. P-tau217 correlated better than p-tau181 with PET measures of neocortical amyloid-β burden and more accurately distinguished AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [18F]flortaucipir were corroborated in an independent EXPEDITION3 trial cohort (n=32). These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.
Mining downy mildew susceptibility genes: a diversity study in grapevine
Authors: Pirrello Carlotta , Zeilmaker Tieme , Bianco Luca , Giacomelli Lisa , Moser Claudio , Vezzulli Silvia
Published: January 2020

Several pathogens continuously threaten viticulture worldwide. Until now, the investigation on resistance loci has been the main trend to understand the interaction between grapevine and mildew causal agents. Dominantly inherited gene-based resistance has shown to be race-specific in some cases, to confer partial immunity and to be potentially overcome within a few years since its introgression. Recently, on the footprint of research conducted on Arabidopsis, the putative hortologues of genes associated with downy mildew susceptibility in this species, have been discovered also in the grapevine genome. In this work, we deep-resequenced four putative susceptibility genes in 190 highly genetically diverse grapevine genotypes to discover new sources of broad-spectrum recessively inherited resistance. The scouted genes areVvDMR6-1, VvDMR6-2, VvDLO1, VvDLO2and predicted to be involved in susceptibility to downy mildew. From all identified mutations, 56% were Single Nucleotide Polymorphisms (SNPs) in heterozygosity, while the remaining 44% were homozygous. Regarding the identified mutations with putative impact on gene function, we observed ~4% genotypes mutated inVvDMR6-1and ~8% mutated inVvDMR6-2, only a handful of genotypes that were mutated in both genes. ~2% and ~7% genotypes showed mutations inVvDLO1andVvDLO2respectively, and again a few genotypes resulted mutated in both genes. In particular, 80% of impacting mutations were heterozygous while 20% were homozygous. The current results will inform grapevine genetics and corroborate genomic-assisted breeding programs for resistance to biotic stresses.

Significance statement

A survey on the genetic diversity of downy mildew susceptibility genes in grapevine varieties and wild species reveals a potential valuable for genomic-assisted breeding as well as tailored gene editing to induce disease resistance.
Expanding the Genetic Architecture of Nicotine Dependence and its Shared Genetics with Multiple Traits: Findings from the Nicotine Dependence GenOmics (iNDiGO) Consortium
Authors: Quach Bryan C. , Bray Michael J. , Gaddis Nathan C. , Liu Mengzhen , Palviainen Teemu , Minica Camelia C. , Zellers Stephanie , Sherva Richard , Aliev Fazil , Nothnagel Michael , Young Kendra A. , Marks Jesse A. , Young Hannah , Carnes Megan U. , Guo Yuelong , Waldrop Alex , Sey Nancy Y.A. , Landi Maria T. , McNeil Daniel W. , Drichel Dmitriy , Farrer Lindsay A. , Markunas Christina A. , Vink Jacqueline M. , Hottenga Jouke-Jan , Iacono William G. , Kranzler Henry R. , Saccone Nancy L. , Neale Michael C. , Madden Pamela , Rietschel Marcella , Marazita Mary L. , McGue Matthew , Won Hyejung ,   Georg Winterer and the German Nicotine Cohort Study, Grucza Richard , Dick Danielle M. , Gelernter Joel , Caporaso Neil E. , Baker Timothy B. , Boomsma Dorret I. , Kaprio Jaakko , Hokanson John E. , Vrieze Scott , Bierut Laura J. , Johnson Eric O. , Hancock Dana B.
Published: January 2020

Cigarette smoking is the leading cause of preventable morbidity and mortality. Knowledge is evolving on genetics underlying initiation, regular smoking, nicotine dependence (ND), and cessation. We performed a genome-wide association study using the Fagerström Test for ND (FTND) in 58,000 smokers of European or African ancestry. Five genome-wide significant loci, including two novel lociMAGI2/GNAI1(rs2714700) andTENM2(rs1862416) were identified, and loci reported for other smoking traits were extended to ND. Using the heaviness of smoking index (HSI) in the UK Biobank (N=33,791), rs2714700 was consistently associated, but rs1862416 was not associated, likely reflecting ND features not captured by the HSI. Both variants werecis-eQTLs (rs2714700 forMAGI2-AS3in hippocampus, rs1862416 forTENM2in lung), and expression of genes spanning ND-associated variants was enriched in cerebellum. SNP-based heritability of ND was 8.6%, and ND was genetically correlated with 17 other smoking traits (rg=0.40–0.95) and co-morbidities. Our results emphasize the FTND as a composite phenotype that expands genetic knowledge of smoking, including loci specific to ND.
Disentangling the effects of sampling scale and size on the shape of species abundance distributions
Authors: de Lima Renato A. Ferreira , Condé Paula Alves , Banks-Leite Cristina , Campos Renata C. , Hernández Malva I. Medina , Rodrigues Ricardo R. , Prado Paulo I.
Published: January 2020

