bluuebunny/crossref_metadata_2025 huggingface dataset:
Statistical approaches in literature: An application of principal component analysis and factor analysis to analyze the different arrangements about the Quran’s Suras
Authors: Wang Yanwen , Garjami Javad , Tsvetkova Milena , Huu Hau Nguyen , Pho Kim-Hung
Published: January 2020

Data mining, statistics, and data analysis are popular techniques to study datasets and extract knowledge from them. In this article, principal component analysis and factor analysis were applied to cluster thirteen different given arrangements about the Suras of the Holy Quran. The results showed that these thirteen arrangements can be categorized in two parts such that the first part includes Blachère, Davood, Grimm, Nöldeke, Bazargan, E’temad-al-Saltane and Muir, and the second part includes Ebn Nadim, Jaber, Ebn Abbas, Hazrat Ali, Khazan, and Al-Azhar.
On aggregating probabilistic evidence
Authors: Artemov Sergei
Published: January 2020

Imagine a database—a set of propositions $\varGamma =\{F_1,\ldots ,F_n\}$ with some kind of probability estimates and let a proposition $X$ logically follow from $\varGamma $. What is the best justified lower bound of the probability of $X$? The traditional approach, e.g. within Adams’ probability logic, computes the numeric lower bound for $X$ corresponding to the worst-case scenario. We suggest a more flexible parameterized approach by assuming probability events $u_1,u_2,\ldots ,u_n$ that support $\varGamma $ and calculating aggregated evidence$e(u_1,u_2,\ldots ,u_n)$ for $X$. The probability of $e$ provides a tight lower bound for any, not only a worst-case, situation. The problem is formalized in a version of justification logic and the conclusions are supported by corresponding completeness theorems. This approach can handle conflicting and inconsistent data and allows the gathering both positive and negative evidence for the same proposition.
The cosmic atomic hydrogen mass density as a function of mass and galaxy hierarchy from spectral stacking
Authors: Hu Wenkai , Catinella Barbara , Cortese Luca , Staveley-Smith Lister , Lagos Claudia del P , Chauhan Garima , Oosterloo Tom , Chen Xuelei
Published: January 2020

We use spectral stacking to measure the contribution of galaxies of different masses and in different hierarchies to the cosmic atomic hydrogen (H i) mass density in the local Universe. Our sample includes 1793 galaxies at z < 0.11 observed with the Westerbork Synthesis Radio Telescope, for which Sloan Digital Sky Survey spectroscopy and hierarchy information are also available. We find a cosmic H i mass density of $\Omega _{\rm H\, \small {I} } = (3.99 \pm 0.54)\times 10^{-4} \, h_{70}^{-1}$ at 〈 z〉 = 0.065. For the central and satellite galaxies, we obtain $\Omega _{\rm H\, {\small {I}}}$ of $(3.51 \pm 0.49)\times 10^{-4} \, h_{70}^{-1}$ and $(0.90 \pm 0.16)\times 10^{-4} \, h_{70}^{-1}$, respectively. We show that galaxies above and below stellar masses of ∼109.3 M⊙ contribute in roughly equal measure to the global value of $\Omega _{\rm H\, \small {I} }$. While consistent with estimates based on targeted H i surveys, our results are in tension with previous theoretical work. We show that these differences are, at least partly, due to the empirical recipe used to set the partition between atomic and molecular hydrogen in semi-analytical models. Moreover, comparing our measurements with the cosmological semi-analytic models of galaxy formation Shark and GALFORM reveals gradual stripping of gas via ram pressure works better to fully reproduce the properties of satellite galaxies in our sample than strangulation. Our findings highlight the power of this approach in constraining theoretical models and confirm the non-negligible contribution of massive galaxies to the H i mass budget of the local Universe.
The connection between the UV/optical and X-ray emission in the neutron star low-mass X-ray binary Aql X-1
Authors: López-Navas E , Degenaar N , Parikh A S , Hernández Santisteban J V , van den Eijnden J
Published: January 2020

Accreting neutron stars and black holes in low-mass X-ray binaries (LMXBs) radiate across the electromagnetic spectrum. Linking the emission produced at different wavelengths can provide valuable information about the accretion process and any associated outflows. In this work, we study simultaneous X-ray and ultraviolet (UV)/optical observations of the neutron star LMXB Aql X-1, obtained with the Neil Gehrels Swift Observatory during its 2013, 2014, and 2016 accretion outbursts. We find that the UV/optical and X-ray emission are strongly correlated during all three outbursts. For the 2013 and 2014 episodes, which had the best Swift sampling, we find that the correlation between the UV/optical and X-ray fluxes is significantly steeper during the decay (soft state) of the outburst than during the rise (hard-to-soft state). We observe a UV/optical hysteresis behaviour that is likely linked to the commonly known X-ray spectral hysteresis pattern. For the decays of the three outbursts, we obtain a correlation index that cannot be directly explained by any single model. We suspect that this is a result of multiple emission processes contributing to the UV/optical emission, but we discuss alternative explanations. Based on these correlations, we discuss which mechanisms are likely dominating the UV/optical emission of Aql X-1.
Kinetic turbulence in shining pair plasma: intermittent beaming and thermalization by radiative cooling
Authors: Zhdankin Vladimir , Uzdensky Dmitri A , Werner Gregory R , Begelman Mitchell C
Published: January 2020

