bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 outbreak: organisation of a geriatric assessment and coordination unit. A French example
Authors: Koeberle Séverine , Tannou Thomas , Bouiller Kévin , Becoulet Nicolas , Outrey Justin , Chirouze Catherine , Aubry Régis
Published: April 2020

Older people are particularly affected by the COVID-19 outbreak because of their vulnerability as well as the complexity of health organisations, particularly in the often-compartmentalised interactions between community, hospital and nursing home actors. In this endemic situation, with massive flows of patients requiring holistic management including specific and intensive care, the appropriate assessment of each patient’s level of care and the organisation of specific networks is essential.

To that end, we propose here a territorial organisation of health care, favouring communication between all actors. This organisation of care is based on three key points:

To use the basis of territorial organisation of health by facilitating the link between hospital settings and geriatric sectors at the regional level. To connect private, medico-social and hospital actors through a dedicated centralised unit for evaluation, geriatric coordination of care and decision support. A geriatrician coordinates this multidisciplinary unit. It includes an emergency room doctor, a supervisor from the medical regulation centre (Centre 15), an infectious disease physician, a medical hygienist and a palliative care specialist. To organise an ad hoc follow-up channel, including the necessary resources for the different levels of care required, according to the resources of the territorial network, and the creation of a specific COVID geriatric palliative care service.

This organisation meets the urgent health needs of all stakeholders, facilitating its deployment and allows the sustainable implementation of a coordinated geriatric management dynamic between the stakeholders on the territory.
Cardiotoxicity of Use of Sequential Aromatase Inhibitors in Women With Breast Cancer
Authors: Khosrow-Khavar Farzin , Bouganim Nathaniel , Filion Kristian B , Suissa Samy , Azoulay Laurent
Published: April 2020

The association between use of aromatase inhibitors (AIs) and cardiovascular outcomes is controversial. While some observational studies have assessed the cardiovascular safety of AIs as upfront treatments, their cardiotoxicity as sequential treatments with tamoxifen remains unknown. Thus, we conducted a population-based cohort study using data from the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. We employed a prevalent new-user design to propensity-score match, in a 1:2 ratio, patients switching from tamoxifen to AIs with patients continuing tamoxifen between 1998 and 2016. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality). Overall, 1,962 patients switching to AIs were matched to 3,874 patients continuing tamoxifen. Compared with tamoxifen, AIs were associated with an increased risk of myocardial infarction (hazard ratio (HR) = 2.08, 95% confidence interval (CI): 1.02, 4.27). The hazard ratios were elevated for ischemic stroke (HR = 1.58, 95% CI: 0.85, 2.93) and heart failure (HR = 1.69, 95% CI: 0.79, 3.62) but not cardiovascular mortality (HR = 0.87, 95% CI: 0.49, 1.54), with confidence intervals including the null value. The elevated hazard ratios observed for the cardiovascular outcomes should be corroborated in future large observational studies.
Novel sources of (co)variation in nestling begging behavior and hunger at different biological levels of analysis
Authors: Wetzel Daniel P , Mutzel Ariane , Wright Jonathan , Dingemanse Niels J
Published: April 2020

Biological hypotheses predicting patterns of offspring begging typically concern the covariance with hunger and/or development at specific hierarchical levels. For example, hunger drives within-individual patterns of begging, but begging also drives food intake among individuals within broods, and begging and food intake can covary positively or negatively among genotypes or broods. Testing biological phenomena that occur at multiple levels, therefore, requires the partitioning of covariance between traits of interest to ensure that each level-specific relationship is appropriately assessed. We performed a partial cross-fostering study on a wild population of great tits (Parus major), then used multivariate mixed models to partition variation and covariation in nestling begging effort and two metrics of nestling hunger within versus among individual nestlings and broods. At the within-individual level, we found that nestlings begged more intensely when hungrier (positive correlation between begging and hunger). However, among individuals, nestlings that were fed more frequently also begged more intensely on average (negative correlation between begging and hunger). Variation in nestling mass did not give rise to the negative correlation between begging and hunger among nestlings, but we did find that lighter nestlings begged more intensely than their heavier biological siblings, suggesting that this effect may be driven by a genetic component linked to offspring size. Our study illustrates how patterns of covariance can differ across biological levels of analysis and addresses biological mechanisms that could produce these previously obscured patterns.
Predicting target genes of non-coding regulatory variants with IRT
Authors: Wu Zhenqin , Ioannidis Nilah M , Zou James
Published: April 2020

