bluuebunny/crossref_metadata_2025 huggingface dataset:
Modelling and DNA topology of compact 2-start and 1-start chromatin fibres
Authors: Wu Chenyi , Travers Andrew
Published: May 2019

We have investigated the structure of the most compact 30-nm chromatin fibres by modelling those with 2-start or 1-start crossed-linker organisations. Using an iterative procedure we obtained possible structural solutions for fibres of the highest possible compaction permitted by physical constraints, including the helical repeat of linker DNA. We find that this procedure predicts a quantized nucleosome repeat length (NRL) and that only fibres with longer NRLs (≥197 bp) can more likely adopt the 1-start organisation. The transition from 2-start to 1-start fibres is consistent with reported differing binding modes of the linker histone. We also calculate that in 1-start fibres the DNA constrains more torsion (as writhe) than 2-start fibres with the same NRL and that the maximum constraint obtained is in accord with previous experimental results. We posit that the coiling of the fibre is driven by overtwisting of linker DNA which, in the most compact forms - for example, in echinoderm sperm and avian erythrocytes - could adopt a helical repeat of ∼10 bp/turn. We argue that in vivo the total twist of linker DNA could be modulated by interaction with other abundant chromatin-associated proteins and by epigenetic modifications of the C-terminal tail of linker histones.
Review of whole grain and dietary fiber recommendations and intake levels in different countries
Authors: Miller Kevin Burke
Published: May 2019

This review of whole grain and dietary fiber recommendations and intake levels was presented at the symposium on whole grains, dietary fiber, and public health, convened in Beijing, China, on May 11, 2018. The review reflects on inconsistencies among the definitions of whole grains and fiber as well as recommended intake levels in different countries. The lack of consistent dietary recommendations from authoritative sources may delay the regional implementation and consumer adoption of diets that include whole grains and fiber. Currently, few countries include specific intake recommendations for whole grain, and even among those countries with guidance the recommendations can be vague and qualitative. As a result of the well-documented associations between increasing whole grain intake and reduced disease risk, there is compelling evidence to create clear, actionable dietary recommendations for both whole grains and fiber. Furthermore, work is ongoing to develop uniform standards for whole grain and whole-grain food to ensure recommendations are being met. Health and regulatory authorities are encouraged to acknowledge the public health benefits that could be derived from strong, clear whole-grain and dietary fiber recommendations; examine existing definitions (whole grain as an ingredient, whole-grain food, and dietary fiber); and adopt the most appropriate approach to best serve public health needs for their respective populations.
Evolutionary Model of Plastidial RNA Editing in Angiosperms Presumed from Genome-Wide Analysis of Amborella trichopoda
Authors: Ishibashi Kota , Small Ian , Shikanai Toshiharu
Published: May 2019

Amborella trichopoda is placed close to the base of the angiosperm lineage (basal angiosperm). By genome-wide RNA sequencing, we identified 184C-to-U RNA editing sites in the plastid genome of Amborella. This number is much higher than that observed in other angiosperms including maize (44 sites), rice (39 sites) and grape (115 sites). Despite the high frequency of RNA editing, the biased distribution of RNA editing sites in the genome, target codon preference and nucleotide preference adjacent to the edited cytidine are similar to that in other angiosperms, suggesting a common editing machinery. Consistent with this idea, the Amborella nuclear genome encodes 2–3 times more of the E- and DYW-subclass members of pentatricopeptide repeat proteins responsible for RNA editing site recognition in plant organelles. Among 165 editing sites in plastid protein coding sequences in Amborella, 100 sites were conserved at least in one out of 38 species selected to represent key branching points of the angiosperm phylogenetic tree. We assume these 100 sites represent at least a subset of the sites in the plastid editotype of ancestral angiosperms. We then mapped the loss and gain of editing sites on the phylogenetic tree of angiosperms. Our results support the idea that the evolution of angiosperms has led to the loss of RNA editing sites in plastids.
Solidarity and Responsibility in Health Care
Authors: Davies Ben , Savulescu Julian
Published: May 2019

Some healthcare systems are said to be grounded in solidarity because healthcare is funded as a form of mutual support. This article argues that health care systems that are grounded in solidarity have the right to penalise some users who are responsible for their poor health. This derives from the fact that solidary systems involve both rights and obligations and, in some cases, those who avoidably incur health burdens violate obligations of solidarity. Penalties warranted include direct patient contribution to costs, and lower priority treatment, but not typically full exclusion from the healthcare system. We also note two important restrictions on this argument. First, failures of solidary obligations can only be assumed under conditions that are conducive to sufficiently autonomous choice, which occur when patients are given ‘Golden Opportunities’ to improve their health. Second, because poor health does not occur in a social vacuum, an insistence on solidarity as part of healthcare is legitimate only if all members of society are held to similar standards of solidarity. We cannot insist upon, and penalise failures of, solidarity only for those who are unwell, and who cannot afford to evade the terms of public health.
Zoochory of zooplankton: seasonality and bird morphological diversity can influence metacommunity dynamics of temporary ponds
Authors: de Morais-Junior Cláudio Simões , de Melo-Júnior Mauro , Gonçalves-Souza Thiago , de Lyra-Neves Rachel Maria
Published: May 2019