Many authors have tried to explain the shape of the species abundance distribution (SAD). Some of them have suggested that sampling scale is an important factor shaping SADs. These suggestions, however, did not consider the indirect and well-known effect of sample size, which increases as samples are combined to generate SADs at larger scales. Here, we separate the effects of sample size and sampling scale on the shape of the SAD for three groups of organisms (trees, beetles and birds) sampled in the Brazilian Atlantic Forest. We compared the observed SADs at different sampling scales with simulated SADs having the same richness, relative abundances but comparable sample sizes, to show that the main effect shaping SADs is sample size and not sampling scale. The effect of scale was minor and deviations between observed and simulated SADs were present only for beetles. For trees, the match between observed and simulated SADs was improved at all scales when we accounted for conspecific aggregation, which was even more important than the sampling scale effect. We build on these results to propose a conceptual framework where observed SADs are shaped by three main factors, in decreasing order of importance: sample size, conspecific aggregation and beta diversity. Therefore, studies comparing SADs across sites or scales should use sampling and/or statistical approaches capable of disentangling these three effects on the shape of SADs.
Impact of b-value on estimates of apparent fibre density
Authors: Genc Sila , Tax Chantal M.W. , Raven Erika P. , Chamberland Maxime , Parker Greg D. , Jones Derek K.
Published: January 2020

Recent advances in diffusion magnetic resonance imaging (dMRI) analysis techniques have improved our understanding of fibre-specific variations in white matter microstructure. Increasingly, studies are adopting multi-shell dMRI acquisitions to improve the robustness of dMRI-based inferences. However, the impact of b-value choice on the estimation of dMRI measures such as apparent fibre density (AFD) derived from spherical deconvolution is not known. Here, we investigate the impact of b-value sampling scheme on estimates of AFD. First, we performed simulations to assess the correspondence between AFD and simulated intra-axonal signal fraction across multiple b-value sampling schemes. We then studied the impact of sampling scheme on the relationship between AFD and age in a developmental population (n=78) aged 8-18 (mean=12.4, SD=2.9 years) using hierarchical clustering and whole brain fixel-based analyses. Multi-shell dMRI data were collected at 3.0T using ultra-strong gradients (300 mT/m), using 6 diffusion-weighted shells ranging from 0 – 6000 s/mm2. Simulations revealed that the correspondence between estimated AFD and simulated intra-axonal signal fraction was improved with high b-value shells due to increased suppression of the extra-axonal signal. These results were supported byin vivodata, as sensitivity to developmental age-relationships was improved with increasing b-value (b=6000 s/mm2, median R2= .34; b=4000 s/mm2, median R2= .29; b=2400 s/mm2, median R2= .21; b=1200 s/mm2, median R2= .17) in a tract-specific fashion. Overall, estimates of AFD and age-related microstructural development were better characterised at high diffusion-weightings due to improved correspondence with intra-axonal properties.
Can we predict real-time fMRI neurofeedback learning success from pre-training brain activity?
Authors: Haugg Amelie , Sladky Ronald , Skouras Stavros , McDonald Amalia , Craddock Cameron , Kirschner Matthias , Herdener Marcus , Koush Yury , Papoutsi Marina , Keynan Jackob N. , Hendler Talma , Kadosh Kathrin Cohen , Zich Catharina , MacInnes Jeff , Adcock Alison , Dickerson Kathryn , Chen Nan-Kuei , Young Kymberly , Bodurka Jerzy , Yao Shuxia , Becker Benjamin , Auer Tibor , Schweizer Renate , Pamplona Gustavo , Emmert Kirsten , Haller Sven , Van De Ville Dimitri , Blefari Maria-Laura , Kim Dong-Youl , Lee Jong-Hwan , Marins Theo , Fukuda Megumi , Sorger Bettina , Kamp Tabea , Liew Sook-Lei , Veit Ralf , Spetter Maartje , Weiskopf Nikolaus , Scharnowski Frank
Published: January 2020

