bluuebunny/crossref_metadata_2025 huggingface dataset:
Generalized logistic growth modeling of the COVID-19 outbreak in 29 provinces in China and in the rest of the world
Authors: Wu Ke , Darcet Didier , Wang Qian , Sornette Didier
Published: March 2020

Background

the COVID-19 has been successfully contained in China but is spreading all over the world. We use phenomenological models to dissect the development of the epidemics in China and the impact of the drastic control measures both at the aggregate level and within each province. We use the experience from China to analyze the calibration results on Japan, South Korea, Iran, Italy and Europe, and make future scenario projections.

Methods

we calibrate the logistic growth model, the generalized logistic growth model, the generalized growth model and the generalized Richards model to the reported number of infected cases from Jan. 19 to March 10 for the whole of China, 29 provinces in China, four severely affected countries and Europe as a whole. The different models provide upper and lower bounds of our scenario predictions.

Results

We quantitatively document four phases of the outbreak in China with a detailed analysis on the heterogenous situations across provinces. Based on Chinese experience, we identify a high risk in Japan with estimated total confirmed cases as of March 25 being 1574 (95% CI: [880, 2372]), and 5669 (95% CI: [988, 11340]) by June. For South Korea, we expect the number of infected cases to approach the ceiling, 7928 (95% CI: [6341, 9754]), in 20 days. We estimate 0.15% (95% CI: [0.03%, 0.30%]) of Italian population to be infected in a positive scenario. We would expect 114867 people infected in Europe in 10 days, in a negative but probable scenario, corresponding to 0.015% European population.

Conclusions

The extreme containment measures implemented by China were very effective with some instructive variations across provinces. For other countries, it is almost inevitable to see the continuation of the outbreak in the coming months. Japan and Italy are in serious situations with no short-term end to the outbreak to be expected. There is a significant risk concerning the upcoming July 2020 Summer Olympics in Tokyo. Iran’s situation is highly uncertain with unclear and negative future scenarios, while South Korea is approaching the end of the outbreak. Both Europe and the USA are at early stages of the outbreak, posing significant health and economic risks to the world in absence of serious measures.
Improving prognosis of surrogate assay for breast cancer patients by absolute quantitation of Ki67 protein levels using Quantitative Dot Blot (QDB) method
Authors: Hao Junmei , Lv Yan , Zou Jiarui , Zhang Yunyun , Xie Shuishan , Jing Lili , Tang Fangrong , Lv Jiahong , Wang Xunting , Zhang Jiandi
Published: March 2020

Purpose

The separation of Luminal A-like from Luminal B-like breast cancer subtypes in surrogate assay relies on Ki67 scores assessed by immunohistochemistry (IHC), a method known to be associated with subjectivity and inconsistency. We attempted to measure Ki67 levels absolutely, quantitatively and objectively in Formalin Fixed Paraffin Embedded (FFPE) specimens, and evaluate its influence on the performance of surrogate assay for breast cancer patients.

Methods

The Ki67 protein levels were assessed using both IHC and Quantitative Dot Blot (QDB) methods respectively in 253 specimens. These patients were assigned into Luminal A-like and Luminal B-like subtypes using either Ki67 score of 14% as cutoff in surrogate assay, or 2.31 nmole/g from QDB method as cutoff in adjusted surrogate assay. These two subtyping methods were compared with the Kaplan-Meier, univariate and multivariate survival analyses of the overall survival (OS) of Luminal-like patients.

Results

Ki67 levels measured using QDB method was highly correlated with those by IHC analysis (r=0.7, p<0.0001). The survival prediction for Luminal A-like patients was improved significantly in adjusted surrogate assay than surrogate assay (p=0.03 vs p<0.00052). The prediction of Hazard Ratio (HR) was also improve from 2.14 (95%CI: 0.89-5.11, p=0.087) to 6.89 (95%CI: 2.66-17.84, p<0.00001) in multivariate survival analysis.

Conclusion

Our study demonstrated that the inherent subjectivity and inconsistency associated with IHC analysis has adverse effect on the performance of surrogate assay.

This issue can be improved by objective and quantitative measurement of Ki67 levels with QDB method in daily clinical practice.
Molecular landscape of pelvic organ prolapse provides insights into disease etiology and clues towards putative novel treatments
Authors: Kluivers Kirsten B. , Lince Sabrina L. , Ruiz-Zapata Alejandra M. , Cartwright Rufus , Kerkhof Manon H. , Widomska Joanna , De Witte Ward , Post Wilke M. , Pecanka Jakub , Kiemeney Lambertus A. , Vermeulen Sita H. , Goeman Jelle J. , Allen-Brady Kristina , Oosterwijk Egbert , Poelmans Geert
Published: March 2020

Background

Pelvic organ prolapse (POP) represents a major health care burden in women but its underlying pathophysiological mechanisms have not been elucidated.

Objective

To integrate the results from a large scale exome chip study with published genetic and expression data into a molecular landscape of POP.

Design, setting, and participants

The exome chip study was conducted in 526 women with POP and 960 healthy controls. To corroborate the findings, we analysed differential gene expression data from 12 POP patients. Vaginal fibroblasts from 4 women with POP were used to test the effect of the anti-diabetic drug metformin.