Harsh and unstable aquatic environments present selective forces that influence environmental heterogeneity, dispersal capacity and specific life history strategies that, in turn, affect species distribution and metacommunity dynamics. To date, relatively few studies have examined the potential of bird-mediated dispersal to connect isolated ephemeral habitats. We used zooplankton from temporary ponds to examine the effects of bird morphological diversity and water availability on microcrustacean diversity in temporary ponds. Three bird feet models were constructed based on small, large and webbed anisodactylous forms in order to simulate bird walking on the pond shore. Bird and zooplankton communities were sampled in two temporary ponds and experimentally simulated zooplankton dispersal by bird on dry sediments. We surveyed in two contrasting seasonal periods. Overall, water availability does affect zooplankton composition, and birds with large feet have higher dispersal capacity. In addition, birds with different feet size and shape carry distinct zooplankton species. During the dry season, sediments hold 100% more species than in the wet season, which indicates that birds have higher potential for dispersing zooplankton in drought conditions. Our findings suggest that bird diversity can maintain zooplankton metacommunities by rescuing dormant organisms from dry ponds and connecting to any available aquatic habitats.
The Use of L2 and L3 Lumbar Sympathetic Blockade for Cancer-Related Pain, an Experience and Recommendation in the Oncologic Population
Authors: Spiegel Matthew A , Hingula Lee , Chen Grant H , Legler Aron , Puttanniah Vinay , Gulati Amitabh
Published: May 2019

Objective

The sympathetic nervous system has a recognized role in transmission of pain, and the lumbar sympathetic blockade is intended to provide analgesia. We share our experiences of lumbar sympathetic blockade in the treatment of cancer-related pain.

Methods

We performed a retrospective analysis of patients with cancer-related pain in the back, abdomen, pelvis, or legs treated at Memorial Sloan Kettering Cancer Center between 2000 and 2018 undergoing lumbar sympathetic blockade at L2 or L3. Blocks were accomplished by injection of local anesthetic or local anesthetic with steroid under fluoroscopy. We measured numerical rating scale scores, percent relief, and relief time. The primary end point was defined as “effective” or “ineffective” pain relief. Effective pain relief was defined as ≥30% relief for at least one day.

Results

We identified 124 data points of lumbar sympathetic blockade at L2 or L3, of which 57 were with complete data and used for analysis. Peri-injection, 42 data points had active disease whereas 15 were in remission. Lumbar sympathetic blockade was 67% effective in the back pain cohort, 82% effective in the abdominopelvic pain cohort, and 75% effective in the leg pain cohort. Seventeen data points went on to neurolysis, two to neuromodulation, and eight to intrathecal pump implantation.

Conclusions

Lumbar sympathetic blockade is effective for back, abdominopelvic, and leg pain related to cancer and its treatments. Future research should be aimed at refining its role within multimodal pain management.
Design of catalytic polypeptides and proteins
Authors: Gutte B , Klauser S
Published: May 2019

The first part of this review article lists examples of complete, empirical de novo design that made important contributions to the development of the field and initiated challenging projects. The second part of this article deals with computational design of novel enzymes in native protein scaffolds; active designs were refined through random and site-directed mutagenesis producing artificial enzymes with nearly native enzyme- like activities against a number of non-natural substrates. Combining aspects of de novo design and biological evolution of nature’s enzymes has started and will accelerate the development of novel enzyme activities.
Systematic revision of Mexican threatened tarantulas Brachypelma (Araneae: Theraphosidae: Theraphosinae), with a description of a new genus, and implications on the conservation
Authors: Mendoza Jorge , Francke Oscar
Published: May 2019

The tarantula genus Brachypelma includes colourful species that are highly sought after in the commercial pet trade. They are all included in CITES appendix II. We present phylogenetic analyses using molecular and morphological characters to revise Brachypelma, in which we include all currently known species. Our results agree with a previous study that shows the non-monophyly of Brachypelma. Both phylogenies strongly favour the division of Brachypelma into two smaller genera. The first clade (Brachypelma s.s.) is formed by B.albiceps, B. auratum, B. baumgarteni, B. boehmei, B. emilia, B. hamorii, B. klaasi and B. smithi. The species included in the second clade are transferred to the new genus Tliltocatl and is formed by T. albopilosum comb. nov., T. epicureanum comb. nov., T. kahlenbergi comb. nov., T. sabulosum comb. nov., T. schroederi comb. nov., T. vagans comb. nov. and T. verdezi comb. nov. Both genera can be differentiated by their coloration and the shape of the genitalia. We transfer to Tliltocatl: T. alvarezi, T. andrewi and T. aureoceps, but should be considered as nomina dubia. In addition, we transfer B. fossorium to Stichoplastoris. We discuss the implications of these taxonomical changes for CITES and for the Mexican Laws for wildlife protection.
Staphylococcus debuckii sp. nov., a coagulase-negative species from bovine milk
Authors: Naushad Sohail , Kanevets Uliana , Nobrega Diego , Carson Domonique , Dufour Simon , Roy Jean-Philippe , Lewis P. Jeffrey , Barkema Herman W.
Published: May 2019

A novel type strain, designated SDB 2975T (=CECT 9737T=DSM 105892T), of the novel species

Staphylococcus
debuckii sp. nov. isolated from bovine milk is described. The novel species belongs to the genus