Neurofeedback training has been shown to influence behavior in healthy participants as well as to alleviate clinical symptoms in neurological, psychosomatic, and psychiatric patient populations. However, many real-time fMRI neurofeedback studies report large interindividual differences in learning success. The factors that cause this vast variability between participants remain unknown and their identification could enhance treatment success. Thus, here we employed a meta-analytic approach including data from 24 different neurofeedback studies with a total of 401 participants, including 140 patients, to determine whether levels of activity in target brain regions during pre-training functional localizer or no-feedback runs (i.e., self-regulation in the absence of neurofeedback) could predict neurofeedback learning success. We observed a slightly positive correlation between pre-training activity levels during a functional localizer run and neurofeedback learning success, but we were not able to identify common brain-based success predictors across our diverse cohort of studies. Therefore, advances need to be made in finding robust models and measures of general neurofeedback learning, and in increasing the current study database to allow for investigating further factors that might influence neurofeedback learning.
Polycomb regulation is coupled to cell cycle transition in pluripotent stem cells
Authors: Asenjo Helena G. , Gallardo Amador , López-Onieva Lourdes , Tejada Irene , Martorell-Marugán Jordi , Carmona-Sáez Pedro , Landeira David
Published: January 2020

When self-renewing pluripotent cells receive a differentiation signal, ongoing cell duplication needs to be coordinated with entry into a differentiation program. Accordingly, transcriptional activation of lineage specifiers genes and cell differentiation is confined to the G1-phase of the cell cycle by unknown mechanisms. We found that Polycomb repressive complex 2 (PRC2) subunits are differentially recruited to lineage specifier gene promoters across cell cycle in mouse embryonic stem cells (mESCs). Jarid2 and the catalytic subunit Ezh2 are dramatically accumulated at target promoters during S and G2, while the transcriptionally activating subunits EPOP and EloB are enriched during G1. Importantly, fluctuations in the recruitment of PRC2 subunits promote changes in RNA synthesis and RNA polymerase II binding that are compromised in Jarid2 -/- mESCs. Overall, we show that differential recruitment of PRC2 subunits across cell cycle enables the establishment of a chromatin state that facilitates the induction of cell differentiation in G1.
Post-transcriptional modulation of the SigF regulon inMycobacterium smegmatisby the PhoH2 toxin-antitoxin
Authors: Andrews Emma S.V. , Rzoska-Smith Elizabeth , Arcus Vickery L.
Published: January 2020

PhoH2 proteins are highly conserved across bacteria and archaea yet their biological function is poorly characterised. We examined the growth profiles ofMycobacterium smegmatisstrainsmc2155andmc2155 ΔphoH2and observed the same growth profile and growth rate in a variety of conditions. In light of the comparable growth rates, we used RNAseq to provide a snapshot of the differences between the transcriptomes ofM. smegmatis mc2155andM. smegmatis mc2155 ΔphoH2during normal growth. At 48 hours, elevated expression of thesigFregulon and its predicted regulatory cascade was observed inΔphoH2relative to wild type. In biochemical assays, PhoH2 showed specific activity towardsigFmRNA insinuating a role of PhoH2 in modulating the pool ofsigFmRNA in the cell during normal growth, adding further complexity to the repertoire of reported mechanisms of post-translational regulation. Multiple copies of the preferred target site of PhoH2 were identified in loops of thesigFmRNA structure, leading us to propose a mechanism for the activity of PhoH2 that is initiated after assembly on specific single-stranded loops of RNA. We hypothesise that PhoH2 is a toxin-antitoxin that contributes to the regulation of SigF at a post-transcriptional level through targeted activity onsigFmRNA. This work presents the first evidence for post-transcriptional regulation of SigF along with the biological function of PhoH2 fromM. smegmatis. This also has implications for the highly conserved PhoH2 toxin-antitoxin module across the mycobacteria including the important human pathogenM. tuberculosis.
The distribution of functional N-cycle related genes and nitrogen in soil profiles fertilized with mineral and organic N fertilizer
Authors: Zilio Massimo , Motta Silvia , Tambone Fulvia , Scaglia Barbara , Boccasile Gabriele , Squartini Andrea , Adani Fabrizio
Published: January 2020