Outcome measurements and statistical analysis

The exome chip study used a case-control design to identify single nucleotide variants (SNVs) associated with POP after Bonferroni correction. The molecular landscape was built using the UniProt and PubMed databases to identify functional interactions between the POP candidate genes/proteins. We performed enrichment and upstream regulator analyses of the differentially expressed genes. The effect of metformin in fibroblasts was assessed using one-sample t-test.

Results and limitations

We found significant association between POP and SNVs in 54 genes. The proteins encoded by 26 of these genes fit into a molecular landscape, together with 37 other POP candidate molecules and two POP-implicated microRNAs. This landscape is located in and around epithelial cells and fibroblasts of the urogenital tract and harbors four interacting biological processes - epithelial-mesenchymal transition, immune response, modulation of the extracellular matrix, and fibroblast function - that are regulated by sex hormones and TGFB1. Based on the landscape, we predicted and showed that metformin alters gene expression in fibroblasts of POP patients in a beneficial direction. The main limitation of our study is that we have no independent replication of the exome chip results.

Conclusions

The integrated molecular landscape of POP that we built provides insights into the biological processes underlying the disease and clues towards novel treatments.

Patient summary

We reported the first exome chip study of POP and combined the genes identified in this study with other data from the literature to build a ‘molecular landscape’ of POP. This landscape will advance our understanding of the disease and may lead to novel treatments.
Rational evaluation of various epidemic models based on the COVID-19 data of China
Authors: Yang Wuyue , Zhang Dongyan , Peng Liangrong , Zhuge Changjing , Hong Liu
Published: March 2020

During the study of epidemics, one of the most significant and also challenging problems is to forecast the future trends, on which all follow-up actions of individuals and governments heavily rely. However, to pick out a reliable predictable model/method is far from simple, a rational evaluation of various possible choices is eagerly needed, especially under the severe threat of COVID-19 epidemics which is spreading worldwide right now.

In this paper, based on the public COVID-19 data of seven provinces/cities in China reported during the spring of 2020, we make a systematical investigation on the forecast ability of eight widely used empirical functions, four statistical inference methods and five dynamical models widely used in the literature. We highlight the significance of a well balance between model complexity and accuracy, over-fitting and under-fitting, as well as model robustness and sensitivity. We further introduce the Akaike information criterion, root mean square errors and robustness index to quantify these three golden means and to evaluate various epidemic models/methods.

Through extensive simulations, we find that the inflection point plays a crucial role in the choice of the size of dataset in forecasting. Before the inflection point, no model considered here could make a reliable prediction. We further notice the Logistic function steadily underestimate the final epidemic size, while the Gomertz's function makes an overestimation in all cases. Since the methods of sequential Bayesian and time-dependent reproduction number take the non-constant nature of the effective reproduction number with the progression of epidemics into consideration, we suggest to employ them especially in the late stage of an epidemic. The transition-like behavior of exponential growth method from underestimation to overestimation with respect to the inflection point might be useful for constructing a more reliable forecast. Towards the dynamical models based on ODEs, it is observed that the SEIR-QD and SEIR-PO models generally show a better performance than SIR, SEIR and SEIR-AHQ models on the COVID-19 epidemics, whose success could be attributed to the inclusion of self-protection and quarantine, and a proper trade-off between model complexity and fitting accuracy.
Ocular manifestations and clinical characteristics of 534 cases of COVID-19 in China: A cross-sectional study
Authors: Chen Liwen , Deng Chaohua , Chen Xuhui , Zhang Xian , Chen Bo , Yu Huimin , Qin Yuanjun , Xiao Ke , Zhang Hong , Sun Xufang
Published: March 2020

Objective

The novel coronavirus disease (COVID-19) was first reported in Wuhan, China in December 2019 and is now pandemic all over the world. Previous study has reported several COVID-19 cases with conjunctivitis. However, the complete profiling of COVID-19 related ocular symptoms and diseases are still missing. We aim to investigate the ocular manifestations and clinical characteristics of COVID-19 patients.

Methods

A total of five hundred and thirty-four patients were recruited at Mobile Cabin Hospital and Tongji Hospital. We collected information on demographic characteristics, exposure history, ocular symptoms, systemic concomitant symptoms, eye drop medication, eye protections, radiologic findings, and SARS-CoV-2 detection in nasopharyngeal swabs by RT-PCR from questionnaires and electronic medical records.

Results

The median age of patients was 40 and 50 years at Mobile Cabin Hospital and Tongji Hospital, respectively. Of 534 COVID-19 patients, 25 patients (4.68%) presented with conjunctival congestion and 3 patients had conjunctival congestion as the initial symptom. The average duration of conjunctival congestion was 4.9 ± 2.6 days (mean [SD]), ranging from 2 to 10 days. Dry eye (112, 20.97%), blurred vision (68, 12.73%), and foreign body sensation (63, 11.80%) ranked as the top three COVID-19 related ocular symptoms. Notably, a total of 332 COVID-19 patients (62%) had a hand-eye contact history. We also found that some COVID-19 patients had a history of eye disease, including conjunctivitis (33, 6.18%), dry eye (24, 4.49%), keratitis (14, 2.62%), cataract (9, 1.69%), and diabetic retinopathy (5, 0.94%). In consistent with previous studies, the most common clinical symptoms were fever, cough, and fatigue. Patients, 60.5% in Mobile Cabin Hospital and 67.5% in Tongji Hospital, respectively were confirmed with positive SARS-CoV-2 detection.

