bluuebunny/crossref_metadata_2025 huggingface dataset:
Varicella Zoster Virus Alters Expression of Cell Adhesion Proteins in Human Perineurial Cells via Interleukin 6
Authors: Blackmon Anna M , Como Christina N , Bubak Andrew N , Mescher Teresa , Jones Dallas , Nagel Maria A
Published: March 2019

Background

In temporal arteries (TAs) from patients with giant cell arteritis, varicella zoster virus (VZV) is seen in perineurial cells that surround adventitial nerve bundles and form the peripheral nerve-extrafascicular tissue barrier (perineurium). We hypothesized that during VZV reactivation from ganglia, virus travels transaxonally and disrupts the perineurium to infect surrounding cells.

Methods

Mock- and VZV-infected primary human perineurial cells (HPNCs) were examined for alterations in claudin-1, E-cadherin, and N-cadherin. Conditioned supernatant was analyzed for a soluble factor(s) mediating these alterations and for the ability to increase cell migration. To corroborate in vitro findings, a VZV-infected TA was examined.

Results

In VZV-infected HPNCs, claudin-1 redistributed to the nucleus; E-cadherin was lost and N-cadherin gained, with similar changes seen in VZV-infected perineurial cells in a TA. VZV-conditioned supernatant contained increased interleukin 6 (IL-6) that induced E-cadherin loss and N-cadherin gain and increased cell migration when added to uninfected HPNCs; anti-IL-6 receptor antibody prevented these changes.

Conclusions

IL-6 secreted from VZV-infected HPNCs facilitated changes in E- and N-cadherin expression and cell migration, reminiscent of an epithelial-to-mesenchymal cell transition, potentially contributing to loss of perineurial cell barrier integrity and viral spread. Importantly, an anti-IL-6 receptor antibody prevented virus-induced perineurial cell disruption.
TNF receptor signalling in autoinflammatory diseases
Authors: Jarosz-Griffiths Heledd H , Holbrook Jonathan , Lara-Reyna Samuel , McDermott Michael F
Published: March 2019

Autoinflammatory syndromes are a group of disorders characterized by recurring episodes of inflammation as a result of specific defects in the innate immune system. Patients with autoinflammatory disease present with recurrent outbreaks of chronic systemic inflammation that are mediated by innate immune cells, for the most part. A number of these diseases arise from defects in the tumour necrosis factor receptor (TNFR) signalling pathway leading to elevated levels of inflammatory cytokines. Elucidation of the molecular mechanisms of these recently defined autoinflammatory diseases has led to a greater understanding of the mechanisms of action of key molecules involved in TNFR signalling, particularly those involved in ubiquitination, as found in haploinsufficiency of A20 (HA20), otulipenia/OTULIN-related autoinflammatory syndrome (ORAS) and linear ubiquitin chain assembly complex (LUBAC) deficiency. In this review, we also address other TNFR signalling disorders such as TNFR-associated periodic syndrome (TRAPS), RELA haploinsufficiency, RIPK1-associated immunodeficiency and autoinflammation, X-linked ectodermal dysplasia and immunodeficiency (X-EDA-ID) and we review the most recent advances surrounding these diseases and therapeutic approaches currently used to target these diseases. Finally, we explore therapeutic advances in TNF-related immune-based therapies and explore new approaches to target disease-specific modulation of autoinflammatory diseases.
Close-up view of an ongoing merger between the NGC 4839 group and the Coma cluster – a post-merger scenario
Authors: Lyskova N , Churazov E , Zhang C , Forman W , Jones C , Dolag K , Roediger E , Sheardown A
Published: March 2019

We study a merger of the NGC 4839 group with the Coma cluster using X-ray observations from the XMM–Newton and Chandra telescopes. X-ray data show two prominent features: (i) a long (∼600 kpc in projection) and bent tail of cool gas trailing (towards south-west) the optical centre of NGC 4839, and (ii) a ‘sheath’ region of enhanced X-ray surface brightness enveloping the group, which is due to hotter gas. While at first glance the X-ray images suggest that we are witnessing the first infall of NGC 4839 into the Coma cluster core, we argue that a post-merger scenario provides a better explanation of the observed features and illustrate this with a series of numerical simulations. In this scenario, the tail is formed when the group, initially moving to the south-west, reverses its radial velocity after crossing the apocenter, the ram pressure ceases and the ram pressure-displaced gas falls back towards the centre of the group and overshoots it. Shortly after the apocenter passage, the optical galaxy, dark matter, and gaseous core move in a north-east direction, while the displaced gas continues moving to the south-west. The ‘sheath’ is explained as being due to interaction of the re-infalling group with its own tail of stripped gas mixed with the Coma gas. In this scenario, the shock, driven by the group before reaching the apocenter, has already detached from the group and would be located close to the famous relic to the south-west of the Coma cluster.
The role of convection in determining the ejection efficiency of common envelope interactions
Authors: Wilson E C , Nordhaus J
Published: March 2019