Nitrogen (N) fertilizers applied to agricultural soils result in the release of nitrogen, mainly nitrate (NO3-) in addition to nitrous oxide (N2O) and ammonia (NH3), into the environment. Nitrogen transformation in soil is a complex process and the soil microbial population can regulate the potential for N mineralization, nitrification and denitrification. Here we show that agricultural soils under standard agricultural N-management are consistently characterized by a high presence of gene copies for some of the key biological activities related to the N-cycle. This led to a strong NO3-reduction (75%) passing from the soil surface (15.38 ± 11.36 g N-NO3kg-1on average) to 1 m deep layer (3.92 ± 4.42 g N-NO3kg-1on average), and ensured low nitrate presence in the deepest layer. Under these circumstances the other soil properties play a minor role in reducing soil nitrate presence in soil. However, with excessive N fertilization, the abundance of bacterial gene copies is not sufficient to explain N leaching in soil and other factors, i.e. soil texture and rainfall, become more important in controlling these aspects.
Temporal dynamics of GABA and Glx in the visual cortex
Authors: Rideaux Reuben
Published: January 2020

Magnetic resonance spectroscopy (MRS) can be used in vivo to quantify neurometabolite concentration and provide evidence for the involvement of different neurotransmitter systems, e.g., inhibitory and excitatory, in sensory and cognitive processes. The relatively low signal-to-noise of MRS measurements has shaped the types of questions that it has been used to address. In particular, temporal resolution is often sacrificed in MRS studies to achieve sufficient signal to produce a reliable estimate of neurometabolite concentration. Here we apply novel analyses with large datasets from human participants (both sexes) to reveal the dynamics of GABA+ and Glx in visual cortex while participants are at rest (with eyes closed) and compare this with changes in posterior cingulate cortex. We find that the dynamic concentration of GABA+ and Glx in visual cortex drifts in opposite directions, that is, GABA+ decreases while Glx increases over time. Further, we find that in visual, but not posterior cingulate cortex, the concentration of GABA+ predicts that of Glx 120 s later, such that a change in GABA+ is correlated with a subsequent opposite change in Glx. Together, these results expose novel temporal trends and interdependencies of primary neurotransmitters in visual cortex. More broadly, we demonstrate the feasibility of using MRS to investigate in vivo dynamic changes of neurometabolites.

SIGNIFICANCE STATEMENT

Using large datasets of magnetic resonance spectroscopy acquisitions from human participants, we develop novel analyses to investigate the temporal dynamics of neurometabolite concentration in visual cortex. We find that while participants are at rest, the concentration of GABA+ and Glx drifts in opposite directions, that is, GABA+ decreases while Glx increases over time. Further, we find that the concentration of GABA+ predicts that of Glx 120 s later, such that a change in GABA+ is correlated with a subsequent opposite change in Glx. We show these phenomena are regionally localized to visual cortex.
A minimum reporting standard for multiple sequence alignments
Authors: Wong Thomas KF , Kalyaanamoorthy Subha , Meusemann Karen , Yeates David K , Misof Bernhard , Jermiin Lars S
Published: January 2020

Multiple sequence alignments (MSAs) play a pivotal role in studies of molecular sequence data, but nobody has developed a minimum reporting standard (MRS) to quantify the completeness of MSAs in terms of completely-specified nucleotides or amino acids. We present an MRS that relies on four simple completeness metrics. The metrics are implemented in AliStat, a program developed to support the MRS. A survey of published MSAs illustrates the benefits and unprecedented transparency offered by the MRS.
Role of astrogial Connexin 43 in pneumococcal meningitis and pneumolysin cytotoxicity
Authors: Bello Chakir , Smail Yasmine , Sainte-Rose Vincent , Podglajen Isabelle , Gilbert Alice , Moreira Vanessa Oliveira , Chrétien Fabrice , Salmon Martine Cohen , Van Nhieu Guy Tran
Published: January 2020