Conclusions

Conjunctival congestion was one of the COVID-19 related ocular symptoms, which may have clinical diagnostic significance. It is essential to provide eye-care equipment and strengthen education on eye protection, as dirty hand-eye contact might be a high risk factor of COVID-19. Further detailed and comprehensive ophthalmological guidance is needed for COVID-19 control.
Calcium-sensing receptor antagonism as a novel therapeutic for pulmonary fibrosis
Authors: Wolffs Kasope L. , Mansfield Bethan , Bruce Richard T. , Huang Ping , Schepelmann Martin , Brennan Sarah C , Verckist Line , Adriaensen Dirk , De Araújo Rachel Paes , Mur Luis A.J. , Attanoos Richard , Lewis Keir E. , Ward Jeremy P.T. , Corrigan Christopher J. , Kemp Paul J. , Hope-Gill Benjamin D. , Riccardi Daniela
Published: March 2020

Background

Idiopathic pulmonary fibrosis (IPF) is a disease with very poor prognosis and no curative therapies. The G protein-coupled, calcium/cation-sensing receptor (CaSR) is activated by environmental pollutants and by arginine-derived polyamines, which are thought to play a role in IPF. Whether the CaSR is involved in the pathogenesis of pulmonary fibrosis is unknown.

Objective

To investigate the CaSR as a novel drug target for the treatment of pulmonary fibrosis (PF).

Methods and results

CaSR protein expression is found in the airway epithelium in the neuroepithelial bodies of the healthy and IPF human lung. Expression of arginine pathway-linked polyamines is increased in PF patient saliva samples compared to non-PF patients. Arginine pathway metabolites, ornithine and spermine, activate the CaSR in primary normal human lung fibroblasts (NHLF), effects prevented by CaSR antagonism using the calcilytic NPS2143. In NHLF calcilytic also reversed the pro-fibrotic effects of exogenous TGFβ1 administration on Rho kinase and αSMA expression, proliferation, collagen production and IL-8 secretion. Targeted CaSR ablation from fibroblasts and smooth muscle cells protects mice from spontaneously occurring, age-related lung fibrosis.

Conclusions

Sustained CaSR activation in the lung drives pro-fibrotic processes, which can be reversed by calcilytic. Pharmacological and genetic CaSR blockade reduce both TGFβ1-induced and naturally occurring pro-fibrotic changes. This work provides the scientific rationale for developing inhaled calcilytics as novel therapeutics for IPF.

KEY MESSAGES

Key question

How does the calcium/cation-sensing receptor (CaSR) promote pulmonary fibrosis?

Bottom line

The CaSR is expressed in human IPF and experimental models of PF where receptor inhibition prevents pro-fibrotic changes and pulmonary remodeling.

Why read on

CaSR blockers, calcilytics, represent a novel treatment for IPF.
Adventurousness cuts both ways: a Mendelian randomization of adventurousness on 10 cognitive and behavioral traits
Authors: Adams Charleen D. , Boutwell Brian B.
Published: March 2020

Adventurousness is speculated to improve happiness but also predispose to risky behaviors. Since non-experimental studies can suffer from confounding and reverse causation, and personality traits cannot be randomized, it is challenging to unravel how adventurousness impacts the mind and behavior. Mendelian randomization (MR), a quasi-randomization technique that uses genetic variants as instruments to avoid confounding and reverse causation, is an attractive option in this setting. We used MR to explore self-reported adventurousness and 10 cognitive and behavioral traits. Adventurousness decreased neuroticism and mood swings and increased years of schooling. In contrast, it also predisposed to risky behaviors (increasing the number of lifetime sexual partners, the propensity to speed in an automobile, and lifetime smoking, and decreasing the age of first having sexual intercourse). The results suggest being adventurous “cuts both ways”, evincing bivalent influences and underscoring the reality that trade-offs often accompany many human personality constructs.
Long-term effects of caesarean delivery on health and behavioural outcomes of the mother and child in Bangladesh
Authors: Khan Md. Nuruzzaman , Rahman Md. Mostafizur , Rahman Md Aminur , Alam Mahmudul , Khan Md. Alam
Published: March 2020

Background

Increasing rate of unnecessary caesarean section (CS) is now reported worldwide that intensified the occurrence of adverse health outcomes for mother-child dyads. We investigated the association of CS with some basic health and behaviour outcomes of the mother-child dyads in Bangladesh.

Methods

We conducted a community based case-control study from May to August 2019. Total of 600 (300 had CS, and 300 had vaginal delivery (VD)) mother-child dyads were interviewed through a structured questionnaire. Method of delivery was the exposure variable classified as CS and VD. The outcome variables were a group of health and behaviour problems of the mothers and their children. A series of binary logistic regression models were carried out to examine the effects of the exposure variable on outcome variables. Mother’s socio-demographic and reproductive characteristics were adjusted in the models.