A widely used method for parametrizing the outcomes of common envelopes (CEs) involves defining an ejection efficiency, $\bar{\alpha }_{\mathrm{eff}}$, that represents the fraction of orbital energy used to unbind the envelope as the orbit decays. Given $\bar{\alpha }_{\mathrm{eff}}$, a prediction for the post-CE orbital separation is possible with knowledge of the energy required to unbind the primary’s envelope from its core. Unfortunately, placing observational constraints on $\bar{\alpha }_{\mathrm{eff}}$ is challenging as it requires knowledge of the primary’s structure at the onset of the CE phase. Numerical simulations have also had difficulties reproducing post-CE orbital configurations as they leave extended, but still bound, envelopes. Using detailed stellar interior profiles, we calculate $\bar{\alpha }_{\mathrm{eff}}$ values for a matrix of primary-companion mass pairs when the primary is at maximal extent in its evolution. We find that the ejection efficiency is most sensitive to the properties of the surface-contact convective region (SCCR). In this region, the convective transport time-scales are often short compared to orbital decay time-scales, thereby allowing the star to effectively radiate orbital energy and thus lower $\bar{\alpha }_{\mathrm{eff}}$. The inclusion of convection in numerical simulations of CEs may aid ejection without the need for additional energy sources as the orbit must shrink substantially further before the requisite energy can be tapped to drive ejection. Additionally, convection leads to predicted post-CE orbital periods of less than a day in many cases, an observational result that has been difficult to reproduce in population studies where $\bar{\alpha }_{\mathrm{eff}}$ is taken to be constant. Finally, we provide a simple method to calculate $\bar{\alpha }_{\mathrm{eff}}$ if the properties of the SCCR are known.
The ultracool helium-atmosphere white dwarf companion of PSR J0740+6620?
Authors: Beronya D M , Karpova A V , Kirichenko A Yu , Zharikov S V , Zyuzin D A , Shibanov Yu A , Cabrera-Lavers A
Published: March 2019

We report detection of the likely companion of the binary millisecond pulsar (MSP) J0740+6620 with the Gran Telescopio Canarias in the r′ and i′ bands. The position of the detected starlike source coincides with the pulsar coordinates within the 1σ uncertainty of ≈0.2 arcsec. Its magnitudes are r′ = 26.51 ± 0.17 and i′ = 25.49 ± 0.15. Comparing the data with the white dwarf (WD) cooling tracks suggests that it can be an ultracool helium-atmosphere WD with the temperature ≲3500 K and cooling age ≳5 Gyr. The age is consistent with the pulsar characteristic age corrected for kinematic effects. This is the reddest source among known WD companions of MSPs. Detection of the source in other bands would be useful to clarify its properties and nature.
The black hole X-ray transient Swift J1357.2–0933 as seen with Swift and NuSTAR during its 2017 outburst
Authors: Beri Aru , Tetarenko B E , Bahramian A , Altamirano Diego , Gandhi Poshak , Sivakoff G R , Degenaar N , Middleton M J , Wijnands R , Hernándz Santisteban J V , Paice John A
Published: March 2019

We report on observations of black hole Swift J1357.2–0933, a member of the modest population of very faint X-ray transients. This source has previously shown intense dips in the optical light curve, a phenomena that has been linked to the existence of a ‘unique toroidal structure’ in the inner region of the disc, seen at a high inclination. Our observations, carried out by the Neil Gehrels Swift and NuSTAR X-ray observatories, do not show the presence of intense dips in the optical light curves. We find that the X-ray light curves do not show any features that would straightforwardly support an edge-on configuration or high inclination configuration of the orbit. This is similar to what was seen in the X-ray observations of the source during its 2011 outburst. Moreover, the broad-band spectra were well described with an absorbed power-law model without any signatures of cut-off at energies above 10 keV, or any reflection from the disc or the putative torus. Thus, the X-ray data do not support the unique ‘obscuring torus’ scenario proposed for J1357. We also performed a multiwavelength study using the data of X-ray telescope and Ultraviolet/Optical Telescope aboard Swift, taken during the ∼4.5 months duration of the 2017 outburst. This is consistent with what was previously inferred for this source. We found a correlation between the simultaneous X-ray and ultraviolet/optical data and our study suggests that most of the reprocessed flux must be coming out in the ultraviolet.
Hidden IR structures in NGC 40: signpost of an ancient born-again event
Authors: Toalá J A , Ramos-Larios G , Guerrero M A , Todt H
Published: March 2019

We present the analysis of infrared (IR) observations of the planetary nebula NGC 40 together with spectral analysis of its [WC]-type central star HD 826. Spitzer IRS observations were used to produce spectral maps centred at polycyclic aromatic hydrocarbons (PAH) bands and ionic transitions to compare their spatial distribution. The ionic lines show a clumpy distribution of material around the main cavity of NGC 40, with the emission from [Ar ii] being the most extended, whilst the PAHs show a rather smooth spatial distribution. Analysis of ratio maps shows the presence of a toroidal structure mainly seen in PAH emission, but also detected in a Herschel PACS 70 $\mu$m image. We argue that the toroidal structure absorbs the UV flux from HD 826, preventing the nebula to exhibit lines of high-excitation levels as suggested by previous authors. We discuss the origin of this structure and the results from the spectral analysis of HD 826 under the scenario of a late thermal pulse.
WISDOM project – IV. A molecular gas dynamical measurement of the supermassive black hole mass in NGC 524
Authors: Smith Mark D , Bureau Martin , Davis Timothy A , Cappellari Michele , Liu Lijie , North Eve V , Onishi Kyoko , Iguchi Satoru , Sarzi Marc
Published: March 2019