Introductory paragraph

Streptococcus pneumoniaeor pneumococcus (PN) is a major causative agent of bacterial meningitis with high mortality in young infants and elderly people. The mechanism underlying PN crossing of the blood brain barrier (BBB) remains poorly understood. Here, we show that the gap junctional component connexin 43 expressed in astrocytes (aCx43) plays a major role in PN meningitis. Following intravenous PN challenge, mice deficient for aCx43 developed milder symptoms and showed severely reduced bacterial counts in the brain. We show a role for aCx43 in the PN-induced fragmentation of astrocytic GFAP filaments associated with bacterial translocation across endothelial vessels and replication in the brain cortex. aCx43 triggers the PN- and Ply-dependent GFAP fragmentation and nuclear shrinkage inin vitrocultured astrocytes. We showed that purified pneumolysin (Ply) co-opted Cx43 to promote the permeabilization and cytosolic calcium (Ca2+) increase of host cells, a process sensitive to extracellular ATP depletion. These results point to aCx43 as a major player during bacterial meningitis and extend cytolytic mechanisms implicating other host cell plasma membrane channels proposed for small pore-forming toxins, to Ply, a cholesterol-dependent cytolysin, at concentrations relevant to bacterial infection.
Fusobacterium nucleatumhost cell binding and invasion induces IL-8 and CXCL1 secretion that drives colorectal cancer cell migration
Authors: Casasanta Michael A. , Yoo Christopher C. , Udayasuryan Barath , Sanders Blake E. , Umaña Ariana , Zhang Yao , Peng Huaiyao , Duncan Alison J. , Wang Yueying , Li Liwu , Verbridge Scott S. , Slade Daniel J.
Published: January 2020

Fusobacterium nucleatumis implicated in the acceleration of colorectal cancer (CRC), yet the mechanisms by which this bacterium modulates the tumor microenvironment remain understudied. Here we show that binding and cellular invasion of CRC cells selectively induces the secretion of the pro-inflammatory and metastatic cytokines IL-8 and CXCL1, which we then show induces robust migration of HCT116 cancer cells. Next, we demonstrate that cytokine signaling by cancer cells is largely driven by invasion coordinated by the surface adhesin Fap2. By contrast, we show thatF. nucleatuminduced secretion of CCL3, CXCL2, and TNFα cytokines from neutrophils and macrophages is Fap2 independent. Finally, we show that inhibitingF. nucleatumhost-cell binding and entry using galactose sugars, neutralizing membrane antibodies, and deletion of thefap2gene, lead to attenuated cytokine secretion and cellular migration. As elevated IL-8 and CXCL1 levels in cancer have been associated with increased metastatic potential and cell seeding, poor prognosis, and enhanced recruitment of tumor-associated macrophages and fibroblasts within tumor microenvironments, these data show thatF. nucleatumdirectly and indirectly modulates immune and cancer cell signaling and migration. In conclusion, as viableF. nucleatumwere previously shown to migrate within metastatic CRC cells, we propose that inhibition of host cell binding and invasion, potentially through vaccination or novel galactoside compounds, could be an effective strategy for reducingF. nucleatum-induced signaling that drives metastasis and cancer cell seeding.
Characterization of Prenylated C-terminal Peptides Using a Novel Capture Technique Coupled with LCMS
Authors: Wilkins James A. , Kaasik Krista , Chalkley Robert J. , Burlingame Al L.
Published: January 2020

Post-translational modifications play a critical and diverse role in regulating cellular activities. Despite their fundamentally important role in cellular function, there has been no report to date of an effective generalized approach to the targeting, extraction and characterization of the critical c-terminal regions of natively prenylated proteins. Various chemical modification and metabolic labelling strategies in cell culture have been reported. However, their applicability is limited to cell culture systems and does not allow for analysis of tissue samples. The chemical characteristics (hydrophobicity, low abundance, highly basic charge) of many of the c-terminal regions of prenylated proteins have impaired the use of standard proteomic workflows. In this context, we sought a direct approach to the problem in order to examine these proteins in tissue without the use of labelling. Here we demonstrate that prenylated proteins can be captured on chromatographic resins functionalized with mixed disulfide functions. Protease treatment of resin-bound proteins using chymotryptic digestion revealed peptides from many known prenylated proteins. Exposure of the protease-treated resin to reducing agents and hydro organic mixtures released c-terminal peptides with intact prenyl groups along with other enzymatic modifications expected in this protein family. Database and search parameters were selected to allow for c-terminal modifications unique to these molecules such as CAAX box processing and c-terminal methylation. In summary, we present a direct approach to enrich and obtain information at a molecular level of detail about prenylation of proteins from tissue and cell extracts using high performance LCMS without the need for metabolic labeling and derivatization.