Staphylococcus

and showed resistance to tetracycline and was oxidase- and coagulase-negative, catalase-positive, and Gram-stain-positive. Phylogenetic relationships of

Staphylococcus
debuckii SDB 2975T to other staphylococcal species were inferred from 16S rRNA gene and whole-genome-based phylogenetic reconstruction. The 16S rRNA gene comparisons showed that the strain is closely related to

Staphylococcus condimenti

(99.73 %),

Staphylococcus piscifermentans

(99.66 %),

Staphylococcus carnosus

(99.59 %) and

Staphylococcus simulans

(98.03 %). Average nucleotide identity (ANI) values between S.taphylococcus debuckii SDB 2975T and its closely related

Staphylococcus

species were 83.96, 94.5, 84.03 and 78.09 %, respectively, and digital DNA–DNA hybridization (dDDH) values were 27.70, 58.02, 27.70 and 22.00 %, respectively. The genome of

Staphylococcus
debuckii SDB 2975T was sequenced with PacBio and Illumina technologies and is 2 691 850 bp long, has a G+C content of 36.6 mol% and contains 2678 genes and 80 RNAs, including six copies of each5S rRNA, 16S rRNA and 23S rRNA genes. Biochemical profiling and a newly developed PCR assay enabled differentiation of

Staphylococcus
debuckii SDB 2975T and three other SDB strains from its closest staphylococcal species. Differentiation was also achieved by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF). Genes unique to

Staphylococcus
debuckii were identified and a PCR-based assay was developed to differentiate

Staphylococcus
debuckii from other staphylococcal species. In conclusion, the results of phylogenetic analysis along with the ANI values <95 %, and dDDH values <70 % from closely related species along with the phenotypic and biochemical characteristics and specific MALDI-TOF profiles demonstrated that

Staphylococcus
debuckii SDB 2975T represents a novel species within the genus

Staphylococcus

, named

Staphylococcus
debuckii sp. nov. (SDB 2975T=CECT 9737T=DSM 105892T).
Estimations of the weather effects on brain functions using functional MRI: a cautionary note
Authors: Di Xin , Wolfer Marie , Kühn Simone , Zhang Zhiguo , Biswal Bharat B.
Published: May 2019

The influences of environmental factors such as weather on the human brain are still largely unknown. A few neuroimaging studies have demonstrated seasonal effects, but were limited by their cross-sectional design or sample sizes. Most importantly, the stability of the MRI scanner hasn’t been taken into account, which may also be affected by environments. In the current study, we analyzed longitudinal resting-state functional MRI (fMRI) data from eight individuals, where the participants were scanned over months to years. We applied machine learning regression to use different resting-state parameters, including the amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and functional connectivity matrix, to predict different weather and environmental parameters. For careful control, the raw EPI and the anatomical images were also used for predictions. We first found that daylight length and air temperatures could be reliably predicted with cross-validation using the resting-state parameters. However, similar prediction accuracies could also be achieved by using one frame of EPI image, and even higher accuracies could be achieved by using segmented or raw anatomical images. Finally, the signals outside of the brain in the anatomical images and signals in phantom scans could also achieve higher prediction accuracies, suggesting that the predictability may be due to the baseline signals of the MRI scanner. After all, we did not identify detectable influences of weather on brain functions other than the influences on the baseline signals of MRI scanners. The results highlight the difficulty of studying long-term effects using MRI.
Caenorhabditis elegansmodel for admixed proteinopathy of Huntington’s and Alzheimer-type
Authors: Kapulkin Wadim J.
Published: May 2019

Formation of proteinaceous deposits composed of abnormally aggregated proteins characterizes a range of pathological conditions. Proteinaceous inclusions detected in the neurodegenerative conditions such Huntington’s chorea (HD) and Alzheimer’s disease (AD) are often referred as pathognomic and regarded as causally implicated. Despite of differences in aetiology and underlying genetics, rare cases of combined HD and AD were reported and described as admixed proteinopathies. Mixed proteopathies are characterized by the co-occurrence of at least two types of abnormal aggregation-prone variants; pathological deposition of proteinaceous inclusions might however, affect different cell populations. Here, combining plaques derived from human ß-amyloid with mutant HTT-like polyglutamine inclusions in a cell-autonomous manner, we report on theCaenorhabditis elegansmodel for admixed proteinopathy of Alzheimer’s and Huntington’s type. We show both types of intracellular foci are formedin vivo: non-amyloidic extended polyglutamine derived inclusions and distinguish those from the presence of mature ß- amyloid fibers. We found that polyglutamines expanded above pathogenic threshold and ß-amyloid act synergistically to promote the progression of proteotoxicity in a temperature dependent manner. We further, implicate thehsp-1(the predominantC. eleganschaperone interacting with ER-routed Aß42) modulate the proteotoxic insults observed in combined proteopathy model. Our results demonstrate how thein vivomodel of admixed proteopathy could be utilized to probe for human pathogenic variants confined to the same cellular type. In that perspective expanded aggregation-prone polyglutamines appended with fluorescent proteins could be regarded as ‘pathogenic probes’ useful in the proteotoxicity assaysi.e.involving ß-amyloid and possibly other comparable models of disease-associated aggregation prone variants.We anticipate models of combined proteopathies will be informative regarding the underlying pathogenesis and provide the sensitized background for sophisticated screening. For example the combinatorial effects of multiple pathogenic aggregation-prone variants could be tested against mutant backgrounds and pharmacological compounds. Furthermore, we surmise the postulated synergistic actions might explain some of the overlaps in observed progression of clinical symptoms in HD and AD. We also formulate the conjecture regarding the polyQ containing proteins as a contributing factor in degenerative conditions associated with increased ß-amyloid formation and deposition.
Damped oscillations of the probability of random events followed by absolute refractory period: exact analytical results
Authors: Paraskevov A.V. , Minkin A.S.
Published: May 2019