Interpreting genetic variants of unknown significance (VUS) is essential in clinical applications of genome sequencing for diagnosis and personalized care. Non-coding variants remain particularly difficult to interpret, despite making up a large majority of trait associations identified in genome-wide association studies (GWAS) analyses. Predicting the regulatory effects of non-coding variants on candidate genes is a key step in evaluating their clinical significance. Here, we develop a machine-learning algorithm, Inference of Connected expression quantitative trait loci (eQTLs) (IRT), to predict the regulatory targets of non-coding variants identified in studies of eQTLs. We assemble datasets using eQTL results from the Genotype-Tissue Expression (GTEx) project and learn to separate positive and negative pairs based on annotations characterizing the variant, gene and the intermediate sequence. IRT achieves an area under the receiver operating characteristic curve (ROC-AUC) of 0.799 using random cross-validation, and 0.700 for a more stringent position-based cross-validation. Further evaluation on rare variants and experimentally validated regulatory variants shows a significant enrichment in IRT identifying the true target genes versus negative controls. In gene-ranking experiments, IRT achieves a top-1 accuracy of 50% and top-3 accuracy of 90%. Salient features, including GC-content, histone modifications and Hi-C interactions are further analyzed and visualized to illustrate their influences on predictions. IRT can be applied to any VUS of interest and each candidate nearby gene to output a score reflecting the likelihood of regulatory effect on the expression level. These scores can be used to prioritize variants and genes to assist in patient diagnosis and GWAS follow-up studies.

Availability and implementation

Codes and data used in this work are available at https://github.com/miaecle/eQTL_Trees.

Supplementary information

Supplementary data are available at Bioinformatics online.
scHLAcount: allele-specific HLA expression from single-cell gene expression data
Authors: Darby Charlotte A , Stubbington Michael J T , Marks Patrick J , Martínez Barrio Álvaro , Fiddes Ian T
Published: April 2020

Bulk RNA sequencing studies have demonstrated that human leukocyte antigen (HLA) genes may be expressed in a cell type-specific and allele-specific fashion. Single-cell gene expression assays have the potential to further resolve these expression patterns, but currently available methods do not perform allele-specific quantification at the molecule level. Here, we present scHLAcount, a post-processing workflow for single-cell RNA-seq data that computes allele-specific molecule counts of the HLA genes based on a personalized reference constructed from the sample’s HLA genotypes.

Availability and implementation

scHLAcount is available under the MIT license at https://github.com/10XGenomics/scHLAcount.

Supplementary information

Supplementary data are available at Bioinformatics online.
‘ISIS is not Islam’: Epistemic Injustice, Everyday Religion, and Young Muslims’ Narrative Resistance
Authors: Sandberg Sveinung , Colvin Sarah
Published: April 2020

Powerful narratives that invoke religious concepts—jihad, Sharia, shahid, Caliphate, kuffar, and al-Qiyāmah—have accompanied jihadi violence but also inspired robust counter-narratives from Muslims. Taking a narrative criminological approach, we explore the rejection of religious extremism that emerges in everyday interactions in a religious community under intense pressure in Western societies. Drawing on qualitative interviews with 90 young Muslims in Norway, we argue that young Muslims suffer epistemic injustice in their narrative exclusion from the mainstream and assess the narrative credibility they try to maintain in the face of marginalization. We suggest that young Muslims’ religious narratives reject a mainstream characterization of Islam as essentially a religion of aggression and simultaneously join forces with that mainstream in seeking the narrative exclusion of the jihadi extremists.
Population Movement, City Closure in Wuhan, and Geographical Expansion of the COVID-19 Infection in China in January 2020
Authors: Liu Kun , Ai Siqi , Song Shuxuan , Zhu Guanghu , Tian Fei , Li Huan , Gao Yuan , Wu Yinglin , Zhang Shiyu , Shao Zhongjun , Liu Qiyong , Lin Hualiang
Published: April 2020

Background

The unprecedented outbreak of corona virus disease 2019 (COVID-19) infection in Wuhan City has caused global concern; the outflow of the population from Wuhan was believed to be a main reason for the rapid and large-scale spread of the disease, so the government implemented a city-closure measure to prevent its transmission considering the large amount of travel before the Chinese New Year.

Methods

Based on the daily reported new cases and the population-movement data between 1 and 31 January, we examined the effects of population outflow from Wuhan on the geographical expansion of the infection in other provinces and cities of China, as well as the impacts of the city closure in Wuhan using different closing-date scenarios.

Results

We observed a significantly positive association between population movement and the number of the COVID-19 cases. The spatial distribution of cases per unit of outflow population indicated that the infection in some areas with a large outflow of population might have been underestimated, such as Henan and Hunan provinces. Further analysis revealed that if the city-closure policy had been implemented 2 days earlier, 1420 (95% confidence interval, 1059–1833) cases could have been prevented, and if 2 days later, 1462 (1090–1886) more cases would have been possible.

Conclusions

Our findings suggest that population movement might be one important trigger for the transmission of COVID-19 infection in China, and the policy of city closure is effective in controlling the epidemic.
Antibody Detection and Dynamic Characteristics in Patients With Coronavirus Disease 2019
Authors: Xiang Fei , Wang Xiaorong , He Xinliang , Peng Zhenghong , Yang Bohan , Zhang Jianchu , Zhou Qiong , Ye Hong , Ma Yanling , Li Hui , Wei Xiaoshan , Cai Pengcheng , Ma Wan-Li
Published: April 2020

Background

The coronavirus disease 2019 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been rapidly spreading nationwide and abroad. A serologic test to identify antibody dynamics and response to SARS-CoV-2 was developed.