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Dynamics of sphingolipids and the serine-palmitoyltransferase complex in oligodendrocytes during myelination
Authors: Davis Deanna L. , Mahawar Usha , Pope Victoria S. , Allegood Jeremy , Sato-Bigbee Carmen , Wattenberg Binks W.
Published: January 2020

Myelin is a unique, lipid-rich membrane structure that accelerates neurotransmission and supports neuronal function. Sphingolipids are critical components of myelin. Here we examined sphingolipid synthesis during the peak period of myelination in the postnatal rat brain. Importantly, we made measurements in isolated oligodendrocytes, the myelin-producing cells in the central nervous system. We analyzed sphingolipid distribution and levels of critical enzymes and regulators in the sphingolipid biosynthetic pathway, with a focus on the serine palmitoyltransferase (SPT) complex, the rate-limiting step in this pathway. During myelination levels of the major SPT subunits increased and oligodendrocyte maturation was accompanied by extensive alterations in the composition of the SPT complex. These included changes in the relative levels of alternate catalytic subunits, SPTLC2 and −3, the relative levels of isoforms of the small subunits ssSPTa and –b, and in the isoform distribution of the SPT regulators, the ORMDLs. As myelination progressed there were distinct changes in both the nature of the sphingoid backbone and the N-acyl chains incorporated into sphingolipids. The distribution of these changes among sphingolipid family members indicates that there is selective channeling of the ceramide backbone towards specific downstream metabolic pathways during myelination.
Single-cell transcriptome maps of myeloid blood cell lineages inDrosophila
Authors: Cho Bumsik , Yoon Sang-Ho , Lee Daewon , Koranteng Ferdinand , Tattikota Sudhir Gopal , Cha Nuri , Shin Mingyu , Do Hobin , Hu Yanhui , Oh Sue Young , Moon Seok Jun , Perrimon Norbert , Nam Jin-Wu , Shim Jiwon
Published: January 2020

Drosophilalymph gland, the larval hematopoietic organ comprised of prohemocytes and hemocytes, has been a valuable model for understanding mechanisms underlying hematopoiesis and immunity. Three types of mature hemocytes have been characterized in the lymph gland: plasmatocytes, lamellocytes, and crystal cells, which are analogous to vertebrate myeloid cells. Here, we used single-cell RNA sequencing to comprehensively analyze heterogeneity of developing hemocytes in the lymph gland, and discovered novel hemocyte types, stem-like prohemocytes, and intermediate prohemocytes. Additionally, we identified the emergence of the lamellocyte lineage following active cellular immunity caused by wasp infestation. We unraveled similarities and differences between embryonically derived- and larval lymph gland hemocytes. Finally, the comparison ofDrosophilalymph gland hemocytes and human immune cells highlights similarities between prohemocytes and hematopoietic stem cell, and between mature hemocytes and myeloid cells across species. Altogether, our study provides detailed insights on the development and evolution of hematopoiesis at single-cell resolution.
Awareness and differential eyeblink conditioning: effects of manipulating auditory CS frequencies
Authors: Bolaram Anudeep , Coe Taylor E. , Power John M. , Cheng Dominic T.
Published: January 2020

The role of awareness in differential delay eyeblink conditioning (EBC) has been a topic of much debate. We tested the idea that awareness is required for differential delay EBC when two cues are perceptually similar. The present study manipulated frequencies of auditory conditioned stimuli (CS) to vary CS similarity in three groups of participants. Our findings indicate that awareness was not necessary for differential delay EBC when two tones are easily discriminable, awareness was also not needed for relatively similar tones but may facilitate earlier conditioning, and awareness alone was not sufficient for differential delay EBC.
Depotentiation depends on IP3 receptor activation sustained by synaptic inputs after LTP induction
Authors: Fujii Satoshi , Yamazaki Yoshihiko , Goto Jun-ichi , Fujiwara Hiroki , Mikoshiba Katsuhiko
Published: January 2020