There are numerous examples of natural and artificial processes that represent stochastic sequences of events followed by an absolute refractory period during which the occurrence of a subsequent event is impossible. In the simplest case of a generalized Bernoulli scheme for uniform random events followed by the absolute refractory period, the event probability as a function of time can exhibit damped transient oscillations. Using stochastically-spiking point neuron as a model example, we present an exact and compact analytical description for the oscillations without invoking the standard renewal theory. The resulting formulas stand out for their relative simplicity, allowing one to analytically obtain the amplitude damping of the 2nd and 3rd peaks of the event probability.
Multilevel feedback architecture for adaptive regulation of learning in the insect brain
Authors: Eschbach Claire , Fushiki Akira , Winding Michael , Schneider-Mizell Casey M. , Shao Mei , Arruda Rebecca , Eichler Katharina , Valdes-Aleman Javier , Ohyama Tomoko , Thum Andreas S. , Gerber Bertram , Fetter Richard D. , Truman James W. , Litwin-Kumar Ashok , Cardona Albert , Zlatic Marta
Published: May 2019

Modulatory (e.g. dopaminergic) neurons provide “teaching signals” that drive associative learning across the animal kingdom, but the circuits that regulate their activity and compute teaching signals are still poorly understood. We provide the first synaptic-resolution connectome of the circuitry upstream of all modulatory neurons in a brain center for associative learning, the mushroom body (MB) of theDrosophilalarva. We discovered afferent pathways from sensory neurons, as well as an unexpected large population of 61 feedback neuron pairs that provide one- and two-step feedback from MB output neurons. The majority of these feedback pathways link distinct memory systems (e.g. aversive and appetitive). We functionally confirmed some of the structural pathways and found that some modulatory neurons compare inhibitory input from their own compartment and excitatory input from compartments of opposite valence, enabling them to compute integrated common-currency predicted values across aversive and appetitive memory systems. This architecture suggests that the MB functions as an interconnected ensemble during learning and that distinct types of previously formed memories can regulate future learning about a stimulus. We developed a model of the circuit constrained by the connectome and by the functional data which revealed that the newly discovered architectural motifs, namely the multilevel feedback architecture and the extensive cross-compartment connections, increase the computational performance and flexibility on learning tasks. Together our study provides the most detailed view to date of a recurrent brain circuit that computes teaching signals and provides insights into the architectural motifs that support reinforcement learning in a biological system.
Type-3 Secretion System–induced pyroptosis protects Pseudomonas against cell-autonomous immunity
Authors: Eren Elif , Planès Rémi , Buyck Julien , Bordignon Pierre-Jean , Colom André , Cunrath Olivier , Dreier Roland F. , Santos José C. , Duplan-Eche Valérie , Näser Emmanuelle , Peixoto Antonio , Bumann Dirk , Cougoule Céline , Coste Agnès , Neyrolles Olivier , Broz Petr , Meunier Etienne
Published: May 2019

Inflammasome-induced pyroptosis comprises a key cell-autonomous immune process against intracellular bacteria, namely the generation of dying cell structures. These so-called pore-induced intracellular traps (PITs) entrap and weaken intracellular microbes. However, the immune importance of pyroptosis against extracellular pathogens remains unclear. Here, we report that Type-3 secretion system (T3SS)-expressingPseudomonas aeruginosa(P. aeruginosa) escaped PIT immunity by inducing a NLRC4 inflammasome-dependent macrophage pyroptosis response in the extracellular environment. To the contrary, phagocytosis ofSalmonellaTyphimurium promoted NLRC4-dependent PIT formation and the subsequent bacterial caging. Remarkably, T3SS-deficientPseudomonaswere efficiently sequestered within PIT-dependent caging, which favored exposure to neutrophils. Conversely, both NLRC4 and caspase-11 deficient mice presented increased susceptibility to T3SS-deficientP. aeruginosachallenge, but not to T3SS-expressingP. aeruginosa.Overall, our results uncovered thatP. aeruginosauses its T3SS to overcome inflammasome-triggered pyroptosis, which is primarily effective against intracellular invaders.

Importance

Although innate immune components confer host protection against infections, the opportunistic bacterial pathogenPseudomonas aeruginosa(P. aeruginosa) exploits the inflammatory reaction to thrive. Specifically the NLRC4 inflammasome, a crucial immune complex, triggers an Interleukin (IL)-1β and -18 deleterious host response toP. aeruginosa. Here, we provide evidence that, in addition to IL-1 cytokines,P. aeruginosaalso exploits the NLRC4 inflammasome-induced pro-inflammatory cell death, namely pyroptosis, to avoid efficient uptake and killing by macrophages. Therefore, our study reveals that pyroptosis-driven immune effectiveness mainly depends onP. aeruginosalocalization. This paves the way toward our comprehension of the mechanistic requirements for pyroptosis effectiveness upon microbial infections and may initiate targeted approaches in order to ameliorate the innate immune functions to infections.