Results

The mean maternal age (±SD) and weight were 25.1 (±5.2) years and 53.1 (±7.2) kilogram, respectively. Higher likelihood of headache, after delivery hip pain, problem of daily activities, and breastfeeding problem were reported among mother had CS in their last birth than VD. Children born through the CS were reported a higher likelihood of breathing problem and frequent illness and a lower likelihood of food demand and sleeping.

Conclusion

The occurrence of CS increases the risk of health and behaviour problems among mothers and their children. This suggests the need for polices to avoid unnecessary CS and to increase awareness of adverse effects of CS. Frequent health checkup following CS is also important.
Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules
Authors: Nabet Behnam , Ferguson Fleur M. , Seong Bo Kyung A. , Kuljanin Miljan , Leggett Alan L. , Mohardt Mikaela L. , Robichaud Amanda , Conway Amy S. , Buckley Dennis L. , Mancias Joseph D. , Bradner James E. , Stegmaier Kimberly , Gray Nathanael S.
Published: March 2020

Chemical biology strategies for directly perturbing protein homeostasis including the degradation tag (dTAG) system provide temporal advantages over genetic approaches and improved selectivity over small molecule inhibitors. We describe dTAGV-1, an exclusively selective VHL-recruiting dTAG molecule, to rapidly degrade FKBP12F36V-tagged proteins. dTAGV-1 overcomes a limitation of previously reported CRBN-recruiting dTAG molecules to degrade recalcitrant oncogenes, supports combination degrader studies and facilitates investigations of protein function in cells and mice.
Visualising uncertainty in brightfield to fluorescent image inference withBFNet
Authors: Warchal Scott , Gautier Célia , Dorval Thierry , Stephan Jean-Philippe
Published: March 2020

Predicting fluorescently labelled cellular structures from brightfield images is a recent application of convolutional neural networks and has already proven a valuable tool in biological imaging studies. These methods reduce the need for time-consuming manual annotations for supervised datasets, potentially reduce the costs in high-throughput imaging screens, and open up a number of potentially novel analyses. However as with any prediction there can be sources of error and uncertainty. Here we present BFNet, a method to visualise the uncertainty in predicted images by applying Monte Carlo dropout during inference and calculating per-pixel variance as an uncertainty map. Our method demonstrates the ability to highlight regions of an image where prediction is difficult or impossible due to imaging artefacts such as occlusions or out-of-focus images, as well as more general uncertainty when a trained model is applied to new data from different imaging of experimental settings. We have provided a python implementation of the method which is available atgithub.com/swarchal/bfnet.
Long-read shotgun metagenome sequencing using PromethION uncovers novel bacteriophages, their abundance, and interaction with host bacterial immunity in the oral microbiota
Authors: Yahara Koji , Suzuki Masato , Hirabayashi Aki , Suzuki Yutaka , Okazaki Yusuke
Published: March 2020

Bacteriophages (phages), or bacterial viruses, are very diverse and highly abundant worldwide, including human microbiomes. Although a few metagenomic studies have focused on oral phages, they relied on short-read sequencing. Here, we conducted a long-read metagenomic study of human saliva for the first time using PromethION that requires a smaller amount of DNA than PacBio. Our analyses, which integrated both PromethION and HiSeq data of >30 Gb per sample, revealed N50 ranging from 187-345 kb and thousands of contigs with >1 kb accounting for > 99% of all contigs on which 94-96% of HiSeq reads were mapped. We identified hundreds of viral contigs (95 phages and 333 prophages on an average per sample); 0-43.8% and 12.5-56.3% of the “most confident” phages and prophages, respectively, didn’t cluster with those reported previously and were identified as novel. Our integrated analyses identified highly abundant oral phages/prophages, including a novelStreptococcusphage cluster and nine jumbo phages/prophages. Interestingly, 86% of the phage cluster and 67% of the jumbo phages/prophages contained remote homologs of antimicrobial resistance genes, suggesting their potential role as a source of recombination to generate new resistance genes. Pan-genome analysis of the phages/prophages revealed remarkable diversity, identifying 0.3% and 86.4% of the genes as core and singletons, respectively. Functional annotation revealed that the highest fraction of the core genes was enriched in phage morphogenesis, followed by the fraction enriched in host cellular processes. Furthermore, our study suggested that oral phages present in human saliva are under selective pressure for escaping CRISPR immunity.