We present high angular resolution (0.3 arcsec or $37\, \mathrm{pc}$) Atacama Large Millimeter/submillimeter Array observations of the CO(2–1) line emission from a central disc in the early-type galaxy NGC 524. This disc is shown to be dynamically relaxed, exhibiting ordered rotation about a compact $1.3\, \mathrm{mm}$ continuum source, which we identify as emission from an active supermassive black hole (SMBH). There is a hole at the centre of the disc slightly larger than the SMBH sphere of influence. An azimuthal distortion of the observed velocity field is found to be due to either a position angle warp or radial gas flow over the inner 2${^{\prime\prime}_{.}}$5. By forward-modelling the observations, we obtain an estimate of the SMBH mass of $4.0^{+3.5}_{-2.0}\times 10^8\,$ M⊙, where the uncertainties are at the 3σ level. The uncertainties are dominated by the poorly constrained inclination and the stellar mass-to-light ratio of this galaxy, and our measurement is consistent with the established correlation between SMBH mass and stellar velocity dispersion. Our result is roughly half that of the previous stellar dynamical measurement, but is consistent within the uncertainties of both. We also present and apply a new tool for modelling complex molecular gas distributions.
Conflict
Authors: Shortland Neil D. , Alison Laurence J. , Moran Joseph M.
Published: March 2019

This book is about decisions in military conflict and the psychological conflict they cause. By drawing on interviews conducted with real soldiers about real situations they faced, the book explores how soldiers choose between seemingly impossible options for which all outcomes appear horrendous. Their vivid and sometimes upsetting stories were part of the experience of war and became part of their identity. This book describes the processes that make choice selection so difficult; the psychology of decisional conflict; and the immediate, short-term, and longer term behavioral consequences of these actions. Special attention is directed to the concept of “decision inertia”—one of several kinds of “failures to act” in which decision-makers are unable to calculate and/or commit to a least-worst course of action. By referring to many real cases, readers are invited to consider their own responses to choosing between difficult options in order to help them understand what it might feel like when faced with making a least-worst decision in war.
Outsiders
Authors: Kramer Zachary
Published: March 2019

What is the future of civil rights? Like a living thing, discrimination evolves, adapting to its time. As discrimination becomes more individualized, as difference becomes more pronounced, we need a civil rights that is attuned to the way identity is performed today. Outsiders: Why Difference Is the Future of Civil Rights is filled with stories that demand attention, stories of people whose search for identity has cast them to the margins. Their stories reveal that we need to refresh our vision of civil rights. Instead of dealing in protected traits, civil rights law should take its cue from religious discrimination law. What we need is a right to personality. The critical question driving equality law should be whether there is space to accommodate a person’s identity. Outsiders: Why Difference Is the Future of Civil Rights seeks to change the way we think about identity, equality, and discrimination. It argues that difference, not sameness, should be the cornerstone of civil rights. Mixing doctrine and theory, art, and personal narrative, Outsiders: Why Difference Is the Future of Civil Rights argues for a civil rights for everyone. Being different is universal. We are all outsiders.
Implicit Stereotypes: Evidence from Teachers’ Gender Bias*
Authors: Carlana Michela
Published: March 2019

I study whether exposure to teacher stereotypes, as measured by the Gender-Science Implicit Association Test, affects student achievement. I provide evidence that the gender gap in math performance, defined as the score of boys minus the score of girls in standardized tests, substantially increases when students are assigned to math teachers with stronger gender stereotypes. Teacher stereotypes induce girls to underperform in math and self-select into less demanding high schools, following the track recommendation of their teachers. These effects are at least partially driven by lower self-confidence on math ability of girls exposed to gender-biased teachers. Stereotypes impair the test performance of girls, who end up failing to achieve their full potential. I do not detect statistically significant effects on student outcomes of literature teacher stereotypes.
Sums of Linear Transformations in Higher Dimensions
Authors: Mudgal Akshat
Published: March 2019

In this paper, we prove the following two results. Let d be a natural number and q, s be co-prime integers such that 1<qs<|q|. Then there exists a constant δ>0 depending only on q, s and d such that for any finite subset A of ℝd that is not contained in a translate of a hyperplane, we have |q⋅A+s⋅A|≥(|q|+|s|+2d−2)|A|−Oq,s,d(|A|1−δ).

The main term in this bound is sharp and improves upon an earlier result of Balog and Shakan. Secondly, let L∈GL2(ℝ) be a linear transformation such that L does not have any invariant one-dimensional subspace of ℝ2. Then, for all finite subsets A of ℝ2, we have |A+L(A)|≥4|A|−O(|A|1−δ), for some absolute constant δ>0. The main term in this result is sharp as well.
MicroRNA-21-5p as a novel therapeutic target for osteoarthritis
Authors: Wang Xiao-bo , Zhao Feng-chao , Yi Lin-hong , Tang Jin-long , Zhu Zheng-ya , Pang Yong , Chen Ye-shuai , Li Dong-ya , Guo Kai-jin , Zheng Xin
Published: March 2019

Objective

Growing evidence indicates that microRNAs (miRNA) play a critical role in the pathogenesis of OA, and overexpressing or silencing miRNA expression in OA models can contribute to the development of miRNA-based therapeutics. The objective of this study was to determine whether intra-articular injection of miRNA can inhibit OA progression.

Methods

The miRNA expression profile was determined in OA cartilage tissues and controls. Functional analysis of the miRNAs on extracellular matrix degradation was performed after miRNA mimic or inhibitor transfection. Luciferase reporter assays and western blotting were employed to determine miRNA targets. To investigate the functional mechanism of miR-21-5p in OA development, miR-21-5pfl/flCol2a1-CreER and wild-type mice were subject to surgical destabilization of the medial meniscus. Therapeutically, wild-type mice undergoing surgical destabilization of the medial meniscus were treated with intra-articular injection of agomir- and antagomir-21-5p.