Methods

The antibodies against SARS-CoV-2 were detected by an enzyme-linked immunosorbent assay based on the recombinant nucleocapsid protein of SARS-CoV-2 in patients with confirmed or suspected COVID-19 at 3–40 days after symptom onset. The gold standard for COVID-19 diagnosis was nucleic acid testing for SARS-CoV-2 by real-time reverse-transcription polymerase chain reaction (rRT-PCR). The serodiagnostic power of the specific immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies against SARS-CoV-2 was investigated in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and consistency rate.

Results

The seroconversion of specific IgM and IgG antibodies were observed as early as the fourth day after symptom onset. In the patients with confirmed COVID-19, sensitivity, specificity, PPV, NPV, and consistency rate of IgM were 77.3% (51/66), 100%, 100%, 80.0%, and 88.1%, respectively, and those of IgG were 83.3% (55/66), 95.0%, 94.8%, 83.8%, and 88.9%. In patients with suspected COVID-19, sensitivity, specificity, PPV, NPV, and consistency rate of IgM were 87.5% (21/24), 100%, 100%, 95.2%, and 96.4%, respectively, and those of IgG were 70.8% (17/24), 96.6%, 85.0%, 89.1%, and 88.1%. Both antibodies performed well in serodiagnosis for COVID-19 and rely on great specificity.

Conclusions

The antibodies against SARS-CoV-2 can be detected in the middle and later stages of the illness. Antibody detection may play an important role in the diagnosis of COVID-19 as a complementary approach to viral nucleic acid assays.
Cell Therapy With Mesenchymal Stem Cells Induces an Innate Immune Memory Response That Attenuates Experimental Colitis in the Long Term
Authors: Lopez-Santalla Mercedes , Hervas-Salcedo Rosario , Fernandez-Garcia Maria , Bueren Juan Antonio , Garin Marina Inmaculada
Published: April 2020

Background and Aims

Mesenchymal stem cells [MSCs] are used in preclinical and clinical studies for treatment of immune-mediated disorders, thanks to their immunomodulatory properties. Cell therapy with MSCs induces multiple effects in the immune system which ultimately lead to increase in the number of immune cells with regulatory phenotype. In this study, we investigated whether the beneficial effects of MSC therapy are maintained in the long term in a clinically relevant mouse model of colitis.

Methods

A single dose of adipose-derived MSCs [aMSCs] was infused into dextran sulphate sodium [DSS]-induced colitic mice during the induction phase of the disease. Following a latency period of 12 weeks, mice were re-challenged with a second 7-day cycle of DSS.

Results

DSS-induced colitic mice treated with aMSCs showed significant reduction in their colitic disease activity index during the second DSS challenge when compared with non-aMSC treated DSS-induced colitic mice. Strikingly, the long-term protection induced by aMSC therapy was also observed in Rag-1-/- mice where no adaptive immune memory cell responses take place. Increased percentages of Ly6G+CD11b+ myeloid cells were observed 12 weeks after the first inflammatory challenge in the peritoneal cavity, spleen, and bone marrow of DSS-induced colitic mice that were infused with aMSCs. Interestingly, upon re-challenge with DSS, these animals showed a concomitant increase in the regulatory/inflammatory macrophage ratio in the colon lamina propria.

Conclusions

Our findings demonstrate for the first time that MSC therapy can imprint an innate immune memory-like response in mice which confers sustained protection against acute inflammation in the long term.
Cannabis-induced recurrent myocardial infarction in a 21-year-old man: a case report
Authors: Lawin Dennis , Lawrenz Thorsten , Tego Andi , Stellbrink Christoph
Published: April 2020

Background

Acute coronary syndrome (ACS) is rarely caused by coronary artery disease in young patients unless cardiovascular risk factors are present. Although non-atherosclerotic causes of ACS are rare, they need to be considered in young patients.

Case summary

We report on a 21-year-old patient referred to our institution with ACS. Electrocardiogram showed ST-segment elevation and coronary angiography revealed thrombotic occlusion of the left anterior descending artery. Reperfusion was achieved by thrombus aspiration, glycoprotein IIb/IIIa inhibitors (GPI), and drug-eluting stent (DES). The patient had no cardiovascular risk factors but reported cannabis consumption before symptom onset. Although he was put on dual antiplatelet therapy and strictly advised to avoid consumption, he continued to abuse cannabis and suffered three further ACS events within 18 months: the first 8 months later caused by thrombotic occlusion of a diagonal branch treated by GPI and DES, the second after 17 months due to thrombotic re-occlusion of the diagonal branch, and the third after 18 months by thrombotic occlusion of the circumflex artery, both events treated by GPI alone (all while still using cannabis). Since then, he stopped cannabis consumption and has been symptom-free for 8 months.

Discussion

This case highlights that cannabis-induced ACS must be considered as a cause of myocardial infarction in young adults. In contrast to ACS in the elderly population, this unusual ACS cause requires specific treatment. The risk of ACS relapse may substantial if cannabis abuse is continued. This potential hazard needs to be taken into consideration when legalization of cannabis is discussed.
Single-shot cryoablation of an epicardial inferoparaseptal accessory pathway: a case report
Authors: Davtyan Karapet V , Topchyan Arpi H , Kalemberg Andrey A , Simonyan Georgiy Yu
Published: April 2020

Background

Catheter ablation (CA) of epicardial accessory pathways (APs) can be performed via the coronary sinus (CS) system. Variable CS anatomy with complications of former CA procedures inside the CS venous system may require using alternative CA approach and technology.