High-energy astrophysical systems frequently contain collision-less relativistic plasmas that are heated by turbulent cascades and cooled by emission of radiation. Understanding the nature of this radiative turbulence is a frontier of extreme plasma astrophysics. In this paper, we use particle-in-cell simulations to study the effects of external inverse Compton radiation on turbulence driven in an optically thin, relativistic pair plasma. We focus on the statistical steady state (where injected energy is balanced by radiated energy) and perform a parameter scan spanning from low magnetization to high magnetization (0.04 ≲ σ ≲ 11). We demonstrate that the global particle energy distributions are quasi-thermal in all simulations, with only a modest population of non-thermal energetic particles (extending the tail by a factor of ∼2). This indicates that non-thermal particle acceleration (observed in similar non-radiative simulations) is quenched by strong radiative cooling. The quasi-thermal energy distributions are well fit by analytic models in which stochastic particle acceleration (due to, e.g. second-order Fermi mechanism or gyroresonant interactions) is balanced by the radiation reaction force. Despite the efficient thermalization of the plasma, non-thermal energetic particles do make a conspicuous appearance in the anisotropy of the global momentum distribution as highly variable, intermittent beams (for high magnetization cases). The beamed high-energy particles are spatially coincident with intermittent current sheets, suggesting that localized magnetic reconnection may be a mechanism for kinetic beaming. This beaming phenomenon may explain rapid flares observed in various astrophysical systems (such as blazar jets, the Crab nebula, and Sagittarius A*).
Evolution of the Autism-Associated Neuroligin-4 Gene Reveals Broad Erosion of Pseudoautosomal Regions in Rodents
Authors: Maxeiner Stephan , Benseler Fritz , Krasteva-Christ Gabriela , Brose Nils , Südhof Thomas C
Published: January 2020

Variants in genes encoding synaptic adhesion proteins of the neuroligin family, most notably neuroligin-4, are a significant cause of autism spectrum disorders in humans. Although human neuroligin-4 is encoded by two genes, NLGN4X and NLGN4Y, that are localized on the X-specific and male-specific regions of the two sex chromosomes, the chromosomal localization and full genomic sequence of the mouse Nlgn4 gene remain elusive. Here, we analyzed the neuroligin-4 genes of numerous rodent species by direct sequencing and bioinformatics, generated complete drafts of multiple rodent neuroligin-4 genes, and examined their evolution. Surprisingly, we find that the murine Nlgn4 gene is localized to the pseudoautosomal region (PAR) of the sex chromosomes, different from its human orthologs. We show that the sequence differences between various neuroligin-4 proteins are restricted to hotspots in which rodent neuroligin-4 proteins contain short repetitive sequence insertions compared with neuroligin-4 proteins from other species, whereas all other protein sequences are highly conserved. Evolutionarily, these sequence insertions initiate in the clade eumuroidea of the infraorder myomorpha and are additionally associated with dramatic changes in noncoding sequences and gene size. Importantly, these changes are not exclusively restricted to neuroligin-4 genes but reflect major evolutionary changes that substantially altered or even deleted genes from the PARs of both sex chromosomes. Our results show that despite the fact that the PAR in rodents and the neuroligin-4 genes within the rodent PAR underwent massive evolutionary changes, neuroligin-4 proteins maintained a highly conserved core structure, consistent with a substantial evolutionary pressure preserving its physiological function.
Bending and looping of long DNA by Polycomb repressive complex 2 revealed by AFM imaging in liquid
Authors: Heenan Patrick R , Wang Xueyin , Gooding Anne R , Cech Thomas R , Perkins Thomas T
Published: January 2020

Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that methylates histone H3 at Lysine 27. PRC2 is critical for epigenetic gene silencing, cellular differentiation and the formation of facultative heterochromatin. It can also promote or inhibit oncogenesis. Despite this importance, the molecular mechanisms by which PRC2 compacts chromatin are relatively understudied. Here, we visualized the binding of PRC2 to naked DNA in liquid at the single-molecule level using atomic force microscopy. Analysis of the resulting images showed PRC2, consisting of five subunits (EZH2, EED, SUZ12, AEBP2 and RBBP4), bound to a 2.5-kb DNA with an apparent dissociation constant ($K_{\rm{D}}^{{\rm{app}}}$) of 150 ± 12 nM. PRC2 did not show sequence-specific binding to a region of high GC content (76%) derived from a CpG island embedded in such a long DNA substrate. At higher concentrations, PRC2 compacted DNA by forming DNA loops typically anchored by two or more PRC2 molecules. Additionally, PRC2 binding led to a 3-fold increase in the local bending of DNA’s helical backbone without evidence of DNA wrapping around the protein. We suggest that the bending and looping of DNA by PRC2, independent of PRC2’s methylation activity, may contribute to heterochromatin formation and therefore epigenetic gene silencing.
A conserved sequence signature is essential for robust plant miRNA biogenesis
Authors: Narjala Anushree , Nair Ashwin , Tirumalai Varsha , Hari Sundar G Vivek , Shivaprasad Padubidri V
Published: January 2020