Results

We found that expression of miR-21-5p was significantly up-regulated in OA cartilage tissues. The articular cartilage degradation of miR-21-5p conditional knockout mice was significantly alleviated compared with that of wild-type mice in spontaneous and destabilization of the medial meniscus models. Through gain-of-function and loss-of-function studies, miR-21-5p was shown to significantly affect matrix synthesis genes expression, and chondrocyte proliferation and apoptosis. Further, fibroblast growth factor 18 (FGF18) was identified as a target of miR-21-5p. Intra-articular injection of antagomir-21-5p significantly attenuated the severity of experimental OA. Clinically, FGF18 expression level was correlated with miR-21-5p expression and a modified Mankin scale.

Conclusion

Our findings reveal a miRNA functional pathway important for OA development, highlighting miRNA-21-5p silencing as an attractive therapeutic regimen in future clinical trials involving patients with OA.
Patterns, Profiles, and Parsimony: dissecting transcriptional signatures from minimal single-cell RNA-seq output with SALSA
Authors: Lozoya Oswaldo A. , McClelland Kathryn S. , Papas Brian , Li Jian-Liang , Yao Humphrey H-C
Published: March 2019

Single-cell RNA sequencing (scRNA-seq) technologies have precipitated the development of bioinformatic tools to reconstruct cell lineage specification and differentiation processes with single-cell precision. However, start-up costs and data volumes currently required for statistically reproducible insight remain prohibitively expensive, preventing scRNA-seq technologies from becoming mainstream. Here, we introduce single-cell amalgamation by latent semantic analysis (SALSA), a versatile workflow to address those issues from a data science perspective. SALSA is an integrative and systematic methodology that introduces matrix focusing, a parametric frequentist approach to identify fractions of statistically significant and robust data within single-cell expression matrices. SALSA then transforms the focused matrix into an imputable mix of data-positive and data-missing information, projects it into a latent variable space using generalized linear modelling, and extracts patterns of enrichment. Last, SALSA leverages multivariate analyses, adjusted for rates of library-wise transcript detection and cluster-wise gene representation across latent patterns, to assign individual cells under distinct transcriptional profiles via unsupervised hierarchical clustering. In SALSA, cell type assignment relies exclusively on genes expressed both robustly, relative to sequencing noise, and differentially, among latent patterns, which represent best-candidates for confirmatory validation assays. To benchmark how SALSA performs in experimental settings, we used the publicly available 10X Genomics PBMC 3K dataset, a pre-curated silver standard comprising 2,700 single-cell barcodes from human frozen peripheral blood with transcripts aligned to 16,634 genes. SALSA identified at least 7 distinct transcriptional profiles in PBMC 3K based on <500 differentially expressed Profiler genes determined agnostically, which matched expected frequencies of dominant cell types in peripheral blood. We confirmed that each transcriptional profile inferred by SALSA matched known expression signatures of blood cell types based on surveys of 15 landmark genes and other supplemental markers. SALSA was able to resolve transcriptional profiles from only ∼9% of the total count data accrued, spread across <0.5% of the PBMC 3K expression matrix real estate (16,634 genes × 2,700 cells). In conclusion, SALSA amalgamates scRNA-seq data in favor of reproducible findings. Furthermore, by extracting statistical insight at lower experimental costs and computational workloads than previously reported, SALSA represents an alternative bioinformatics strategy to make single-cell technologies affordable and widespread.
TraitCorr – correlating gene expression measurements with phenotypic data
Authors: Nussbaumer Thomas , Wagner Christian , Heidari Parviz
Published: March 2019

Today, transcriptomes and microarrays can be generated and analysed in high quantity. In addition, experiments often include descriptive information about each sample which needs to be compared to the gene expression profiles. The understanding of the relationships between gene expression and phenotype is introduced as new challenge in system biology. Combining expression (RNA-seq and microarray) and phenotype data could reveal the role or effects of each gene on traits. To address all these needs, the user-interface TraitCorr was developed which allows to determine genes that are significantly correlating with a selected trait. Furthermore, it allows to determine significantly correlated genes among different traits and provides visualisation and analysis possibilities.
Optimised prophylactic vaccination in metapopulations
Authors: Teo Mingmei , Bean Nigel , Ross Joshua V.
Published: March 2019

A highly effective method for controlling the spread of an infectious disease is vaccination. However, there are many situations where vaccines are in limited supply. The ability to determine, under this constraint, a vaccination strategy which minimises the number of people that become infected over the course of a potential epidemic is essential. Two questions naturally arise: when is it best to allocate vaccines, and to whom should they be allocated? We address these questions in the context of metapopulation models of disease spread. We discover that it is optimal to distribute all vaccines prophylactically, rather than withholding until infection is introduced. For small metapopulations, we provide a method for determining the optimal allocation. As the optimal strategy becomes computationally intensive to obtain when the population size increases, we detail an approximation method to determine an approximately optimal vaccination scheme. Through comparisons with other strategies in the literature, we find that our approximate strategy is superior.
Hypothesis, analysis and synthesis: it’s all Greek to me!
Authors: Iliopoulos Ioannis , Ananiadou Sophia , Danchin Antoine , Ioannidis John P. A. , Katsikis Peter D. , Ouzounis Christos A. , Promponas Vasilis J.
Published: March 2019