Importance

Despite the abundance and grave implications oral bacterial viruses in health and disease, little is known regarding the different groups of oral bacterial viruses, their relative abundances under various conditions, and their activities. We provided answers to these questions for the first time utilizing a recently developed sequencer that can capture and sequence long DNA fragments, including viruses, and requires only a small amount of DNA input, making it suitable for analyzing human oral samples. We identified hundreds of viral sequences, including “jumbo” viruses and a distinctive group of highly abundant oral viruses, which often contained parts of antimicrobial resistance genes; the entire repertoire of these viral genes showed remarkable diversity and supported a recently proposed hypothesis that phages modulate oral microbiota through multiple mechanisms. We also revealed genomic signs of coevolution of viruses and host bacteria that have been missed in large viromic studies in humans.
HflX controls hypoxia-induced non-replicating persistence in slow growing mycobacteria
Authors: Ngan Jie Yin Grace , Pasunooti Swathi , Tse Wilford , Meng Wei , Ngan So Fong Cam , Ng Sze Wai , Jaafar Muhammad Taufiq , Jia Huan , Cho Su Lei Sharol , Lim Jieling , Koh Hui Qi Vanessa , Abdulghani Noradibah , Pethe Kevin , Sze Siu Kwan , Lescar Julien , Alonso Sylvie
Published: March 2020

GTPase HflX is highly conserved in prokaryotes and is a ribosome splitting factor during heat shock inE. coli.Here we report that HflX produced by slow growingM. tuberculosisandM. bovisBCG is a GTPase that plays a critical role in the pathogen’s transition to a non-replicating, drug-tolerant state in response to hypoxia. Indeed, HflX-deficientM. bovisBCG (KO) replicated markedly faster in the microaerophilic phase of a hypoxia model, that precipitated entry into dormancy. The KO displayed the hallmarks of dormant mycobacteria including phenotypic drug resistance, altered morphology, low intracellular ATP and up-regulated dormancydosregulon. KO-infected mice displayed increased bacterial burden during the chronic phase of infection, consistent with the higher replication rate observedin vitroin microaerophilic phase. Unlike fast-growing mycobacteria, BCG HlfX was not involved in antibiotic resistance under normoxia. Proteomics, pull-down and ribo-sequencing supported that mycobacterial HflX is a ribosome binding protein that controls the translational activity of the cell. Collectively, our study provides further insights into the mechanisms deployed by mycobacteria to adapt to their hypoxic microenvironment.
Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks
Authors: Elliott Kelsey H. , Chen Xiaoting , Salomone Joseph , Chaturvedi Praneet , Schultz Preston A. , Balchand Sai K. , Servetas Jeffrey D. , Zuniga Aimée , Zeller Rolf , Gebelein Brian , Weirauch Matthew T. , Peterson Kevin A. , Brugmann Samantha A.
Published: March 2020

Despite a common understanding that Gli TFs are utilized to reiterate a Hh morphogen gradient, genetic analyses suggest craniofacial development does not completely fit this paradigm. We demonstrated that rather than being driven by a Hh threshold, robust Gli3 transcriptional activity during skeletal and glossal development required interaction with the bHLH TF Hand2. Not only did genetic and expression data support a co-factorial relationship, but genomic analysis further revealed that Gli3 and Hand2 were enriched at regulatory elements for genes essential for mandibular patterning and development. Interestingly, motif analysis at sites co-occupied by Gli3 and Hand2 uncovered mandibular-specific, low-affinity, ‘divergent’ Gli binding motifs (dGBMs). Functional validation revealed thesedGBMs conveyed synergistic activation of Gli targets essential for mandibular patterning and development. In summary, this work elucidates a novel, sequence-dependent mechanism for Gli transcriptional activity within the craniofacial complex that is independent of a graded Hh signal.
Differential brain activity in visuo-perceptual regions during landmark-based navigation in young and healthy older adults
Authors: Ramanoël Stephen , Durteste Marion , Bécu Marcia , Habas Christophe , Arleo Angelo
Published: March 2020

Older adults exhibit prominent impairments in their capacity to navigate, reorient in unfamiliar environments or update their path when faced with obstacles. This decline in navigational capabilities has traditionally been ascribed to memory impairments and dysexecutive function whereas the impact of visual aging has often been overlooked. The ability to perceive visuo-spatial information such as salient landmarks is essential to navigate in space efficiently. To date, the functional and neurobiological factors underpinning landmark processing in aging remain insufficiently characterized. To address this issue, this study used functional magnetic resonance imaging (fMRI) to investigate the brain activity associated with landmark-based navigation in young and healthy older participants. Twenty-five young adults (μ=25.4 years, σ=4.7; 7F) and twenty-one older adults (μ=73.0 years, σ=3.9; 10F) performed a virtual navigation task in the scanner in which they could only orient using salient landmarks. The underlying whole-brain patterns of activity as well as the functional roles of scene-selective regions, the parahippocampal place area (PPA), the occipital place area (OPA), and the retrosplenial cortex (RSC) were analyzed. We found that older adults’ navigational abilities were diminished compared to young adults’ and that the two age groups relied on distinct navigational strategies to solve the task. Better performance during landmark-based navigation was found to be associated with increased neural activity in an extended neural network comprising several cortical and cerebellar regions. Direct comparisons between age groups further revealed that young participants had enhanced anterior temporal activity. In addition, young adults only were found to recruit occipital areas corresponding to the cortical projection of the central visual field during landmark-based navigation. The region-of-interest analysis revealed increased OPA activation in older adult participants. There were no significant between-group differences in PPA and RSC activations. These results hint at the possibility that aging diminishes fine-grained information processing in occipital and temporal regions thus hindering the capacity to use landmarks adequately for navigation. This work helps towards a better comprehension of the neural dynamics subtending landmark-based navigation and it provides new insights on the impact of age-related visuo-spatial processing changes on navigation capabilities.
In-depth characterization of Staurosporine induced proteome thermal stability changes
Authors: Chernobrovkin Alexey L. , Lengqvist Johan , Körner Cindy Caceres , Amadio Daniele , Friman Tomas , Molina Daniel Martinez
Published: March 2020