Micro (mi)RNAs are 20–22nt long non-coding RNA molecules involved in post-transcriptional silencing of targets having high base-pair complementarity. Plant miRNAs are processed from long Pol II-transcripts with specific stem-loop structures by Dicer-like (DCL) 1 protein. Although there were reports indicating how a specific region is selected for miRNA biogenesis, molecular details were unclear. Here, we show that the presence of specific GC-rich sequence signature within miRNA/miRNA* region is required for the precise miRNA biogenesis. The involvement of GC-rich signatures in precise processing and abundance of miRNAs was confirmed through detailed molecular and functional analysis. Consistent with the presence of the miRNA-specific GC signature, target RNAs of miRNAs also possess conserved complementary sequence signatures in their miRNA binding motifs. The selection of these GC signatures was dependent on an RNA binding protein partner of DCL1 named HYL1. Finally, we demonstrate a direct application of this discovery for enhancing the abundance and efficiency of artificial miRNAs that are popular in plant functional genomic studies.
Early net ultrafiltration rate and mortality in critically ill patients receiving continuous renal replacement therapy
Authors: Naorungroj Thummaporn , Neto Ary Serpa , Zwakman-Hessels Lara , Yanase Fumitaka , Eastwood Glenn , Murugan Raghavan , Kellum John A , Bellomo Rinaldo
Published: January 2020

Background

In patients treated with continuous renal replacement therapy (CRRT), early net ultrafiltration (NUF) rates may be associated with differential outcomes. We tested whether higher early NUF rates are associated with increased mortality in CRRT patients.

Methods

We performed a retrospective, observational study of all patients treated with CRRT within 14 days of intensive care unit admission. We defined the early (first 48 h) NUF rate as the volume of fluid removed per hour adjusted for patient body weight and analysed as a categorical variable (>1.75, 1.01–1.75 and <1.01 mL/kg/h). The primary outcome was 28-day mortality. To deal with competing risk, we also compared different time epochs.

Results

We studied 347 patients {median age 64 [interquartile range (IQR) 53–71] years and Acute Physiology and Chronic Health Evaluation III score 73 [IQR 54–90]}. Compared with NUF rates <1.01 mL/kg/h, NUF rates >1.75 mL/kg/h were associated with greater mortality rates in each epoch: Days 0–5, adjusted hazard ratio (aHR) 1.27 [95% confidence interval (CI) 1.21–1.33]; Days 6–10, aHR 1.62 (95% CI 1.55–1.68); Days 11–15, aHR 1.87 (95% CI 1.79–1.94); Days 16–26, aHR 1.92 (95% CI 1.84–2.01) and Days 27–28, aHR 4.18 (95% CI 3.98–4.40). For every 0.5 mL/kg/h NUF rate increase, mortality similarly increased during these epochs.

Conclusion

Compared with early NUF rates <1.01 mL/kg/h, NUF rates >1.75 mL/kg/h are associated with increased mortality. These observations provide the rationale for clinical trials to confirm or refute these findings.
Surface Perturbation Training to Prevent Falls in Older Adults: A Highly Pragmatic, Randomized Controlled Trial
Authors: Lurie Jon D , Zagaria Alexandra B , Ellis Lisa , Pidgeon Dawna , Gill-Body Kathleen M , Burke Christina , Armbrust Kurt , Cass Sharil , Spratt Kevin F , McDonough Christine M
Published: January 2020

Background

Falls are the leading cause of injuries among older adults, and trips and slips are major contributors to falls.

Objective

The authors sought to compare the effectiveness of adding a component of surface perturbation training to usual gait/balance training for reducing falls and fall-related injury in high-risk older adults referred to physical therapy.

Design

This was a multi-center, pragmatic, randomized, comparative effectiveness trial.

Setting

Treatment took place within 8 outpatient physical therapy clinics.

Patients

This study included 506 patients 65+ years of age at high fall risk referred for gait/balance training.

Intervention

This trial evaluated surface perturbation treadmill training integrated into usual multimodal exercise-based balance training at the therapist’s discretion versus usual multimodal exercise-based balance training alone.

Measurements

Falls and injurious falls were assessed with a prospective daily fall diary, which was reviewed via telephone interview every 3 months for 1 year.

A total of 211/253 (83%) patients randomized to perturbation training and 210/253 (83%) randomized to usual treatment provided data at 3-month follow-up. At 3 months, the perturbation training group had a significantly reduced chance of fall-related injury (5.7% versus 13.3%; relative risk 0.43) but no significant reduction in the risk of any fall (28% versus 37%, relative risk 0.78) compared with usual treatment. Time to first injurious fall showed reduced hazard in the first 3 months but no significant reduction when viewed over the entire first year.

Limitations

The limitations of this trial included lack of blinding and variable application of interventions across patients based on pragmatic study design.