The linguistic foundations of science and technology have relied on a range of terms many of which are borrowed from ancient languages, a known but little researched fact from a statistical perspective. Precise definitions and novel concepts are often crafted with those — frequently used — terms, yet their etymology from Greek or Latin might not always be fully appreciated. Herein, we demonstrate that frequently used terms span almost the entire PubMed®database, while a handful of terms of Greek origin retrieve 80% of all entries. We argue that the etymology of those critical terms needs to be fully grasped to ensure correct use, in conjunction with other concepts. We further propose a number of terms for genomics, using prepositions that can accurately define subtle sub-disciplines of this ever-expanding field. Finally, we invite commentary by both the science community and the humanities, for possible adoption of suggested terms, not least to avoid inaccurate usage or inappropriate notions that may compromise clarity of meaning.
The Microbial Metagenome and Tissue Composition in Mice with Microbiome-Induced Reductions in Bone Strength
Authors: Guss Jason D , Taylor Erik , Rouse Zach , Roubert Sebastian , Higgins Catherine H , Thomas Corinne J , Baker Shefford P , Vashishth Deepak , Donnelly Eve , Shea M Kyla , Booth Sarah L , Bicalho Rodrigo C , Hernandez Christopher J
Published: March 2019

The genetic components of microbial species that inhabit the body are known collectively as the microbiome. Modifications to the microbiome have been implicated in disease processes throughout the body and have recently been shown to influence bone. Prior work has associated changes in the microbial taxonomy (phyla, class, species, etc.) in the gut with bone phenotypes but has provided limited information regarding mechanisms. With the goal of achieving a more mechanistic understanding of the effects of the microbiome on bone, we perform a metagenomic analysis of the gut microbiome that provides information on the functional capacity of the microbes (all microbial genes present) rather than only characterizing the microbial taxa. Male C57Bl/6 mice were subjected to disruption of the gut microbiota (ΔMicrobiome) using oral antibiotics (from 4-16 weeks of age) or remained untreated (n=6-7/group). Disruption of the gut microbiome in this manner has been shown to lead to reductions in tissue mechanical properties and whole bone strength in adulthood with only minor changes in bone geometry and density. ΔMicrobiome led to modifications in the abundance of microbial genes responsible for the synthesis of the bacterial cell wall and capsule; bacterially synthesized carbohydrates; and bacterially synthesized vitamins (B and K) (p <0.01). Follow up analysis focused on vitamin K, a factor that has previously been associated with bone health. The vitamin K content of the cecum, liver and kidneys was primarily microbe-derived forms of vitamin K (menaquinones) and was decreased by 32-66% in ΔMicrobiome mice compared to untreated animals (p < 0.01). Bone mineral crystallinity was decreased (p=0.01) was decreased in ΔMicrobiome mice (p < 0.001) and matrix carbonate-phosphoate ratio was increased. This study illustrates the use of metagenomic analysis to link the microbiome to bone phenotypes and implicates microbially synthesized vitamin-K as a regulator of bone matrix quality.
Large-scale multivariate multi-ancestry Interaction analyses point towards different genetic mechanisms by population and exposure
Authors: Laville Vincent , Majarian Timothy , Sung Yun J , Schwander Karen , Feitosa Mary F , Chasman Daniel , Bentley Amy R , Rotimi Charles N , Cupples L Adrienne , de Vries Paul S , Brown Michael R , Morrison Alanna C , Kraja Aldi T , Province Mike , Gu C. Charles , Gauderman James , Rao DC , Manning Alisa , Aschard Hugues ,   on behalf of the CHARGE Gene-Lifestyle Interactions Working Group
Published: March 2019

TheCHARGE Gene-Lifestyle Interactions Working Groupis a unique initiative formed to improve our understanding of the role and biological significance of gene-environment interactions in human traits and diseases. The consortium published several multi-ancestry genome-wide interaction studies (GWIS) involving up to 610,475 individuals for three lipids and four blood pressure traits while accounting for interaction effects with drinking and smoking exposures. Here we used GWIS summary statistics from these studies to decipher potential differences in genetic associations and GxE interactions across phenotype-exposure-population trios, and to derive new insights on the potential mechanistic underlying GxE through in-silico functional analyses. Our comparative analysis shows first that interaction effects likely contribute to the commonly reported ancestry-specific genetic effect in complex traits, and second, that some phenotype-exposures pairs are more likely to benefit from a greater detection power when accounting for interactions. It also highlighted a negligible correlation between main and interaction effects, providing material for future methodological development and biological discussions. We also estimated contributions to phenotypic variance, including in particular the genetic heritability conditional on the exposure, and heritability partitioned across a range of functional annotations and cell-types. In these analyses, we found multiple instances of heterogeneity of functional partitions between exposed and unexposed individuals, providing new evidence for likely exposure-specific genetic pathways. Finally, along this work we identified potential biases in methods used to jointly meta-analyses genetic and interaction effects. We performed a series of simulations to characterize these limitations and to provide the community with guideline for future GxE studies.
Multi-site sampling and risk prioritization reveals the public health relevance of antibiotic resistance genes found in wastewater environments
Authors: Dai Chengzhen L. , Duvallet Claire , Zhang An Ni , Matus Mariana G. , Ghaeli Newsha , Park Shinkyu , Endo Noriko , Isazadeh Siavash , Jamil Kazi , Ratti Carlo , Alm Eric J.
Published: March 2019