In CA1 neurons of guinea pig hippocampal slices, long-term potentiation (LTP) was induced in field excitatory postsynaptic potentials (EPSPs) or population spikes (PSs) by the delivery of high-frequency stimulation (HFS, 100 pulses at 100 Hz) to CA1 synapses, and was reversed by the delivery of a train of low-frequency stimulation (LFS, 1000 pulses at 2 Hz) at 30 min after HFS (depotentiation), and this effect was inhibited when test synaptic stimulation was halted for a 19-min period after HFS or for a 20-min period after LFS or applied over the same time period in the presence of an antagonist of N-methyl-D-aspartate receptors (NMDARs), group I metabotropic glutamate receptors (mGluRs), or inositol 1, 4, 5-trisphosphate receptors (IP3Rs). Depotentiation was also blocked by the application of a Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor or a calcineurin inhibitor applied in the presence of test synaptic input for a 10-min period after HFS or for a 20-min period after LFS. These results suggest that, in postsynaptic neurons, the coactivation of NMDARs and group I mGluRs due to sustained synaptic activity following LTP induction results in the activation of IP3Rs and CaMKII, which leads to the activation of calcineurin after LFS and depotentiation of CA1 synaptic responses.
Syntheses and crystal structures of new aurate salts of adenine or guanine nucleobases
Authors: Savchenkov Anton , Demina Ludmila , Safonov Alexey , Grigoriev Mikhail , Solovov Roman , Abkhalimov Evgeny
Published: January 2020

Two new gold(III) complexes with adenine or guanine nitrogenous bases as counter-cations were synthesized. These are 6-amino-7H-purine-1,9-diium tetrachloridogold(III) chloride monohydrate, (C5H7N5)[AuCl4]Cl·H2O, 1, and 2-amino-6-oxo-6,7-dihydro-1H-purin-9-ium tetrachloridogold(III) hemihydrate, (C5H6N5O)[AuCl4]·0.5H2O, 2. Their crystal structures were studied using single-crystal X-ray diffraction and FT–IR spectroscopic techniques. The arrangement of species in the studied crystal structures implies π-stacking interactions, as well as concomitant C—H...π interactions, hydrogen bonds and other types of noncovalent interactions, which were studied qualitatively and quantitatively using the method of molecular Voronoi–Dirichlet polyhedra. The variation of the nitrogenous base from adenine to guanine results in evident differences in the packing of the species in the crystals of 1 and 2. The splitting and shifting of bands in the FT–IR spectra of the title compounds reveals several features representative of noncovalent interactions in their crystal structures.
Temperature-induced solid-to-solid transformation in helical homochiral coordination polymers
Authors: Xu Zhong-Xuan , Chen Guo-Guo , Li Li-Feng
Published: January 2020

The reactions of (R)- and (S)-4-(1-carboxyethoxy)benzoic acid (H2CBA) with 1,3-bis(2-methyl-1H-imidazol-1-yl)benzene (1,3-BMIB) ligands afforded a pair of homochiral coordination polymers (CPs), namely, poly[[[μ-1,3-bis(2-methyl-1H-imidazol-1-yl)benzene][μ-(S)-4-(1-carboxylatoethoxy)benzoato]zinc(II)] monohydrate], {[Zn(C10H8O5)(C14H14N4)]·H2O}
n
or {[Zn{(S)-CBA}(1,3-BMIB)]·H2O}
n
(1-L), and poly[[[μ-1,3-bis(2-methyl-1H-imidazol-1-yl)benzene][μ-(R)-4-(1-carboxylatoethoxy)benzoato]zinc(II)] monohydrate] (1-D). Three kinds of helical chains exist in compounds 1-D and 1-L, which are constructed from ZnII atoms, 1,3-BMIB ligands and/or CBA2− ligands. When the as-synthesized crystals of 1-L and 1-D were further heated in the mother liquor or air, poly[[μ-1,3-bis(2-methyl-1H-imidazol-1-yl)benzene][μ-(S)-4-(1-carboxylatoethoxy)benzoato]zinc(II)], [Zn(C10H8O5)(C14H14N4)]
n
or [Zn{(S)-CBA}(1,3-BMIB)]
n
(2-L), and poly[[μ-1,3-bis(2-methyl-1H-imidazol-1-yl)benzene][μ-(R)-4-(1-carboxylatoethoxy)benzoato]zinc(II)] (2-D) were obtained, respectively. The single-crystal structure analysis revealed that 2-L and 2-D only contained one type of helical chain formed by ZnII atoms and 1,3-BMIB and CBA2− ligands, which indicated that the helical chains were reconstructed though solid-to-solid transformation. This result not only means the realization of helical transformation, but also gives a feasible strategy to build homochiral CPs.