Case summary

We report the case of a 23-year-old man with Wolff–Parkinson–White syndrome and history of aborted sudden cardiac death (SCD) and unsuccessful previous AP radiofrequency ablation (RFA). CS venography during the redo procedure revealed an early CS trifurcation with cardiac veins stenosis, thus with difficulties in maintaining cardiac veins’ access and catheter manoeuvring inside CS venous system. The last office visit with electrocardiogram (ECG) performance was in 3 months after the CA. Neither delta wave on the ECG nor any complaints/adverse health effects was detected at that time.

Discussion

Successful CA of epicardial AP in patients with a high risk of SCD is essential. However, CS complex anatomy and changes after former RFA inside it may lead to CS venous system access limitations. Alternative CA approach and technology should be considered to ensure CS venous system cannulation and epicardial AP CA performance.
Abundance, distribution, and habitat use of fishes in a large river (Danube, Austria): mobile, horizontal hydroacoustic surveys vs. a standard fishing method
Authors: Kerschbaumer Philip , Tritthart Michael , Keckeis Hubert
Published: April 2020

We tested a novel approach for fish abundance and size estimates along a 3.6-km reach in the main stem of a free-flowing section of the Danube River east of Vienna. We deployed an adaptive resolution imaging sonar (ARIS) with horizontal beam orientation from a moving boat in order to assess spatial and temporal fish abundance distributions in different mesohabitats. To validate the results obtained from imaging sonar, hydroacoustic abundance and fish length estimates were compared with those received from boat electrofishing surveys conducted at the same time and place. Furthermore, fish occurrence was related to hydraulic conditions based on a three-dimensional hydrodynamic model in order to reveal patterns of habitat use. Hydroacoustic abundance expressed as catch per unit effort estimates deviated significantly from fish abundances assessed by boat electrofishing, but when comparing relative abundances both methods yielded a similar spatial and temporal pattern. Total fish length estimates obtained from the two methods did not differ significantly. The mobile application of the non-invasive ARIS technology offers the opportunity to quickly gain detailed information on fish abundance and position of individuals. This yields more specific information on temporal and spatial distribution patterns, habitat use and fish size distributions in large rivers.
Full Exceptional Collections on Lagrangian Grassmannians
Authors: Fonarev Anton
Published: April 2020

We show fullness of the exceptional collections of maximal length constructed by Kuznetsov and Polishchuk in the bounded derived categories of coherent sheaves on Lagrangian Grassmannians.
Scalability and cost-effectiveness analysis of whole genome-wide association studies on Google Cloud Platform and Amazon Web Services
Authors: Krissaane Inès , De Niz Carlos , Gutiérrez-Sacristán Alba , Korodi Gabor , Ede Nneka , Kumar Ranjay , Lyons Jessica , Manrai Arjun , Patel Chirag , Kohane Isaac , Avillach Paul
Published: April 2020

Objective

Advancements in human genomics have generated a surge of available data, fueling the growth and accessibility of databases for more comprehensive, in-depth genetic studies.

Methods

We provide a straightforward and innovative methodology to optimize cloud configuration in order to conduct genome-wide association studies. We utilized Spark clusters on both Google Cloud Platform and Amazon Web Services, as well as Hail (http://doi.org/10.5281/zenodo.2646680) for analysis and exploration of genomic variants dataset.

Results

Comparative evaluation of numerous cloud-based cluster configurations demonstrate a successful and unprecedented compromise between speed and cost for performing genome-wide association studies on 4 distinct whole-genome sequencing datasets. Results are consistent across the 2 cloud providers and could be highly useful for accelerating research in genetics.

Conclusions

We present a timely piece for one of the most frequently asked questions when moving to the cloud: what is the trade-off between speed and cost?
The N-terminal amino-latch region of Hlg2 component of staphylococcal bi-component γ-haemolysin is dispensable for prestem release to form β-barrel pores
Authors: Takeda Kein , Tanaka Yoshikazu , Kaneko Jun
Published: April 2020

The contribution of N-terminal regions of staphylococcal bi-component γ-haemolysin toxin components to haemolytic activity towards human erythrocyte cells was investigated in this study. A deletion construct of N-terminal amino acids 1–10 of Hlg2 (Hlg2 ΔN10), which is the S-component protein of γ-haemolysin, had little effect on its haemolytic activity, whereas N-terminal 1–11 amino acid deletion (Hlg2 ΔN11) significantly delayed haemolysis. Moreover, a deletion of N-terminal amino acids 1–17 of LukF, which is the F-component protein of γ-haemolysin, increased its haemolytic activity in combination with either the wild-type or Hlg2 ΔN10. Unlike the N-terminal amino-latch region of staphylococcal α-haemolysin, which is a single component β-barrel pore-forming toxin, the N-terminal regions present in γ-haemolysin components are dispensable for the haemolytic activity of the bi-component toxin. These results strengthen our recent proposal that staphylococcal bi-component γ-haemolysin toxin uses an N-terminal amino-latch independent molecular switch for prestem release during the formation of β-barrel pores.
The Multiple Stories Behind the Modern Ceramic Coffee Tables of the Grand National Assembly of Turkey
Authors: Hasirci Deniz , Tuna Ultav Zeynep
Published: April 2020