Graphical abstract

Macrophages infected with T3SS-expressingP. aeruginosadie in a NLRC4-dependent manner, which allows bacterial escape from PIT-mediated cell-autonomous immunity and neutrophil efferocytosis. However, T3SS-deficientP. aeruginosais detected by both NLRC4 and caspase-11 inflammasomes, which promotes bacterial trapping and subsequent efferocytosis ofP. aeruginosa-containing-PITs by neutrophils.
Low support values and lack of reproducibility of molecular phylogenetic analysis of Copepoda orders
Authors: Mikhailov Kirill V. , Ivanenko Viatcheslav N.
Published: May 2019

Reanalysis of the dataset used by Khodami et al. (2017) reveals low support values for the key nodes of the copepod (Crustacea) phylogeny and fails to reproduce the results obtained in the study. Maximum likelihood (ML) and Bayesian analyses with the dataset produce phylogenies that are inconsistent with the branching of copepod groups proposed by Khodami et al. (2017). The proposed phylogeny is refuted by the approximately unbiased (AU) statistical test, which undermines several conclusions drawn from the original study.
jackalope: a swift, versatile phylogenomic and high-throughput sequencing simulator
Authors: Nell Lucas A.
Published: May 2019

High-throughput sequencing (HTS) is central to the study of population genomics and has an increasingly important role in constructing phylogenies. Choices in research design for sequencing projects can include a wide range of factors, such as sequencing platform, depth of coverage, and bioinformatic tools. Simulating HTS data better informs these decisions. However, current standalone HTS simulators cannot generate genomic variants under even somewhat complex evolutionary scenarios, which greatly reduces their usefulness for fields such as population genomics and phylogenomics. Here I present the R package jackalope that simply and efficiently simulates (i) variants from reference genomes and (ii) reads from both Illumina and Pacific Biosciences (PacBio) platforms. Genomic variants can be simulated using phylogenies, gene trees, coalescent-simulation output, population-genomic summary statistics, and Variant Call Format (VCF) files. jackalope can simulate single, paired-end, or mate-pair Illumina reads, as well as reads from Pacific Biosciences. These simulations include sequencing errors, mapping qualities, multiplexing, and optical/PCR duplicates. It can read reference genomes from FASTA files and can simulate new ones, and all outputs can be written to standard file formats. jackalope is available for Mac, Windows, and Linux systems.
Improving Convolutional Network Interpretability with Exponential Activations
Authors: Koo Peter K. , Ploenzke Matt
Published: May 2019

Deep convolutional networks trained on regulatory genomic sequences tend to learn distributed representations of sequence motifs across many first layer filters. This makes it challenging to decipher which features are biologically meaningful. Here we introduce the exponential activation that – when applied to first layer filters – leads to more interpretable representations of motifs, both visually and quantitatively, compared to rectified linear units. We demonstrate this on synthetic DNA sequences which have ground truth with various convolutional networks, and then show that this phenomenon holds on in vivo DNA sequences.
Age-Related Changes in Neural Networks Supporting Complex Visual and Social Processing in Adolescence
Authors: Lerner Yulia , Scherf K. Suzanne , Katkov Mikhail , Hasson Uri , Behrmann Marlene
Published: May 2019

Despite our differences, there is much about the natural visual world that almost all observers apparently perceive in common. This coherence across observers is evidenced by the finding that, across adults, approximately 30% of the brain is activated in a consistent fashion in response to viewing naturalistic input. The critical question addressed here is how does this consistency emerge and is this pattern of coherence apparent from early in development or does it evolve with time and/or experience? We focused our investigation at a key developmental juncture that might bridge the child and adult patterns, namely, the period of adolescence. We acquired fMRI BOLD data evoked by an 11-minute age-appropriate movie in younger (age 9-14 years) and older adolescents (age 15-19 years) and in adults. Using an intra-subject correlation approach, we characterized the consistency of the neural response within-individual (across two separate runs of the movie), and then, using an inter-subject correlation approach, evaluated the similarity of the response profile within individuals of the same age group and between age-groups. In primary sensory areas (A1+, V1) the response profiles in both groups of adolescents were highly similar to those of the adults, suggesting that these areas are functionally mature at earlier stages of the development. In contrast, some other regions exhibited higher within-age correlations in the adolescent groups than in the adult group. Last, we evaluated the brain responses across the whole cortex and identified the different patterns of maturation as reflected in different inter-subject correlations across the age groups. Together, these findings provide a fine-grained characterization of functional neural development. The approach offers the potential for careful tracking of the development of widespread cortical networks that support the emerging stereotypical responses to naturalistic visual and social stimuli and has important implications for future studies of cortical development.
Castration-mediated IL-8 Promotes Myeloid Infiltration and Prostate Cancer Progression
Authors: Lopez-Bujanda Zoila A. , Haffner Michael C. , Chaimowitz Matthew G. , Chowdhury Nivedita , Venturini Nicholas J. , Obradovic Aleksandar , Hansen Corey S. , Jacków Joanna , Sfanos Karen S. , Bieberich Charles J. , Hurley Paula J. , Selby Mark J. , Korman Alan J. , Christiano Angela M. , De Marzo Angelo M. , Drake Charles G.
Published: May 2019