Cellular thermal shift assay (CETSA) coupled with high-resolution mass-spectrometry (MS) has proven to be indispensable tool to track thermal stability changes in cellular proteins caused by various external or internal perturbations. One of the major applications of CETSA MS is still binding profile characterization of small molecule drugs. Before applying the method for characterization of novel compound it is crucially important to understand the limitations, sensitivity and ways to improve the throughput of the different method implementations. Here we present deep comprehensive profiling of Staurosporine induced proteome thermal stability alteration utilizing different experiment layouts. By applying unbiased straightforward sample preparation and data analysis approaches we were able to compare and benchmark different experiment layouts for detecting compound-induced protein stability changes in CETSA MS experiments.
Whole transcriptome data of uninfected andNosema ceranae-infected midguts of eastern honeybee workers
Authors: Chen Huazhi , Zhou Dingding , Du Yu , Xiong Cuiling , Zheng Yanzhen , Chen Dafu , Guo Rui
Published: March 2020

Apis cerana ceranais a subspecies of eastern honeybee,Apis cerana. Nosema ceranaeis a widespread fungal parasite of honeybee, causing heavy losses for beekeeping industry all over the world. In this article, total RNA of normal midguts (AcCK1, AcCK2) andN. ceranae-infected midguts ofA. c. ceranaworkers at 7 d and 10 d post inoculation (AcT1, AcT2) were respectively isolated followed by strand-specific cDNA library construction and next-generation RNA sequencing. In tolal, 56270223688, 44860946964, 78991623806, and 92712308296 raw reads were derived from AcCK1, AcCK2, AcT1 and AcT2, respectively. Following strict quality control, 54495191388, 43570608753, 76708161525, and 89467858351 clean reads were obtained, with Q30 value of 95.80%, 95.99%, 96.07% and 96.04%, and GC content of 44.20%, 43.44%, 44.83% and 43.63%, respectively. The raw data were submitted to the NCBI Sequence Read Archive database and connected to BioProject PRJNA562784. These data offers a valuable resource for deep investigation of mechanisms underlying eastern honeybee responding toN. ceranaeinfection and host-fungal parasite interaction during microsporidiosis.

Value of the Data

Current dataset offers a valuable resource for exploring mRNAs, lncRNAs and circRNAs involved in response ofA. c. ceranaworker toN. ceranaeinfection.

The accessible data can be used to investigate differential expression pattern and regulatory network of non-coding RNAs inA. c. ceranaworkers’ midguts responding toN. ceranaechallenge.

This data will enable a better understanding of the molecular mechanism regulating eastern honeybee-N. ceranaeinteraction.
Genetic disruption of the Blood Brain Barrier leads to protective barrier formation at the Glia Limitans
Authors: Hollier Pierre-Louis , Guimbal Sarah , Mora Pierre , Diop Aïssata , Cornuault Lauriane , Couffinhal Thierry , Gadeau Alain-Pierre , Renault Marie-Ange , Chapouly Candice
Published: March 2020

Recent work demonstrated that Central Nervous System (CNS) inflammation induces endothelial Blood Brain Barrier (BBB) opening as well as the formation of a tight junction barrier between reactive astrocytes at the Glia Limitans. We hypothesized that these two barriers may be reciprocally regulated by each other state and further, that the CNS parenchyma may acquire protection from the reactive astrocytic Glia Limitans not only in neuro-inflammation but also when BBB integrity is compromised under resting condition, without pathology. Previous studies identified Sonic hedgehog (Shh) astrocytic secretion as implicated in stabilizing the BBB during neuropathology and we recently demonstrated that desert hedgehog (Dhh) is expressed at the BBB in adults.

Here we unraveled the role of the morphogen Dhh in maintaining BBB tightness and, using endothelial Dhh knockdown as a model of permeable BBB, we demonstrated that a double barrier system comprising both the BBB and Glia Limitans, is implemented in the CNS and regulated by a crosstalk going from endothelial cell to astrocytes.