Conclusion

The addition of some surface perturbation training to usual physical therapy significantly reduced injurious falls up to 3 months posttreatment. Further study is warranted to determine the optimal frequency, dose, progression, and duration of surface perturbation aimed at training postural responses for this population.
Controlling parenting and perfectionism is associated with an increased error-related negativity (ERN) in young adults
Authors: Meyer Alexandria , Wissemann Karl
Published: January 2020

A substantial amount of research focuses on the error-related negativity (ERN)—a negative deflection in the event-related potential waveform that occurs when individuals commit errors on lab-based tasks. The ERN has been link to concurrent and prospective risk for psychopathology and is thought to index sensitivity or reactivity to errors. The ERN can be potentiated in the lab with punishment and has been shown to be increased among offspring of harsh or controlling parents. A separate line of work has demonstrated that the ERN is increased among individuals high in perfectionism. In the current study, we integrate these separate lines of work by examining parenting styles, perfectionism and the ERN in a sample of young adults. Results suggest that the ERN is increased among offspring of controlling parents (both maternal and paternal). Additionally, the ERN is increased among individuals who report being high in perfectionism—specifically, the concerns over mistake and the personal standard perfectionism subscales of the Frost Multidimensional Perfectionism Scale. Moreover, results supported a mediation model wherein the indirect pathway from controlling parenting style to perfectionism (personal standard subscale) was mediated by the ERN—for paternal parenting.
Approaching intellectual property scholarship differently: A qualitative research review and agenda
Authors: Parthasarathy Shobita
Published: January 2020

Social and policy interest in intellectual property, and patents, in particular, is growing. This is reflected in the rise of scholarly inquiry on the topic beyond the legal community, including among social scientists and humanists. In this article, I advocate for expanding qualitative research on patents and intellectual property related to innovation, arguing that it is essential for political and policy discussion. I review existing work and suggest avenues forward along four lines of inquiry: the political economy of intellectual property, the relationship between patents and innovation, the broader implications of intellectual property for social and political orders, and public participation in intellectual property law and policy. Throughout, I use the emerging field of precision medicine—and specifically, efforts to create intellectual property policies that promote open science and innovation—to explore how qualitative methodologies can help us understand the context and consequences of intellectual property law and policy and, ultimately, make better decisions to govern innovation.
Effects of supplementing late-gestation sow diets with zinc on preweaning mortality of pigs under commercial rearing conditions1
Authors: Holen Julia P , Urriola Pedro E , Schwartz Mark , Jang Jae-Cheol , Shurson Gerald C , Johnston Lee J
Published: January 2020

The objective of this experiment was to determine preweaning survival of pigs when sows were supplemented with 3 dietary levels of zinc (Zn) in late gestation. Gilts and sows (n = 339) were assigned to 1 of 3 dietary treatments based on parity. Dietary treatments were 1) Control—sows fed a corn–soybean meal-based diet containing 125 ppm total supplemental Zn supplied by ZnSO4 (75 ppm Zn) and AvailaZn (50 ppm Zn, CON); 2) Intermediate—as Control + 240 ppm supplemental Zn as ZnSO4 (INT); and 3) High—as Control + 470 ppm supplemental Zn as ZnSO4 (HI). Final supplemental Zn concentrations of the 3 dietary treatments were 1) CON—125 ppm; 2) INT—365 ppm; and 3) HI—595 ppm. Sows received dietary treatments from about day 85 of gestation until farrowing. Individual piglet birth weights were recorded within 12 h of parturition. Instances of piglet mortality were recorded daily. The statistical model considered fixed effects of treatment and random effects of parity. Piglets from sows fed the INT diet had heavier (P < 0.05) birth weights than those fed CON (1.42 vs. 1.38 kg, respectively), while offspring from sows fed HI tended to have heavier (P < 0.10) birth weights (1.40 kg) than pigs from INT sows. Furthermore, incidence of low birth weight pigs was less (P < 0.05) for sows consuming INT compared with sows fed CON and HI. Despite differences in birth weight, there were no differences (P > 0.05) in total pigs born, born alive, or weaned, nor differences in individual piglet gain or weaning weight across treatments. Mortality of low birth weight pigs was lowest (P < 0.05) for offspring from sows fed HI (28.1%) compared with offspring from sows fed INT (36.1%) and CON (38.3%). Similarly, overall piglet mortality tended to decrease (P < 0.10) as dietary Zn content increased (CON: 15.0%, INT: 13.2%, and HI: 12.2%). A subset of pigs (n = 420, n = 140/treatment) were selected at weaning to evaluate effects of dietary treatment on postweaning performance. There were no significant effects of sow Zn supplementation on final body weight, days to market, or carcass characteristics of market pigs. Overall, effects of supplemental dietary Zn at 365 and 595 ppm in late gestation improved preweaning survival of low birth weight piglets and reduced overall preweaning mortality of piglets.
Age as Moderator of the Relationship Between Self-efficacy and Effort in Occupational Teams
Authors: Gärtner Laura U A , Hertel Guido
Published: January 2020

Demographic changes increase the age range in occupational teams, which has potential consequences for collaboration not only at the team level (age diversity) but also at the individual level regarding how much effort workers expend. By integrating a life span perspective into theories on effort expenditure in teams, we assumed that workers’ chronological age moderates the relationship between task-specific self-efficacy beliefs and effort expenditure in organizational teamwork. More specifically, we assumed that task-specific self-efficacy beliefs are more strongly related with effort for older as compared with younger team members. Hypotheses were tested in 2 online studies (N = 209 and 271 workers, respectively) using the event reconstruction method. Participants were instructed to reexperience specific work events from the last few days (Study 1: 2 teamwork events; Study 2: 1 teamwork event and 1 working-alone event) and to indicate their self-efficacy and effort expenditure in each event. Results of both studies showed the expected age moderation of the self-efficacy–effort link in team settings, whereas no such moderation was observed in working-alone settings in Study 2. Finally, Study 2 also showed a stronger age moderation effect in unfamiliar as compared with familiar tasks.
Developing the Evidence-Grading Tools and Process for the Complex Attention-Deficit/Hyperactivity Disorder Guideline
Authors: Chan Eugenia , Froehlich Tanya E. , Barbaresi William J. , Fogler Jason
Published: January 2020