Immunotherapy is a treatment for many types of cancer, primarily due to deep and durable clinical responses mediated by immune checkpoint blockade (ICB)1, 2. Prostate cancer is a notable exception in that it is generally unresponsive to ICB. The standard treatment for advanced prostate cancer is androgen-deprivation therapy (ADT), a form of castration (CTX). ADT is initially effective, but over time patients eventually develop castration-resistant prostate cancer (CRPC). Here, we focused on defining tumor-cell intrinsic factors that contribute to prostate cancer progression and resistance to immunotherapy. We analyzed cancer cells isolated from castration-sensitive and castration-resistant prostate tumors, and discovered that castration resulted in significant secretion of Interleukin-8 (IL-8) and it’s likely murine homolog Cxcl15. These chemokines drove subsequent intra-tumoral infiltration with polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), promoting tumor progression. PMN-MDSC infiltration was abrogated when IL-8 was deleted from prostate cancer epithelial cells using CRISPR/Cas9, or when PMN-MDSC migration was blocked with antibodies against the IL-8 receptor CXCR2. Blocking PMN-MDSC infiltration in combination with anti-CTLA-4 delayed the onset of castration resistance and increased the density of polyfunctional CD8 T cells in tumors. Taken together, our findings establish castration-mediated IL-8 secretion and subsequent PMN-MDSC infiltration as a key suppressive mechanism in the progression of prostate cancer. Targeting of the IL-8/CXCR2 axis around the time of ADT, in combination with ICB, represents a novel therapeutic approach to delay prostate cancer progression to advanced disease.
Single-cell analysis of Non-CG methylation dynamics and gene expression in human oocyte maturation
Authors: Yu Bo , Jayavelu Naresh Doni , Battle Stephanie L. , Smith Thomas H. , Zimmerman Samuel E , Schimmel Timothy , Cohen Jacques , Mar Jessica C. , Hawkins R. David
Published: May 2019

Oocyte maturation is a coordinated process that is tightly linked to reproductive potential. A better understanding of gene regulation during human oocyte maturation will not only answer an important question in biology, but also facilitate the development of in vitro maturation technology as a fertility treatment. We generated single-cell transcriptome and use previously published single-cell methylome data from human oocytes at different maturation stages to investigate how genes are regulated during oocyte maturation, focusing on the potential regulatory role of non-CG methylation. DNMT3B, a gene encoding a key non-CG methylation enzyme, is one of the 1000 genes upregulated in mature oocytes, which may be at least partially responsible for the increased non-CG methylation as oocytes mature. Non-CG differentially methylated regions (DMRs) between mature and immature oocytes have multiple binding motifs for transcription factors, some of which bind with DNMT3B and may be important regulators of oocyte maturation through non-CG methylation. Over 98% of non-CG DMRs locate in transposable elements, and these DMRs are correlated with expression changes of the nearby genes. Taken together, this data indicates that global non-CG hypermethylation during oocyte maturation may play an active role in gene expression regulation, potentially through the interaction with transcription factors.
Language beyond the language system: dorsal visuospatial pathways support processing of demonstratives and spatial language during naturalistic fast fMRI
Authors: Rocca Roberta , Coventry Kenny R. , Tylén Kristian , Staib Marlene , Lund Torben E. , Wallentin Mikkel
Published: May 2019

Spatial demonstratives are powerful linguistic tools used to establish joint attention. Identifying the meaning of semantically underspecified expressions like “this one” hinges on the integration of linguistic and visual cues, attentional orienting and pragmatic inference. This synergy between language and extralinguistic cognition is pivotal to language comprehension in general, but especially prominent in demonstratives.

In this study, we aimed to elucidate which neural architectures enable this intertwining between language and extralinguistic cognition using a naturalistic fMRI paradigm. In our experiment, 28 participants listened to a specially crafted dialogical narrative with a controlled number of spatial demonstratives. A fast multiband-EPI acquisition sequence (TR = 388ms) combined with finite impulse response (FIR) modelling of the hemodynamic response was used to capture signal changes at word-level resolution.

We found that spatial demonstratives bilaterally engage a network of parietal areas, including the supramarginal gyrus, the angular gyrus, and precuneus, implicated in information integration and visuospatial processing. Moreover, demonstratives recruit frontal regions, including the right FEF, implicated in attentional orienting and reference frames shifts. Finally, using multivariate similarity analyses, we provide evidence for a general involvement of the dorsal (“where”) stream in the processing of spatial expressions, as opposed to ventral pathways encoding object semantics.