The spread of bacterial antibiotic resistance across human and environmental habitats is a global public health challenge. Wastewater has been implicated as a major source of antibiotic resistance in the environment, as it carries resistant bacteria and resistance genes from humans into natural ecosystems. However, different wastewater environments and antibiotic resistance genes in wastewater do not all present the same level of risk to human health. In this study, we investigate the public health relevance of antibiotic resistance found in wastewater by combining metagenomic sequencing with risk prioritization of resistance genes, analyzing samples across urban sewage system environments in multiple countries. We find that many of the resistance genes commonly found in wastewater are not readily present in humans. Ranking antibiotic resistance genes based on their potential pathogenicity and mobility reveals that most of the resistance genes in wastewater are not clinically relevant. Additionally, we show that residential wastewater resistomes pose greater risk to human health than those in wastewater treatment plant samples, and that residential wastewater can be as risky as hospital effluent. Across countries, differences in antibiotic resistance in residential wastewater can, in some cases, reflect differences in antibiotic drug consumption. Finally, we find that the flow of antibiotic resistance genes is influenced by geographical distance and environmental selection. Taken together, we demonstrate how different analytical approaches can provide greater insights into the public health relevance of antibiotic resistance in wastewater.
A knowledge–based scoring function to assess the stability of quaternary protein assemblies
Authors: Dhawanjewar Abhilesh S. , Roy Ankit , Madhusudhan M.S.
Published: March 2019

Motivation

Elucidation of protein-protein interactions is a necessary step towards understanding the complete repertoire of cellular biochemistry. Given the enormity of the problem, the expenses and limitations of experimental methods, it is imperative that this problem is tackled computationally. In silico predictions of protein interactions entail sampling different conformations of the purported complex and then scoring these to assess for interaction viability. In this study we have devised a new scheme for scoring protein-protein interactions.

Results

Our method, PIZSA (Protein Interaction Z Score Assessment) is a binary classification scheme for identification of stable protein quaternary assemblies (binders/non-binders) based on statistical potentials. The scoring scheme incorporates residue-residue contact preference on the interface with per residue-pair atomic contributions and accounts for clashes. PIZSA can accurately discriminate between native and non-native structural conformations from protein docking experiments and outperform other recently published scoring functions, demonstrated through testing on a benchmark set and the CAPRI Score_set. Though not explicitly trained for this purpose, PIZSA potentials can identify spurious interactions that are artefacts of the crystallization process.

Availability

PIZSA is implemented as awebserverat http://cospi.iiserpune.ac.in/pizsa/.

Contact

madhusudhan@iiserpune.ac.in
Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies
Authors: Gurbatri Candice , Coker Courtney , Hinchliffe Taylor E. , Lia Ioana , Castro Samuel , Treuting Piper M. , Arpaia Nicholas , Danino Tal
Published: March 2019

Immunotherapies such as checkpoint inhibitors have revolutionized cancer therapy yet lead to a multitude of immune-related adverse events, suggesting the need for more targeted delivery systems. Due to their preferential colonization of tumors and advances in engineering capabilities from synthetic biology, microbes are a natural platform for the local delivery of cancer therapeutics. Here, we present an engineered probiotic bacteria system for the controlled production and release of novel immune checkpoint targeting nanobodies from within tumors. Specifically, we engineered genetic lysis circuit variants to effectively release nanobodies and safely control bacteria populations. To maximize therapeutic efficacy of the system, we used computational modeling coupled with experimental validation of circuit dynamics and found that lower copy number variants provide optimal nanobody release. Thus, we subsequently integrated the lysis circuit operon into the genome of a probioticE. coliNissle 1917, and confirmed lysis dynamics in a syngeneic mouse model usingin vivobioluminescent imaging. Expressing a nanobody against PD-L1 in this strain demonstrated enhanced efficacy compared to a plasmid-based lysing variant, and similar efficacy to a clinically relevant monoclonal antibody against PD-L1. Expanding upon this therapeutic platform, we produced a nanobody against cytotoxic T-lymphocyte associated protein -4 (CTLA-4), which reduced growth rate or completely cleared tumors when combined with a probiotically-expressed PD-L1 nanobody in multiple syngeneic mouse models. Together, these results demonstrate that our engineered probiotic system combines innovations in synthetic biology and immunotherapy to improve upon the delivery of checkpoint inhibitors.

SENTENCE SUMMARY

We designed a probiotic platform to locally deliver checkpoint blockade nanobodies to tumors using a controlled lysing mechanism for therapeutic release.
Occurrence ofCryptosporidium hominisin cattle bordering the Lake Mburo National Park in Kiruhura district, Western Uganda
Authors: Witto Sarah Gift , Kankya Clovice , Kazibwe Anne , Akurut Gloria , Ochwo Sylvester
Published: March 2019

Background

Cryptosporidiumis an emerging opportunistic zoonotic pathogen that causes diarrheal illness in a wide range of hosts including livestock and humans. Globally there is exponential increase in livestock production to meet the worlds’ demand for animal protein as well as for financial reasons. However, there is raised concern of the public health threat due to contamination of the environment by livestock waste carrying zoonotic pathogens such asCryptosporidium. This study set out to establish the prevalence ofCryptosporidiumas well as the circulating genotypes in order to elucidate the potential role of cattle in the spread of human cryptosporidiosis. We collected rectal coprological samples from 363 cattle in 11 households in Kiruhura district, Southwestern Uganda. The samples were screened for presence ofCryptosporidiumoocysts using the phenol auramine staining method followed by fluorescent microscopy. DNA was then extracted from the microscopy positive samples and the COWP gene amplified using PCR. Amplified gene products were sequenced and subjected to phylogenetic analysis.