Clinical practice guidelines (CPGs) rely on a robust assessment of the quality of evidence supporting guideline recommendations. For the Society for Developmental and Behavioral Pediatrics (SDBP) CPG for the Assessment and Treatment of Children and Adolescents with Complex Attention-Deficit Hyperactivity Disorder (ADHD), the nature of the evidence and resource constraints led the guideline panel to develop an innovative, yet rigorous, approach to evidence grading. This study will (1) describe the challenges of evidence grading for the SDBP Complex ADHD Guideline; (2) discuss the rationale, process, and tools developed to conduct evidence grading; and (3) report on the experiences and readiness of the volunteer reviewers with diverse background in research methodology to conduct evidence grading. This evidence review process may serve as an example of approaches that can be used by other groups tasked with evaluating the evidence in support of new CPGs.
Graphene quantum dot electrochemiluminescence increase by bio-generated H
2
O
2
and its application in direct biosensing
Authors: Yang Shanli , Chu Mingfu , Du Jie , Li Yingru , Gai Tao , Tan Xinxin , Xia Binyuan , Wang Shaofei
Published: January 2020

In this study, a novel signal-increase electrochemiluminescence (ECL) biosensor has been developed for the detection of glucose based on graphene quantum dot/glucose oxidase (GQD/GO
x
) on Ti foil. The proposed GQD with excellent ECL ability is synthesized through a green one-step strategy by the electrochemical reduction of graphene oxide quantum dot. Upon the addition of glucose, GO
x
can catalytically oxidize glucose and the direct electron transfer between the redox centre of GO
x
and the modified electrode also has been realized, which results in the bio-generated H
2
O
2
for ECL signal increase in GQD and realizes the direct ECL detection of glucose. The signal-increase ECL biosensor enables glucose detection with high sensitivity reaching 5 × 10
−6
mol l
−1
in a wide linear range from 5 × 10
−6
to 1.5 × 10
−3
mol l
−1
. Additionally, the fabrication process of such GQD-based ECL biosensor is also suitable to other biologically produced H
2
O
2
system, suggesting the possible applications in the sensitive detection of other biologically important targets (e.g. small molecules, protein, DNA and so on).
Elliptical adhesive contact under biaxial stretching
Authors: Argatov I. , Papangelo A. , Ciavarella M.
Published: January 2020

Adhesive contact of the Hertzian indenter with an incompressible elastic substrate bi-directionally stretched along the indenter principal planes of curvature is considered in the Johnson–Kendall–Roberts theoretical framework. An approximate model is constructed by examining energy release rate conditions only on the edges of the minor and major axes of the contact ellipse. The effect of weak coupling between fracture modes I and II is introduced using a phenomenological mode-mixity function. This study was motivated by the need to model a passive–adhesive mechanism in cell mechanics on stretchable substrates.
Coupled flow and deformation fields due to a line load on a poroelastic half space: effect of surface stress and surface bending
Authors: Liu Zezhou , Bouklas Nikolaos , Hui Chung-Yuen
Published: January 2020

In the past decade, many experiments have indicated that the surfaces of soft elastic solids can resist deformation by surface stresses. A common soft elastic solid is a hydrogel which consists of a polymer network swollen in water. Although experiments suggest that solvent flow in gels can be affected by surface stress, there is no theoretical analysis on this subject. Here we study the solvent flow near a line load acting on a linear poroelastic half space. The surface of this half space resists deformation by a constant, isotropic surface stress. It can also resist deformation by surface bending. The time-dependent displacement, stress and flow fields are determined using transform methods. Our solution indicates that the stress field underneath the line load is completely regularized by surface bending—it is bounded and continuous. For small surface bending stiffness, the line force is balanced by surface stresses; these forces form what is commonly known as ‘Neumann's triangle’. We show that surface stress reduces local pore pressure and inhibits solvent flow. We use our line load solution to simulate the relaxation of the peak which is formed by applying and then removing a line force on the poroelastic half space.
Summary-data-based mendelian randomisation reveals druggable targets for multiple sclerosis
Authors: Jacobs Benjamin Meir , Taylor Thomas , Awad Amine , Baker David , Giovanonni Gavin , Noyce Alastair , Dobson Ruth
Published: January 2020

Background

Multiple Sclerosis (MS) is a complex autoimmune disease caused by a combination of genetic and environmental factors. Translation of Genome-Wide Association Study (GWAS) findings in MS into therapeutics and effective preventive strategies has been limited to date.