Overall, our results suggest that language processing relies on a distributed architecture, recruiting neural resources for perception, attention, and extra-linguistic aspects of cognition in a dynamic and context-dependent fashion.
Evaluation of copy number burden in specific epilepsy types from a genome-wide study of 18,564 subjects
Authors: Niestroj Lisa-Marie , Howrigan Daniel P. , Perez-Palma Eduardo , Saarentaus Elmo , Nürnberg Peter , Stevelink Remi , Daly Mark J. , Palotie Aarno , Lal Dennis ,   Epi25 Collaborative
Published: May 2019

Rare and large copy number variants (CNVs) around known genomic ‘hotspots’ are strongly implicated in epilepsy etiology. But it remains unclear whether the observed associations are specific to an epilepsy phenotype, and if additional risk signal can be found outside hotspots. Here, we present the largest CNV burden and first CNV breakpoint level association analysis in epilepsy to date with 11,246 European epilepsy cases and 7,318 ancestry-matched controls. We studied five epilepsy phenotypes: genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, epileptic encephalopathy, and unclassified epilepsy. We discovered novel epilepsy-associated CNV loci and further characterized the CNV burden enrichment among phenotype-specific epilepsies. Finally, we provide evidence for deletion burden outside of known hotspot regions and show that CNVs play a significant role in the genetic architecture of lesional focal epilepsies.
Secondary Structure Motifs Made Searchable to Facilitate the Functional Peptide Design
Authors: Tsai Cheng-Yu , Salawu Emmanuel O , Li Hongchun , Lin Guan-Yu , Kuo Ting-Yu , Voon Liyin , Sharma Adarsh , Hu Kai-Di , Cheng Yi-Yun , Sahoo Sobha , Stuart Lutimba , Chen Chih-Wei , Chang Yuan-Yu , Lu Yu-Lin , Ke Ximai , Wu Chen-Chi , Lan Chung-Yu , Fu Hua-Wen , Yang Lee-Wei
Published: May 2019

To ensure a physicochemically desired sequence motif to adapt a specific type of secondary structures, we compile an α-helix database allowing complicate search patterns to facilitate a data-driven design of therapeutic peptides. Nearly 1.7 million helical peptides in >130 thousand proteins are extracted along with their interacting partners from the protein data bank (PDB). The sequences of the peptides are indexed with patterns and gaps and deposited in our Therapeutic Peptide Design dataBase (TP-DB). We here demonstrate its utility in three medicinal design cases. By our pattern-based search engine but not PHI-BLAST, we can identify a pathogenic protein, Helicobacter pylori neutrophil-activating protein (HP-NAP), a virulence factor of H. pylori, which contains a motif DYKYLE that belongs to the affinity determinant motif DYKXX[DE] of the FLAG-tag and can be recognized by the anti-FLAG M2 antibody. By doing so, the known purification-tag-specific antibody is repurposed into a diagnostic kit for H. pylori. Also by leveraging TP-DB, we discovered a stretch of helical peptide matching the potent membrane-insertion pattern WXXWXXW, elucidated by MD simulations. The newly synthesized peptide has a better minimal inhibitory concentration (MIC) and much lower cytotoxicity against Candida albicans (fungus) than that of previously characterized homologous antimicrobial peptides. In a similar vein, taking the discontinued anchoring residues in the helix-helix interaction interface as the search pattern, TP-DB returns several helical peptides as potential tumor suppressors of hepatocellular carcinoma (HCC) whose helicity and binding affinity were examined by MD simulations. Taken together, we believe that TP-DB and its pattern-based search engine provide a new opportunity for a (secondary-)structure-based design of peptide drugs and diagnostic kits for pathogens without inferring evolutionary homology between sequences sharing the same pattern. TP-DB is made available at http://dyn.life.nthu.edu.tw/design/.
Localization of genetic determinants for pathogenicity of Maize dwarf mosaic virus and Bermudagrass southern mosaic virus
Authors: Mostafavi Neyshabouri Farveh sadat , Yamchi Ahad , Sabbagh Seyed Kazem , Masumi Mahmoud
Published: May 2019

Maize dwarf mosaic virus (MDMV) and Bermuda grass southern mosaic virus (BgSMV) are economically important potyviruses of cereals. BgSMV is very similar in genomic sequence to MDMV, but cannot infect Johnsongrass and is not transmitted by Rhopalosiphum maidis. Comparison of their genomes showed an additional stretch of 90 nucleotides in BgSMV coat protein but not in MDMV. Since the 90-nucleotide region is located in the N-terminal of BgSMV coat protein, it seems to have a role in biological properties such as vector transmission and pathogenicity. Recombinant virus constructs were made with and without the 90 nucleotides using SOEing PCR (MDMV (+90) and BgSMV (−90). Johnsongrass plants inoculated with the wild-type MDMV and recombinant BgSMV (−90) showed mosaic symptoms after 16 and 23 days, respectively, whereas plants inoculated with the wild-type BgSMV and recombinant MDMV (+90) didn’t show any symptoms until three months after inoculation. The qRT-PCR results detected significantly higher levels of BgSMV (−90) and MDMV compared to BgSMV and MDMV (+90), respectively. Also, R. maidis was able to transfer only the wild type MDMV and BgSMV (−90) from infected to healthy plants. These results confirmed that the insertion of the 90-nt region into the coat protein of MDMV affects the pathogenicity of the virus.
Velocity coupling of grid cell modules: stable embedding of a low dimensional variable in a high dimensional neural attractor
Authors: Mosheiff Noga , Burak Yoram
Published: May 2019