At the end of the 1950s, 200 coffee tables and other furniture and fittings were created by interior designers who won a design competition organized by the Grand National Assembly of Turkey (GNAT) in Ankara. The tables were envisioned to be made by modern ceramic artists and designers of the time. Despite never meeting, they created joint works that were celebrated at the time for their artistic quality. The coffee tables, which were used by government ministers, were useful for introducing ceramics into government interiors while informing the leaders of a modernizing Turkish nation about modern art. This study traces the stories behind the creation of these unique artworks based on the personal stories of Füreya Koral, Sadun Ersin, and the Taylan Ceramics Atelier, who were all significant contributors to the history of this furniture. The method used included literature review, a comprehensive archival research through popular magazines, and interviews with artists and designers of the time. The interviews helped uncover data that could not be accessed otherwise. The findings contribute to Turkish and international design history, uncovering artworks and identifying modernist artists and designers of the time in Turkey.
Sherlock at the ICC?
Authors: Braga da Silva Rafael
Published: April 2020

The International Criminal Court (ICC or the Court) is currently suffering from an evidence problem. Since the time the ICC became functional, some judges have criticized the investigative practices of the Office of the Prosecutor (OTP), and some cases have crumbled due to the quality of evidence. This article tackles these problems from the perspective of third-party investigations and their role in ICC cases. It examines the difference between private and public investigators under the legal framework of the Rome Statute to find whether and how third-party investigations can be used in (and by) the ICC. Evidence collected by third-party investigators will likely face challenges of admissibility in being introduced into trial. Those challenges could, however, be overcome if third-party investigations are regulated within the legal framework of the ICC. Ultimately, this article aims to provide a legal framework to optimize the use of third-party investigations in the ICC.
Delayed presentation of a traumatic descending thoracic aorta aneurysm as an aorto-oesophageal fistula
Authors: Mohamed Saifullah , Patel Akshay J , Iqbal Yassir H , Ranasinghe Aaron
Published: April 2020

Aorto-oesophageal fistula is a rarely described but life-threatening complication presenting with upper gastrointestinal haemorrhage. We present a case of a 58-year-old gentleman who presented to a peripheral hospital with a short duration of haematemesis and melaena and recent onset symptoms of dysphagia. This gentleman had a past medical history of alcohol excess and a history of trauma following a road traffic accident 38 years ago. Initial computer tomography scan demonstrated a large saccular aneurysm arising from the descending thoracic aorta adjacent to the oesophagus. The patient underwent radiological stenting of the large aneurysm with thoracic endovascular aortic replacement procedure. Follow-up computerized tomography (CT) angiography demonstrated satisfactory appearances of the thoracic aortic stent graft with no evidence of endo-leak. The triad of dysphagia, occult gastrointestinal blood loss and CT findings of a large aneurysm should prompt diagnosis or aorto-oesophageal fistula until proven otherwise.
The Indian Doctress in the Nineteenth-Century United States: Race, Medicine, and Labor
Authors: Hudson Angela Pulley
Published: April 2020

This article addresses the robust market in “Indian medicine” that flourished in the nineteenth century—partly due to the influence of urbanization, industrialization, and new technologies of print—and the specific roles that Indian doctresses played in that phenomenon. Indian doctresses in the United States operated at the intersection of cultural values and beliefs regarding womanhood, medicine, and American Indians. Not all of these women were of Native ancestry, but they all mobilized widespread ideas about Native peoples while seeking entrepreneurial success as healers. Using print culture, the author analyzes strategies employed by women who worked as Indian doctresses and patterns of reactions to their efforts. By combining profiles of women who worked as Indian doctresses with popular but not always positive representations of the type, the article offers a kind of composite biography of an occupation. Women from a wide variety of backgrounds fused caregiving skills with popular assumptions—particularly those involving “indigenous anti-modernity”—to make a living. In this way, Indian doctresses also became useful symbolic figures upon whom changing conceptions of race, gender, and class could be projected and debated. The author thus aims to shed new light not only on histories of American medicine but also on the labors of American women and the business of Indian representation during the nineteenth century.
The CLE53–SUNN genetic pathway negatively regulates arbuscular mycorrhiza root colonization in Medicago truncatula
Authors: Karlo Magda , Boschiero Clarissa , Landerslev Katrine Gram , Blanco Gonzalo Sancho , Wen Jiangqi , Mysore Kirankumar S , Dai Xinbin , Zhao Patrick X , de Bang Thomas C
Published: April 2020