Methods

We used Summary Data-Based Mendelian Randomisation (SMR) to synthesise findings from public expression quantitative trait locus (eQTL; eQTLgen and CAGE), methylation quantitative trait locus (mQTL; Lothian Birth Cohort and Brisbane Systems Genetics Study), and MS GWAS datasets (International Multiple Sclerosis Genetics Consortium). By correlating the effects of methylation on MS (M-2-MS), methylation on expression (M-2-E), and expression on MS susceptibility (E-2-MS), we prioritise genetic loci with strong evidence of causally influencing MS susceptibility. We overlay these findings onto a list of ‘druggable’ genes, i.e. genes which are currently, or could theoretically, be targeted by therapeutic compounds. We use GeNets and STRING to identify protein-protein interactions and druggable pathways enriched in our results. We extend these findings to a model of Epstein-Barr Virus-infected B cells, Lymphoblastoid Cell Lines (LCLs). We conducted a systematic review of prioritised genes using the Open Targets platform to identify completed and planned trials targeted prioritised genes in MS and related disease areas.

Results

Expression of 45 genes in peripheral was strongly associated with MS susceptibility (False discovery rate 0.05). Of these 45 genes, 20 encode a protein which is currently targeted by an existing therapeutic compound. These genes were enriched for Gene Ontology terms pertaining to immune system function and leukocyte signalling. We refined this prioritised gene list by restricting to loci where CpG site methylation was associated with MS susceptibility (M-2-MS), with gene expression (M-2-E), and where expression was associated with MS susceptibility (E-2-MS). This approach yielded a list of 15 prioritised druggable target genes for which there was evidence of a causal pathway linking methylation, expression, and MS. Five of these 15 genes are targeted by existing drugs (CD40, ERBB2, VEGFB, MERTK, and PARP1), and three were replicated in a smaller eQTL dataset (CD40, MERTK, and PARP1). In LCLs, SMR prioritised 7 druggable gene targets, of which only one was priortised by the multi-omic approach in peripheral blood (FCRL3). Systematic review of Open Targets revealed multiple early-phase trials targeting 13/20 prioritised genes in disorders related to MS.

Conclusions

We use public datasets and SMR to identify a list of prioritised druggable genetic targets in Multiple Sclerosis. We hope our findings could be translated into effective repurposing of existing drugs to provide novel therapies for MS and, potentially, provide a platform for developing preventive therapies.
Modelling the epidemic trend of the 2019 novel coronavirus outbreak in China
Authors: Shen Mingwang , Peng Zhihang , Xiao Yanni , Zhang Lei
Published: January 2020

We present a timely evaluation of the Chinese 2019-nCov epidemic in its initial phase, where 2019-nCov demonstrates comparable transmissibility but lower fatality rates than SARS and MERS. A quick diagnosis that leads to case isolation and integrated interventions will have a major impact on its future trend. Nevertheless, as China is facing its Spring Festival travel rush and the epidemic has spread beyond its borders, further investigation on its potential spatiotemporal transmission pattern and novel intervention strategies are warranted.
Single-color Fluorescence Lifetime Cross-Correlation Spectroscopyin vivo
Authors: Štefl M. , Herbst K. , Rübsam M. , Benda A. , Knop M.
Published: January 2020

The ability to quantify protein concentrations and to measure protein interactionsin vivois key information needed for the understanding of complex processes inside cells, but the acquisition of such information from living cells is still demanding. Fluorescence based methods like two-color fluorescence cross-correlation spectroscopy can provide this information but measurement precision is hampered by various sources of errors caused by instrumental or optical limitations such as imperfect overlap of detection volumes or detector cross-talk. Furthermore, the nature and properties of used fluorescent proteins or fluorescent dyes, such as labeling efficiency, fluorescent protein maturation, photo-stability, bleaching and fluorescence brightness can have an impact.

Here we take advantage of lifetime differences as a mean to discriminate fluorescent proteins with similar spectral properties and to use them for single-color fluorescence lifetime cross-correlation spectroscopy (sc-FLCCS). By using only one excitation and one detection wavelength, this setup avoids all sources of errors resulting from chromatic aberrations and detector cross-talk. To establish sc-FLCCS we first engineered and tested multiple GFP-like fluorescent proteins for their suitability. This identified a novel GFP variant termed slmGFP (short lifetime monomeric GFP) with the so-far shortest lifetime. Monte-Carlo simulations were employed to explore the suitability of different combinations of GFP variants. Two GFPs, Envy and slmGFP were predicted to constitute the best performing couple for sc-FLCCS measurements. We demonstrated application of this GFP pair for measuring protein interactions between the proteasome and interacting proteins and for measuring protein interactions between three partners when combined with a red florescent protein. Together, our findings establish sc-FLCCS as a valid alternative for conventional dual-color(dc)-FCCS measurements.