First, we showed that, under neuro-inflammatory conditions, Dhh expression is severely down regulated at the BBB and that Dhh is necessary for endothelial intercellular junction integrity as Dhh knockdown leads to CNS vascular leakage. We then demonstrated that, in Dhh endothelial knockout (DhhECKO) mice which display an open BBB, astrocytes are reactive and express the tight junction Claudin 4 (Cldn4) and showed that astrocytes can respond to signals secreted by the permeable endothelial BBB by becoming reactive and expressing Cldn4. To examine the consequences of the above results on disease severity, we finally induced multiple sclerosis in DhhECKOmice versus control littermates and showed that the pathology is less severe in the knockout animals due to Glia Limitans tightening, in response to BBB leakage, which drives inflammatory infiltrate entrapment into the perivascular space. Altogether these results suggest that genetic disruption of the BBB generates endothelial signals capable of driving the implementation of a secondary barrier at the Glia Limitans to protect the parenchyma. The concept of a reciprocally regulated CNS double barrier system has implications for treatment strategies in both the acute and chronic phases of multiple sclerosis pathophysiology.
Decoding mRNA translatability and stability from 5’UTR
Authors: Jia Longfei , Mao Yuanhui , Ji Quanquan , Dersh Devin , Yewdell Jonathan W. , Qian Shu-Bing
Published: March 2020

Precise control of protein synthesis by engineering sequence elements in 5’ untranslated region (5’UTR) remains a fundamental challenge. To accelerate our understanding ofcis-regulatory code embedded in 5’UTR, we devised massively parallel reporter assays from a synthetic mRNA library composed of over one million 5’UTR variants. A completely randomized 10-nucleotide sequence preceding an upstream open reading frame (uORF) and downstream GFP leads to a broad range of mRNA translatability and stability in mammalian cells. While efficient translation protects mRNA from degradation, uORF translation triggers mRNA decay in a UPF1-dependent manner. We also identified translational inhibitory elements in 5’UTR with G-quadruplex as a mark for mRNA decay in the P-body. Unexpectedly, an unstructured A-rich element in 5’UTR, while enabling cap-independent translation, destabilizes mRNAs in the absence of translation. Our results not only expose diverse sequence features of 5’UTR in controlling mRNA translatability, but also reveal ribosome-dependent and -independent mRNA surveillance pathways.
Rapidly predicting vancomycin resistance ofEnterococcus faeciumthrough MALDI-TOF MS spectrum obtained in real-world clinical microbiology laboratory
Authors: Wang Hsin-Yao , Lu Ko-Pei , Chung Chia-Ru , Tseng Yi-Ju , Lee Tzong-Yi , Horng Jorng-Tzong , Chang Tzu-Hao , Wu Min-Hsien , Lin Ting-Wei , Liu Tsui-Ping , Lu Jang-Jih
Published: March 2020

Enterococcus faeciumis one of the leading pathogens in the world. In this study, we proposed a strategy to rapidly and accurately distinguish vancomycin-resistantEnterococcus faecium(VREfm) and vancomycin-susceptibleE. faecium(VSEfm) to help doctors correctly determine the use of vancomycin by a machine learning (ML)-based algorithm. A predictive model was developed and validated to distinguish VREfmand VSEfmby analyzing MALDI-TOF MS spectra of uniqueE. faeciumisolates from different specimen types. Firstly, 5717 mass spectra, including 2795 VREfmand 2922 VSEfm, were used to develop the algorithm. And 2280 mass spectra of isolates, namely 1222 VREfmand 1058 VSEfm, were used to externally validate the algorithm. The random forest-based algorithm demonstrated good classification performances for overall specimens, whose mean AUROC in 5-fold cross validation, time-wise validation, and external validation was all greater than 0.84. For the detection of VREfmin blood, sterile body fluid, urinary tract, and wound, the AUROC in external validation was also greater than 0.84. The predictions with algorithms were significantly more accurate than empirical antibiotic use. The accuracy of antibiotics administration could be improved by 30%. And the algorithm could provide rapid antibiotic susceptibility results at least 24 hours ahead of routine laboratory tests. The turn-around-time of antibiotic susceptibility could be reduced by 50%. In conclusion, a ML algorithm using MALDI-TOF MS spectra obtained in routine workflow accurately differentiated VREfmfrom VSEfm, especially in blood and sterile body fluid, which can be applied to facilitate the clinical testing process due to its accuracy, generalizability, and rapidness.
Tape lures swell bycatch on a Mediterranean island harbouring illegal bird trapping
Authors: Sebastianelli Matteo , Savva Georgios , Moysi Michaella , Kirschel Alexander N. G.
Published: March 2020

Mediterranean islands are critical for migrating birds, providing shelter and sustenance for millions of individuals each year. Humans have long exploited bird migration through hunting and illegal trapping. On the island of Cyprus, trapping birds during their migratory peak is considered a local tradition, but has long been against the law. Illegal bird trapping is a lucrative business, however, with trappers using tape lures that broadcast species’ vocalizations because it is expected to increase numbers of target species. Yet, by how much the use of song playback increases capture rates remains underappreciated. In particular, it is not known whether song playback of target species affects bycatch rates. Here, we show with the use of playback experiments that song playback is highly effective in luring birds towards trapping sites. We found that playback increases six to eight times the number of individuals of target species captured, but also significantly increases bycatch. Our findings thus show that in contrast to popular belief that tape lures are a selective trapping method, they also lead to increased captures of non-target species, which can include species of conservation concern.
Nuclear Transport Factor 2 (NTF2) suppresses metastatic melanoma by modifying cell migration, metastasis, and gene expression
Authors: Vuković Lidija D. , White Karen H. , Gigley Jason P. , Levy Daniel L.
Published: March 2020