Plants and arbuscular mycorrhizal fungi (AMF) engage in mutually beneficial symbioses based on a reciprocal exchange of nutrients. The beneficial character of the symbiosis is maintained through a mechanism called autoregulation of mycorrhization (AOM). AOM includes root-to-shoot-to-root signaling; however, the molecular details of AOM are poorly understood. AOM shares many features of autoregulation of nodulation (AON) where several genes are known, including the receptor-like kinase SUPER NUMERIC NODULES (SUNN), root-to-shoot mobile CLAVATA3/ENDOSPERM SURROUNDING REGION (ESR)-RELATED (CLE) peptides, and the hydroxyproline O-arabinosyltransferase ROOT DETERMINED NODULATION1 (RDN1) required for post-translational peptide modification. In this work, CLE53 was identified to negatively regulate AMF symbiosis in a SUNN- and RDN1-dependent manner. CLE53 expression was repressed at low phosphorus, while it was induced by AMF colonization and high phosphorus. CLE53 overexpression reduced AMF colonization in a SUNN- and RDN1 dependent manner, while cle53, rdn1, and sunn mutants were more colonized than the wild type. RNA-sequencing identified 700 genes with SUNN-dependent regulation in AMF-colonized plants, providing a resource for future identification of additional AOM genes. Disruption of AOM genes in crops potentially constitutes a novel route for improving AMF-derived phosphorus uptake in agricultural systems with high phosphorus levels.
Performance characteristics of Fungitell STAT™, a rapid (1→3)-β-D-glucan single patient sample in vitro diagnostic assay
Authors: D'Ordine Robert L , Garcia Kevin A , Roy Josee , Zhang Yonglong , Markley Barbara , Finkelman Malcolm A
Published: April 2020

Serum (1→3)-β-D-glucan (BDG), is an adjunct test in the diagnosis of invasive fungal disease (IFD). Fungitell STAT™, a facile, rapid, single patient option, executable for one or more patient specimens in approximately an hour, has been developed to address a need for rapid in-house testing. This method presents qualitative information concerning serum BDG levels, using an index value that allows the rapid categorization of patients as positive, negative, or indeterminate relative to serum BDG titer. The categorical and analytical performance of Fungitell STAT was evaluated. The categorical agreement between methods was established by testing patient samples which had been previously categorized with Fungitell. Receiver Operating Characteristic curves were used to identify cut-offs using 93 de-identified patient specimens. Subsequently, using these cutoffs, an independent group of 488 patient specimens was analyzed. Positive percent agreement (PPA) with, and without, indeterminate results was 74% and 99%, respectively. Negative percent agreement (NPA) was 91% and 98% with, and without, indeterminate results, respectively. Additionally, commercially available normal off-the-clot sera were spiked with Saccharomyces cerevisiae-derived (1→3)-β-D-glucan to produce analytical samples. Analytical reproducibility using spiked samples was excellent with 94% of the CV (coefficient of variation) values ≤10% among three independent laboratories. Good correlation with the predicate method was demonstrated with correlation coefficients of 0.90 or better with patient samples and 0.99 with spiked samples. The Fungitell STAT index assay provides a rapid and suitable method for serum BDG testing.
Effect of bars on evolution of SDSS spiral galaxies
Authors: Kim Minbae , Choi Yun-Young , Kim Sungsoo S
Published: April 2020

We explore the significance of bars in triggering central star formation (SF) and active galactic nucleus (AGN) activity for spiral galaxy evolution using a volume-limited sample with 0.020 < z < 0.055, Mr < −19.5, and σ > 70 km s−1 selected from Sloan Digital Sky Survey Data Release 7. On a central SF rate–σ plane, we measure the fraction of galaxies with strong bars in our sample and also the AGN fractions for barred and non-barred galaxies, respectively. The comparison between the bar and AGN fractions reveals a causal connection between the two phenomena of SF quenching and AGN activity. A massive black hole and abundant gas fuels are sufficient conditions to trigger AGNs. We infer that the AGNs triggered by satisfying the two conditions drive the strong AGN feedback, suddenly suppressing the central SF and leaving the SF sequence. We find that in galaxies where either of the two conditions is not sufficient, bars are a great help for the AGN triggering, accelerating the entire process of evolution, which is particularly evident in pseudo-bulge galaxies. All of our findings are obtained only when plotted in terms of their central velocity dispersion and central SFR (not galactic scale SFR), indicating that the AGN-driven SF quenching is confined in the central kpc region.
Not all stars form in clusters – Gaia-DR2 uncovers the origin of OB associations
Authors: Ward Jacob L , Kruijssen J M Diederik , Rix Hans-Walter
Published: April 2020

Historically, it has often been asserted that most stars form in compact clusters. In this scenario, present-day gravitationally unbound OB associations are the result of the expansion of initially gravitationally bound star clusters. However, this paradigm is inconsistent with recent results, both theoretical and observational, that instead favour a hierarchical picture of star formation in which stars are formed across a continuous distribution of gas densities and most OB associations never were bound clusters. Instead they are formed in situ as the low-density side of this distribution, rather than as the remnants of expanding clusters. We utilize the second Gaia data release to quantify the degree to which OB associations are undergoing expansion and, therefore, whether OB associations are the product of expanding clusters, or whether they were born in situ, as the large-scale globally unbound associations that we see today. We find that the observed kinematic properties of associations are consistent with highly substructured velocity fields and additionally require some degree of localized expansion from subclusters within the association. While most present-day OB associations do exhibit low levels of expansion, there is no significant correlation between radial velocity and radius. Therefore, the large-scale structure of associations is not set by the expansion of clusters, rather it is a relic of the molecular gas cloud from which the association was formed. This finding is inconsistent with a monolithic model of association formation and instead favours a hierarchical model, in which OB associations form in situ, following the fractal structure of the gas from which they form.
SPEED2: inferring upstream pathway activity from differential gene expression
Authors: Rydenfelt Mattias , Klinger Bertram , Klünemann Martina , Blüthgen Nils
Published: April 2020