STATEMENT OF SIGNIFICANCE

The quantification of protein concentrations and protein-protein interactionsin vivois a crucial information needed for the understanding of complex processes inside cells. Determination of such information is unfortunately still challenging. Fluorescence-based method like fluorescence cross-correlation spectroscopy (FCCS) is the only method which provides this informationin vivoand almost in the real time, however it suffers from limitations caused by experimental setup and biological origin of fluorescent proteins. We present single-color fluorescence lifetime cross-correlation spectroscopy as an alternative to FCCS, which uses the information of fluorescence lifetime to overcome some of these limitations. We challenged the method and determined its advantages and limitations and demonstrated the applicability of the method on the proteins of yeast proteasome.
Tumor Neoantigenicity Assessment with CSiN Score Incorporates Clonality and Immunogenicity to Predict Immunotherapy Outcomes
Authors: Lu Tianshi , Wang Shidan , Xu Lin , Zhou Qinbo , Singla Nirmish , Gao Jianjun , Manna Subrata , Pop Laurentiu , Xie Zhiqun , Chen Mingyi , Luke Jason J. , Brugarolas James , Hannan Raquibul , Wang Tao
Published: January 2020

Lack of responsiveness to checkpoint inhibitors is a central problem in the modern era of cancer immunotherapy. Tumor neoantigens are critical mediators of host immune response and immunotherapy treatment efficacy. Current studies of neoantigens almost entirely focus on total neoantigen load, which simplistically treats all neoantigens equally. Besides, neoantigen loads have been linked with treatment response and prognosis only in some studies, but not others. We developed a Cauchy-Schwarz index of Neoantigens (CSiN) score to characterize the degree of concentration of immunogenic neoantigens in truncal mutations. Unlike simple neoantigen loads, CSiN incorporates the effect of both clonality and MHC-binding affinity of neoantigens when characterizing patient neoantigen profiles. By exploiting the clinical responses in 501 treated patients (mostly by checkpoint inhibitors) and the overall survival of 1,978 baseline patients, we showed that CSiN scores predict treatment response to checkpoint inhibitors and prognosis in melanoma, lung cancer, and kidney cancer patients. CSiN substantially outperforms prior genetics-based prediction methods of responsiveness. Overall, our work fulfilled an important gap in current research involving neoantigens.

One Sentence Summary

The quality of tumor neoantigens predicts response to immunotherapy
One cell, one drop, one click: hybrid microfluidic mammalian single-cell isolation
Authors: Samlali Kenza , Ahmadi Fatemeh , Quach Angela B.V. , Soffer Guy , Shih Steve C.C.
Published: January 2020

The process of generating a stable knockout cell line is a complex process that can take several months to complete. In this work, we introduce a microfluidic method that is capable of isolating single cells, selecting successful edited clones, and expansion of these isoclones. Using a hybrid microfluidics method, droplets in channels can be individually addressed using a co-planar electrode system. In our hybrid microfluidic device, we show that we can trap single cells and subsequently encapsulate them on demand into pL-sized droplets. Furthermore, individual cells inside the droplet can be released from the traps or merged with other droplets by simply applying an electric potential to the electrodes that is actuated through a user interface. We use this high precision control to sort and to recover single isoclones to establish monoclonal cell lines, which is demonstrated with a heterozygous NCI-H1299 lung squamous cell population resulting from loss-of-function eGFP and RAF1 gene knock-out transfections.
Measurement Reliability for Individual Differences in Multilayer Network Dynamics: Cautions and Considerations
Authors: Yang Zhen , Telesford Qawi K. , Franco Alexandre R. , Lim Ryan , Gu Shi , Xu Ting , Ai Lei , Castellanos Francisco X. , Yan Chao-Gan , Colcombe Stan , Milham Michael P.
Published: January 2020

Multilayer network models have been proposed as an effective means of capturing the dynamic configuration of distributed neural circuits and quantitatively describing how communities vary over time. Beyond general insights into brain function, a growing number of studies have begun to employ these methods for the study of individual differences. However, test-retest reliabilities for multilayer network measures have yet to be fully quantified or optimized, potentially limiting their utility for individual difference studies. Here, we systematically evaluated the impact of multilayer community detection algorithms, selection of network parameters, scan duration, and task condition on test-retest reliabilities of multilayer network measures (i.e., flexibility, integration, and recruitment). A key finding was that the default method used for community detection by the popular generalized Louvain algorithm can generate erroneous results. Although available, an updated algorithm addressing this issue is yet to be broadly adopted in the neuroimaging literature. Beyond the algorithm, the present work identified parameter selection as a key determinant of test-retest reliability; however, optimization of these parameters and expected reliabilities appeared to be dataset-specific. Once parameters were optimized, consistent with findings from the static functional connectivity literature, scan duration was a much stronger determinant of reliability than scan condition. When the parameters were optimized and scan duration was sufficient, both passive (i.e., resting state, Inscapes, and movie) and active (i.e., flanker) tasks were reliable, although reliability in the movie watching condition was significantly higher than in the other three tasks. The minimal data requirement for achieving reliable measures for the movie watching condition was 20 min, and 30 min for the other three tasks. Our results caution the field against the use of default parameters without optimization based on the specific datasets to be employed - a process likely to be limited for most due to the lack of test-retest samples to enable parameter optimization.

Highlights

Dynamic network reliability is highly dependent on many methodological decisions

The default multilayer community detection algorithm generates erroneous results

Reliability-optimized intra-/inter-layer coupling parameters are dataset-dependent

Scan duration is a much stronger determinant of reliability than scan condition

Movies are the most reliable condition, requiring at least 20 min of data
Pharmacological depletion of microglia prevents vascular cognitive impairment in Ang II-induced hypertension
Authors: Kerkhofs Danielle , van Hagen Britt T. , Milanova Irina V. , Schell Kimberly J. , van Essen Helma , Wijnands Erwin , Goossens Pieter , Blankesteijn W. Matthijs , Unger Thomas , Prickaerts Jos , Biessen Erik A. , van Oostenbrugge Robert J. , Foulquier Sebastien
Published: January 2020

Rationale:Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Ang II infusion is associated with increased permeability of the blood-brain barrier (BBB) and chronic activation of microglia. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach.