Grid cells in the medial entorhinal cortex (mEC) encode position using a distributed representation across multiple neural populations (modules), each possessing a distinct spatial scale. The modular structure of the representation confers the grid cell neural code with large capacity. Yet, the modularity poses significant challenges for the neural circuitry that maintains the representation, and updates it based on self motion. Small incompatible drifts in different modules, driven by noise, can rapidly lead to large, abrupt shifts in the represented position, resulting in catastrophic readout errors. Here we propose a theoretical model of coupled modules. The coupling suppresses incompatible drifts, allowing for a stable embedding of a two dimensional variable (position) in a higher dimensional neural attractor, while preserving the large capacity. We propose that coupling of this type may be implemented by recurrent synaptic connectivity within the mEC with a relatively simple and biologically plausible structure.
Root morphology and exudate availability is shaped by particle size and chemistry in Brachypodium distachyon
Authors: Sasse Joelle , Jordan Jacob S. , DeRaad Markus , Whiting Katherine , Zhalnina Katherina , Northen Trent
Published: May 2019

Root morphology and exudation define a plants sphere of influence in soils, and are in turn shaped by the physiochemical characteristics of soil. We explored how particle size and chemistry of growth substrates affect root morphology and exudation of the model grass Brachypodium distachyon. Root fresh weight and root lengths were correlated with particle size, whereas root number and shoot weight remained constant. Mass spectrometry imaging suggested that both, root length and number shape root exudation. Exudate metabolite profiles detected with liquid chromatography / mass spectrometry were comparable for plants growing in glass beads or sand with various particles sizes, but distinct for plants growing in clay. However, when exudates of clay-grown plants were collected by removing the plants from the substrate, their exudate profile was similar to sand- or glass beads-grown plants. Clay particles sorbed 20% of compounds exuded by clay-grown plants, and 70% of compounds of a defined exudate medium. The sorbed compounds belonged to a range of chemical classes, among them nucleosides/nucleotides, organic acids, sugars, and amino acids. Some of the sorbed compounds could be de-sorbed by a rhizobacterium (Pseudomonas fluorescens WCS415), supporting its growth. We show that root morphology is affected by substrate size, and that root exudation in contrast is not affected by substrate size or chemistry. The availability of exuded compounds, however, depends on the substrate present. These findings further support the critical importance of the physiochemical properties of soils are crucial to consider when investigating plant morphology, exudation, and plant-microbe interactions.
Echo State Network models for nonlinear Granger causality
Authors: Duggento Andrea , Guerrisi Maria , Toschi Nicola
Published: May 2019

While Granger Causality (GC) has been often employed in network neuroscience, most GC applications are based on linear multivariate autoregressive (MVAR) models. However, real-life systems like biological networks exhibit notable non-linear behavior, hence undermining the validity of MVAR-based GC (MVAR-GC). Current nonlinear GC estimators only cater for additive nonlinearities or, alternatively, are based on recurrent neural networks (RNN) or Long short-term memory (LSTM) networks, which present considerable training difficulties and tailoring needs. We define a novel approach to estimating nonlinear, directed within-network interactions through a RNN class termed echo-state networks (ESN), where training is replaced by random initialization of an internal basis based on orthonormal matrices. We reformulate the GC framework in terms of ESN-based models, our ESN-based Granger Causality (ES-GC) estimator in a network of noisy Duffing oscillators, showing a net advantage of ES-GC in detecting nonlinear, causal links. We then explore the structure of ES-GC networks in the human brain employing functional MRI data from 1003 healthy subjects drawn from the human connectome project, demonstrating the existence of previously unknown directed within-brain interactions. ES-GC performs better than commonly used and recently developed GC approaches, making it a valuable tool for the analysis of e.g. multivariate biological networks.
MaxQuant software for ion mobility enhanced shotgun proteomics
Authors: Prianichnikov Nikita , Koch Heiner , Koch Scarlet , Lubeck Markus , Heilig Raphael , Brehmer Sven , Fischer Roman , Cox Jürgen
Published: May 2019

Ion mobility can add a dimension to LC-MS based shotgun proteomics which has the potential to boost proteome coverage, quantification accuracy and dynamic range. Required for this is suitable software that extracts the information contained in the four-dimensional (4D) data space spanned by m/z, retention time, ion mobility and signal intensity. Here we describe the ion mobility enhanced MaxQuant software, which utilizes the added data dimension. It offers an end to end computational workflow for the identification and quantification of peptides, proteins and posttranslational modification sites in LC-IMS-MS/MS shotgun proteomics data. We apply it to trapped ion mobility spectrometry (TIMS) coupled to a quadrupole time-of-flight (QTOF) analyzer. A highly parallelizable 4D feature detection algorithm extracts peaks which are assembled to isotope patterns. Masses are recalibrated with a non-linear m/z, retention time, ion mobility and signal intensity dependent model, based on peptides from the sample. A new matching between runs (MBR) algorithm that utilizes collisional cross section (CCS) values of MS1 features in the matching process significantly gains specificity from the extra dimension. Prerequisite for using CCS values in MBR is a relative alignment of the ion mobility values between the runs. The missing value problem in protein quantification over many samples is greatly reduced by CCS aware MBR.MS1 level label-free quantification is also implemented which proves to be highly precise and accurate on a benchmark dataset with known ground truth. MaxQuant for LC-IMS-MS/MS is part of the basic MaxQuant release and can be downloaded from http://maxquant.org.