Extracting signalling pathway activities from transcriptome data is important to infer mechanistic origins of transcriptomic dysregulation, for example in disease. A popular method to do so is by enrichment analysis of signature genes in e.g. differentially regulated genes. Previously, we derived signatures for signalling pathways by integrating public perturbation transcriptome data and generated a signature database called SPEED (Signalling Pathway Enrichment using Experimental Datasets), for which we here present a substantial upgrade as SPEED2. This web server hosts consensus signatures for 16 signalling pathways that are derived from a large number of transcriptomic signalling perturbation experiments. When providing a gene list of e.g. differentially expressed genes, the web server allows to infer signalling pathways that likely caused these genes to be deregulated. In addition to signature lists, we derive ‘continuous’ gene signatures, in a transparent and automated fashion without any fine-tuning, and describe a new algorithm to score these signatures.
On-target activity predictions enable improved CRISPR–dCas9 screens in bacteria
Authors: Calvo-Villamañán Alicia , Ng Jérome Wong , Planel Rémi , Ménager Hervé , Chen Arthur , Cui Lun , Bikard David
Published: April 2020

The ability to block gene expression in bacteria with the catalytically inactive mutant of Cas9, known as dCas9, is quickly becoming a standard methodology to probe gene function, perform high-throughput screens, and engineer cells for desired purposes. Yet, we still lack a good understanding of the design rules that determine on-target activity for dCas9. Taking advantage of high-throughput screening data, we fit a model to predict the ability of dCas9 to block the RNA polymerase based on the target sequence, and validate its performance on independently generated datasets. We further design a novel genome wide guide RNA library for E. coli MG1655, EcoWG1, using our model to choose guides with high activity while avoiding guides which might be toxic or have off-target effects. A screen performed using the EcoWG1 library during growth in rich medium improved upon previously published screens, demonstrating that very good performances can be attained using only a small number of well designed guides. Being able to design effective, smaller libraries will help make CRISPRi screens even easier to perform and more cost-effective. Our model and materials are available to the community through crispr.pasteur.fr and Addgene.
DXO/Rai1 enzymes remove 5′-end FAD and dephospho-CoA caps on RNAs
Authors: Doamekpor Selom K , Grudzien-Nogalska Ewa , Mlynarska-Cieslak Agnieszka , Kowalska Joanna , Kiledjian Megerditch , Tong Liang
Published: April 2020

In eukaryotes, the DXO/Rai1 enzymes can eliminate most of the incomplete and non-canonical NAD caps through their decapping, deNADding and pyrophosphohydrolase activities. Here, we report that these enzymes can also remove FAD and dephospho-CoA (dpCoA) non-canonical caps from RNA, and we have named these activities deFADding and deCoAping. The crystal structures of mammalian DXO with 3′-FADP or CoA and fission yeast Rai1 with 3′-FADP provide elegant insight to these activities. FAD and CoA are accommodated in the DXO/Rai1 active site by adopting folded conformations. The flavin of FAD and the pantetheine group of CoA contact the same region at the bottom of the active site tunnel, which undergoes conformational changes to accommodate the different cap moieties. We have developed FAD-capQ to detect and quantify FAD-capped RNAs and determined that FAD caps are present on short RNAs (with less than ∼200 nucleotides) in human cells and that these RNAs are stabilized in the absence of DXO.
Fuse to defuse: a self-limiting ribonuclease-ring nuclease fusion for type III CRISPR defence
Authors: Samolygo Aleksei , Athukoralage Januka S , Graham Shirley , White Malcolm F
Published: April 2020

Type III CRISPR systems synthesise cyclic oligoadenylate (cOA) second messengers in response to viral infection of bacteria and archaea, potentiating an immune response by binding and activating ancillary effector nucleases such as Csx1. As these effectors are not specific for invading nucleic acids, a prolonged activation can result in cell dormancy or death. Some archaeal species encode a specialised ring nuclease enzyme (Crn1) to degrade cyclic tetra-adenylate (cA4) and deactivate the ancillary nucleases. Some archaeal viruses and bacteriophage encode a potent ring nuclease anti-CRISPR, AcrIII-1, to rapidly degrade cA4 and neutralise immunity. Homologues of this enzyme (named Crn2) exist in type III CRISPR systems but are uncharacterised. Here we describe an unusual fusion between cA4-activated CRISPR ribonuclease (Csx1) and a cA4-degrading ring nuclease (Crn2) from Marinitoga piezophila. The protein has two binding sites that compete for the cA4 ligand, a canonical cA4-activated ribonuclease activity in the Csx1 domain and a potent cA4 ring nuclease activity in the C-terminal Crn2 domain. The cA4 binding affinities and activities of the two constituent enzymes in the fusion protein may have evolved to ensure a robust but time-limited cOA-activated ribonuclease activity that is finely tuned to cA4 levels as a second messenger of infection.
Phosphorothioate modified oligonucleotide–protein interactions
Authors: Crooke Stanley T , Vickers Timothy A , Liang Xue-hai
Published: April 2020