Results

The overall animal level prevalence ofCryptosporidiumwas 7.7% (95% CI: 5.1-10.9), and herd level prevalence was 33.3% (95% CI: 18.5-52.2). We found a statistically significant difference (p=0.02) between infection in bulls as compared to cows. There was however no significant difference in the prevalence among the different cattle breeds sampled, with the following prevalence’s observed in Crosses 9.2%, Ankole 5.7%, Friesian 7.1%, and Boran 2.8% respectively. The COWP gene was successfully amplified from 20 of the 28 microscopy positive samples. All the sequenced DNA amplicons were confirmed to beC. hominis, with 98%-100% identity to sequences in the GenBank.C. hominiswas the only genotype isolated from this study, further asserting that cattle could be a potential high risk source of human cryptosporidiosis.

Conclusion

This study represents the first time naturally occurringC. hominishas been isolated from cattle in Uganda. This further provides evidence of cattle possibly being biological reservoirs forC. hominisand cattle could be a potential high risk source of human cryptosporidiosis.
Isolating the key factors defining the magnitude of hippocampal neurogenesis’ effects on anxiety, memory and pattern separation
Authors: França Thiago F. A.
Published: March 2019

In this paper, I analyze the hypothesis that hippocampal neurogenesis (HN) exerts its effects on behavior via activation of inhibitory circuits in the hippocampus. Using a very simple mathematical model (half-borrowed from biochemistry) to aid the reasoning, I show that the key factors determining the magnitude of HN’s effects on behavior are: the baseline levels of HN in the animal, the efficiency of the animal’s inhibitory circuits, the strength/intensity of the stimulus presented to the animal and how much accuracy the behavioral task requires from the information contained in the hippocampal representations. Taken together, those factors can help explain patterns observed in the behavioral results for memory, pattern separation and anxiety. The conclusions of the analysis suggest that HN’s effects on inhibitory circuits can explain the impact of neurogenesis in both emotion and cognition and provide a framework to interpret future studies with rodents and possibly with other species as well.
Slide-seq: A Scalable Technology for Measuring Genome-Wide Expression at High Spatial Resolution
Authors: Rodriques Samuel G. , Stickels Robert R. , Goeva Aleksandrina , Martin Carly A. , Murray Evan , Vanderburg Charles R. , Welch Joshua , Chen Linlin M. , Chen Fei , Macosko Evan Z.
Published: March 2019

The spatial organization of cells in tissue has a profound influence on their function, yet a high-throughput, genome-wide readout of gene expression with cellular resolution is lacking. Here, we introduce Slide-seq, a highly scalable method that enables facile generation of large volumes of unbiased spatial transcriptomes with 10 µm spatial resolution, comparable to the size of individual cells. In Slide-seq, RNA is transferred from freshly frozen tissue sections onto a surface covered in DNA-barcoded beads with known positions, allowing the spatial locations of the RNA to be inferred by sequencing. To demonstrate Slide-seq’s utility, we localized cell types identified by large-scale scRNA-seq datasets within the cerebellum and hippocampus. We next systematically characterized spatial gene expression patterns in the Purkinje layer of mouse cerebellum, identifying new axes of variation across Purkinje cell compartments. Finally, we used Slide-seq to define the temporal evolution of cell-type-specific responses in a mouse model of traumatic brain injury. Slide-seq will accelerate biological discovery by enabling routine, high-resolution spatial mapping of gene expression.

One Sentence Summary

Slide-seq measures genome-wide expression in complex tissues at 10-micron resolution.
Theta phase synchrony is sensitive to corollary discharge abnormalities in early illness schizophrenia but not in the clinical high-risk syndrome
Authors: Ford Judith M. , Roach Brian J. , Loewy Rachel L. , Stuart Barbara K. , Ford Judith M. , Mathalon Daniel H.
Published: March 2019

Background

Across the animal kingdom, responses in auditory cortex are dampened during vocalizing compared to passive listening, reflecting the action of the corollary discharge mechanism. In humans, it is seen as suppression of the EEG-based N1 event-related potential, with less N1-suppression seen in people with schizophrenia and those at clinical high risk (CHR) for psychosis. Because N1 is an admixture of theta (4-7Hz) power and phase synchrony, we asked which is responsible for N1 effects and if they outperform the sensitivity of N1 to corollary discharge and schizophrenia.

Methods

Theta phase and power values were extracted from EEG data acquired from CHR youth (n=71), early illness schizophrenia patients (ESZ; n=84), and healthy controls (HC; n=103) as they said /ah/ (Talk) and then listened to the sounds played back (Listen). A principal components analysis extracted theta inter-trial coherence (ITC; phase consistency) and event related spectral power, peaking in the N1 latency range.

Results

Theta ITC-suppression (Cohen d=1.46) was greater than N1-suppression in HC (Cohen d=.63). Both were both reduced in ESZ, but only N1-suppression was reduced in CHR. When deprived of the variance shared with theta-ITC suppression, N1-suppression was no longer sensitive to HC vs. ESZ or HC vs. CHR group differences. Deficits in theta ITC-suppression were correlated with delusions (p=.007) in ESZ. Suppression of theta power was not affected by Group.