Methods:For this study, adultCx3Cr1gfp/wtxThy1yfp/0reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF-1R inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory were assessed during an Object Location task and a Morris Water Maze task (MWM). At the end of the study, microglia depletion efficacy and BBB leakages were assessed using flow cytometry and immunohistochemistry.

Results:SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, but not in Ang II mice treated with PLX5622. Histological and flow cytometry analyses revealed almost complete ablation of microglia upon CSF1R inhibition, while brain resident perivascular macrophages, were reduced by 60%. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment.

Conclusion:Our results show that depletion of microglia, and less so PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. This novel finding supports the critical role of brain immune cells, and most in particular microglia, in the pathogenesis of hypertension-related cognitive impairment.
Aphid feeding induces the relaxation of epigenetic control and the associated regulation of the defense response inArabidopsis
Authors: Annacondia Maria Luz , Markovic Dimitrije , Reig-Valiente Juan Luis , Scaltsoyiannes Vassilis , Pieterse Corné M.J. , Ninkovic Velemir , Slotkin R. Keith , Martinez German
Published: January 2020

Environmentally induced changes in the epigenome help individuals to quickly adapt to fluctuations in the conditions of their habitats. Here we explored those changes inArabidopsis thalianaplants subjected to multiple biotic and abiotic stresses, and identified transposable element (TE) activation in plants infested with the green peach aphid,Myzus persicae. We performed a genome-wide analysis of DNA methylation, mRNA expression, mRNA degradation and small RNA accumulation. Our results demonstrate that aphid feeding induces loss of methylation of hundreds of loci, mainly TEs. This loss of methylation has the potential to regulate gene expression and we found evidence that it is involved in the control of key plant immunity genes. Accordingly, we find that mutant plants deficient in epigenetic silencing show increased resistance toM.persicaeinfestation. Collectively, our results show that changes in DNA methylation play a significant role in the regulation of the plant transcriptional response and induction of defense response against aphid feeding.
A biomimetic five-module chimeric antigen receptor (5MCAR) designed to target and eliminate antigen-specific T cells
Authors: Kobayashi Shio , Thelin Martin A. , Parrish Heather L. , Deshpande Neha R. , Lee Mark S. , Karimzadeh Alborz , Niewczas Monika A. , Serwold Thomas , Kuhns Michael S.
Published: January 2020

T cells express clonotypic T cell receptors (TCRs) that recognize peptide antigens in the context of class I or II MHC molecules (pMHCI/II). These receptor modules associate with three signaling modules (CD3γε, δε, and ζζ), and work in concert with a coreceptor module (either CD8 or CD4), to drive T cell activation in response to pMHCI/II. Here we describe a first generation biomimetic 5-module chimeric antigen receptor (5MCAR). We show that: (i) chimeric receptor modules built with the ectodomains of pMHCII assemble with CD3 signaling modules into complexes that redirect cytotoxic T lymphocyte (CTL) specificity and function in response to the clonotypic TCRs of pMHCII-specific CD4+T cells; and, (ii) surrogate coreceptor modules enhance the function of these complexes. Furthermore, we demonstrate that adoptively transferred5MCAR-CTLs can mitigate type I diabetes by targeting autoimmune CD4+T cells in NOD mice. This work provides a framework for the construction of biomimetic5MCARs that can be used as tools to study the impact of particular antigen-specific T cells in immune responses, and may hold potential for ameliorating diseases mediated by pathogenic T cells.
Involuntary orienting and conflict resolution during auditory attention: The role of ventral and dorsal streams
Authors: Stewart Hannah J , Shen Dawei , Sham Nasim , Alain Claude
Published: January 2020

Selective attention to sound object features such as pitch and location is associated with enhanced brain activity in ventral and dorsal streams, respectively. We examined the role of these pathways in involuntary orienting and conflict resolution using functional magnetic resonance imaging (fMRI). Participants were presented with two tones that may share, or not, the same non-spatial (frequency) or spatial (location) auditory features. In separate blocks of trials, participants were asked to attend to sound frequency or sound location and ignore the change in the task-irrelevant feature. In both attend-frequency and attend-location tasks, response times were slower when the task-irrelevant feature changed than when it stayed the same (involuntary orienting). This behavioural cost coincided with enhanced activity in the prefrontal cortex and superior temporal gyrus (STG). Conflict resolution was examined by comparing situations where the change in stimulus features was congruent (both features changed) and incongruent (only one feature changed). Participants were slower and less accurate for incongruent than congruent sound features. This congruency effect was associated with enhanced activity in the prefrontal cortex, and was greater in the right STG and medial frontal cortex during the attend-location than during the attend-frequency task. Together, these findings do not support a strict division of ‘labour’ into ventral and dorsal streams, but rather suggest interactions between these pathways in situations involving changes in task-irrelevant sound feature and conflict resolution. These findings also validate the Test of Attention in Listening task by revealing distinct neural correlates for involuntary orienting and conflict resolution.