Antisense oligonucleotides (ASOs) interact with target RNAs via hybridization to modulate gene expression through different mechanisms. ASO therapeutics are chemically modified and include phosphorothioate (PS) backbone modifications and different ribose and base modifications to improve pharmacological properties. Modified PS ASOs display better binding affinity to the target RNAs and increased binding to proteins. Moreover, PS ASO protein interactions can affect many aspects of their performance, including distribution and tissue delivery, cellular uptake, intracellular trafficking, potency and toxicity. In this review, we summarize recent progress in understanding PS ASO protein interactions, highlighting the proteins with which PS ASOs interact, the influence of PS ASO protein interactions on ASO performance, and the structure activity relationships of PS ASO modification and protein interactions. A detailed understanding of these interactions can aid in the design of safer and more potent ASO drugs, as illustrated by recent findings that altering ASO chemical modifications dramatically improves therapeutic index.
Measured sodium excretion is associated with CKD progression: results from the KNOW-CKD study
Authors: Kang Minjung , Kang Eunjeong , Ryu Hyunjin , Hong Yeji , Han Seung Seok , Park Sue K , Hyun Young Youl , Sung Su Ah , Kim Soo Wan , Yoo Tae-Hyun , Kim Jayoun , Ahn Curie , Oh Kook-Hwan
Published: April 2020

Background

Diet is a modifiable factor of chronic kidney disease (CKD) progression. However, the effect of dietary salt intake on CKD progression remains unclear. Therefore, we analyzed the effect of dietary salt intake on renal outcome in Korean patients with CKD.

Methods

We measured 24-h urinary sodium (Na) excretion as a marker of dietary salt intake in the prospective, multi-center, longitudinal KoreaN cohort study for Outcome in patients With CKD (KNOW-CKD). Data were analyzed from CKD patients at Stages G3a to G5 (n = 1254). We investigated the association between dietary salt intake and CKD progression. Patients were divided into four quartiles of dietary salt intake, which was assessed using measured 24-h urinary Na excretion. The study endpoint was composite renal outcome, which was defined as either halving the estimated glomerular filtration rate or developing end-stage renal disease.

Results

During a median (interquartile range) follow-up of 4.3 (2.8–5.8) years, 480 (38.7%) patients developed the composite renal event. Compared with the reference group (Q2, urinary Na excretion: 104.2 ≤ Na excretion < 145.1 mEq/day), the highest quartile of measured 24-h urinary Na excretion was associated with risk of composite renal outcome [Q4, urinary Na excretion ≥192.9 mEq/day, hazard ratio 1.8 (95% confidence interval 1.12–2.88); P = 0.015] in a multivariable hazards model. Subgroup analyses showed that high-salt intake was particularly associated with a higher risk of composite renal outcome in women, in patients <60 years of age, in those with uncontrolled hypertension and in those with obesity.

Conclusions

High salt intake was associated with increased risk of progression in CKD.
Clinical and immunological characteristics of 56 patients with systemic lupus erythematosus in Uganda
Authors: Bongomin Felix , Sekimpi Maria , Kaddumukasa Mark
Published: April 2020

Objectives

The prevalence and burden of SLE in Africa are poorly understood. This health-facility-based retrospective study aimed to describe the frequency and the clinical and immunological characteristics of SLE in Uganda.

Methods

We reviewed clinical notes of patients presenting with rheumatological complaints in two large rheumatology outpatient clinics in Uganda between January 2014 and December 2019.

Results

Of the 1019 charts reviewed, 5.5% (56) of the patients had confirmed SLE, with a median age of 29 (range: 14–65) years. The male-to-female ratio was ∼1:10, and 19.6% (11/56) of the patients had SLE and RA overlap syndrome. Patients presented with joint pains or swellings (n = 39, 69.6%), typical photosensitive malar rash (n = 34, 60.7%), oral ulceration (n = 23, 41.1%), anaemia (n = 14, 25.0%), hair loss and polyserositis (n = 12, 21.4% each), constitutional symptoms (n = 10, 17.9%), RP (n = 4, 7.1%) or LN (n = 3, 5.4%). ANA and anti-dsDNA autoantibodies were both positive in 25 (75.8%) of the 33 patients with available results. ANA titres were ≥1:160, with a median titre of 1:160 (range: 1:160 to 1:3200). Six patients had titres ≥1:320. The median dsDNA level was 80 (range: 40–283) IU. Ten patients had results of C3 and C4 complement protein levels and, of these, 4 patients had low C3 levels and 3 had low C4 levels.

Conclusion

SLE is uncommon among patients presenting with rheumatological complains in Uganda. SLE overlaps with RA in our setting, and a majority of patients present to care with complications.