Conclusions

Theta ITC-suppression may provide a simpler assay of the corollary discharge mechanism than N1-suppression. Deficits in circuits that generate low frequency oscillations may be an important component of schizophrenia.
Dissection of the Hydrogen Metabolism of the EnterobacteriumTrabulsiella guamensis: Identification of a Formate-Dependent and Essential Formate Hydrogenlyase Complex Exhibiting Phylogenetic Similarity to Complex I
Authors: Lindenstrauß Ute , Pinske Constanze
Published: March 2019

Trabulsiella guamensisis a non-pathogenic enterobacterium that was isolated from a vacuum cleaner on the island of Guam. It has one H2-oxidizing Hyd-2-type hydrogenase (Hyd), and encodes a H2-evolving Hyd that is most similar to the uncharacterizedEscherichia coliformate hydrogenlyase (FHL-2Ec) complex. The FHL-2Tgcomplex is predicted to have 5 membrane-integral and between 4-5 cytoplasmic subunits. We could show that FHL-2Tgcomplex catalyses the disproportionation of formate to CO2and H2. FHL-2Tghas an activity similar to theE. coliFHL-1Eccomplex in H2-evolution from formate, but the complex appears more labile upon cell lysis. Cloning of the entire 13 kbp FHL-2Tgoperon in the heterologousE. colihost has now enabled us to prove FHL-2Tgactivity unambiguously and allowed us to characterize the FHL-2Tgcomplex biochemically. Although the formate dehydrogenase (FdhH) genefdhFis not encoded in the operon, the FdhH is part of the complex and FHL-2Tgactivity was dependent on the presence ofE. coliFdhH. Also, in contrast toE. coli, T. guamensiscan ferment the alternative carbon source cellobiose, and we further investigated the participation of both the H2-oxidizing Hyd-2Tgand the H2-forming FHL-2Tgunder these conditions.

Importance

Biological H2-production presents an attractive alternative for fossil fuels. But in order to compete with conventional H2-production methods, the process requires our understanding on the molecular level. FHL complexes are efficient H2-producers and the prototype FHL-1Eccomplex inE. coliis well studied. This paper presents the first biochemical characterisation of an FHL-2-type complex. The data presented here will enable us to solve the long-standing mystery of the FHL-2Eccomplex, allow a first biochemical characterisation ofT. guamensis’s fermentative metabolism and establish this enterobacterium as model organism for FHL-dependent energy conservation.
Parasite histones mediate leak and coagulopathy in cerebral malaria
Authors: Moxon Christopher A , Alhamdi Yasir , Storm Janet , Toh Julien MH , Ko Joo Yeon , Murphy George , Taylor Terrie E , Seydel Karl B , Kampondeni Sam , Potchen Michael , O’Donnell James S. , O’Regan Niamh , Wang Guozheng , García-Cardeña Guillermo , Molyneux Malcolm , Craig Alister , Abrams Simon T , Toh Cheng-Hock
Published: March 2019

Coagulopathy and leak, specific to the brain vasculature, are central pathogenetic components of cerebral malaria (CM). It is unclear how the parasite, Plasmodium falciparum, triggers these processes. Extracellular histones, released from damaged host cells, bind to cell membranes and cause coagulation activation, platelet aggregation and vascular leak in diverse critical illnesses. In CM patients with P. falciparum, serum histones correlate with fibrin formation, thrombocytopenia, and endothelial activation and predict brain swelling on magnetic resonance imaging and fatal outcome. Post-mortem, histones bind to the luminal vascular surface, co-localizing with P. falciparum-infected erythrocytes (IE), and with thrombosis and leak. Purified P. falciparum histones cause toxicity and barrier disruption in cultured human brain microvascular endothelial cells, as does serum from CM patients, reversed by anti-histone antibodies and non-anticoagulant heparin. These data implicate parasite histones as a key trigger of fatal brain swelling in CM. Neutralizing histones with agents such as non-anticoagulant heparin warrant exploration to prevent brain swelling and improve outcome.
CTCF confers local nucleosome resiliency after DNA replication and during mitosis
Authors: Owens Nick , Papadopoulou Thaleia , Festuccia Nicola , Tachtsidi Alexandra , Gonzalez Inma , Dubois Agnès , Vandoermel-Pournin Sandrine , Nora Elphège P. , Bruneau Benoit G. , Cohen-Tannoudji Michel , Navarro Pablo
Published: March 2019

The access of Transcription Factors (TFs) to their cognate DNA binding motifs requires a precise control over nucleosome posi-tioning. This is especially important following DNA replication and during mitosis, both resulting in profound changes in nu-cleosome organization over TF binding regions. Using mouse Embryonic Stem (ES) cells, we show that the TF CTCF displaces nucleosomes from its binding site and locally organizes large and phased nucleosomal arrays, not only in interphase steady-state but also immediately after replication and during mitosis. While regions bound by other TFs, such as Oct4 and Sox2, display major rearrangement, the post-replication and mitotic nucleosome organization activity of CTCF is not likely to be unique: Esrrb binding regions are also characterized by persistent nucleosome positioning. Therefore, we propose that selected TFs, such as CTCF and Esrrb, govern the inheritance of nucleosome positioning at gene regulatory regions through-out the ES cell-cycle.