While changes in nuclear structure and organization are frequently observed in cancer cells, relatively little is known about how nuclear architecture impacts cancer progression and pathology. To begin to address this question, we studied Nuclear Transport Factor 2 (NTF2) because its levels decrease during melanoma progression. We show that increasing NTF2 expression in metastatic melanoma cells reduces cell proliferation and motility while increasing apoptosis. We also demonstrate that increasing NTF2 expression in these cells significantly inhibits metastasis and increases survival of mice. Mechanistically, we show that NTF2 levels affect the expression and nuclear positioning of a number of genes associated with cell proliferation and migration. We propose that by decreasing nuclear size and/or lamin A nuclear localization, ectopic expression of NTF2 in metastatic melanoma alters chromatin organization to generate a gene expression profile with characteristics of primary melanoma, concomitantly abrogating several phenotypes associated with advanced stage cancer bothin vitroandin vivo. Thus NTF2 acts as a melanoma tumor suppressor to maintain proper nuclear structure and gene expression and could be a novel therapeutic target to improve health outcomes of melanoma patients.
ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738
Authors: Jette Nicholas R. , Radhamani Suraj , Ye Ruiqiong , Yu Yaping , Arthur Greydon , Goutam Siddhartha , Bizmar Tarek A , Kumar Mehul , Bose Pinaki , Yip Steven , Kolinsky Michael , Lees-Miller Susan P.
Published: March 2020

Background

The ataxia telangiectasia mutated (ATM) protein kinase is mutated in several human cancers, presenting potential opportunities for targeted cancer therapy. We previously reported that the poly-ADP ribose polymerase (PARP) inhibitor olaparib induced transient G2 arrest but not cell death in ATM-deficient A549 lung cancer cells, while the combination of olaparib with the ATM-, Rad3-related (ATR) inhibitor VE-821 induced cell death. Here, we show that the clinically relevant ATR inhibitor, AZD6738, sensitizes ATM-deficient A549 lung, prostate and pancreatic cancer cells to olaparib.

Methods

ATM was depleted from A549 lung cancer cells, PC-3 prostate cancer cells and Panc 10.05 pancreatic cancer cells, and the effects of olaparib alone and in combination with AZD6738 were determined.

Results

The combination of olaparib plus AZD6738 induced cell death in ATM-deficient lung, prostate and pancreatic cancer cells with little effect on their ATM-proficient counterparts.

Conclusions

Lung, prostate and pancreatic patients whose tumours exhibit loss or inactivation of ATM may benefit from combination of a PARP inhibitor plus an ATR inhibitor.
ICEs are the main reservoirs of the ciprofloxacin-modifyingcrpPgene inPseudomonas aeruginosa
Authors: Botelho João , Grosso Filipa , Peixe Luísa
Published: March 2020

The ciprofloxacin-modifyingcrpPgene was recently identified in a plasmid isolated from a clinicalPseudomonas aeruginosaclinical isolate. Homologues of this gene were also identified inEscherichia coli, Klebsiella pneumoniaeandAcinetobacter baumannii. We set out to explore the mobile genetic elements involved in the acquisition and spread of this gene in publicly available and complete genomes ofPseudomonas. ThecrpPgene was identified only inP. aeruginosa, in more than half of the complete chromosomes (61.9%, n=133/215) belonging to 52 sequence types, of which the high-risk clone ST111 was the most frequent. We identified 136crpP-harboring ICEs, with 93.4% belonging to the mating-pair formation G (MPFG) family. The ICEs were integrated at the end of a tRNALysgene and were all flanked by highly conserved 45-bp direct repeats. The core ICEome contains 26 genes (2.2% of all genes), which are present in 99% or more of thecrpP-harboring ICEs. The most frequently encoded traits on these ICEs include replication, transcription, intracellular trafficking and cell motility. Our work reveals that ICEs are the main vectors promoting the dissemination of the ciprofloxacin-modifyingcrpPgene inP. aeruginosa.

Author Notes

All supporting data has been provided within the article or through supplementary data files. Supplementary material is available with the online version of this article.

Impact Statement

A high proportion ofPseudomonas aeruginosaclinical isolates are resistant to ciprofloxacin. Resistance to this antibiotic is often mediated by chromosomal mutations, but recently horizontally transferred genes have been identified. We assessed the repartition of the ciprofloxacin-modifyingcrpPgene amongPseudomonasgenomes and we characterized the mobile elements associated with its acquisition. We found that this gene is prevalent inP. aeruginosaand frequently associated with integrative and conjugative elements (ICEs). Importantly, we also identified highly conserved direct repeats that can be used to accurately delimitcrpP-carrying ICEs inP. aeruginosagenomes.

Data Summary

All the bacterial genomes scanned in this study have been deposited previously in the National Center for Biotechnology Information genome database and are listed on the supplementary tables. The newick files used to create the trees in Figures 1 and 4 are deposited on figshare athttps://figshare.com/projects/ICEs_are_the_main_reservoirs_of_the_ciprofloxacin-modifying_crpP_gene_in_Pseudomonas_aeruginosa/79308.
Measuring site-specific glycosylation similarity between influenza A virus variants with statistical certainty
Authors: Chang Deborah , Hackett William E. , Zhong Lei , Wan Xiu-Feng , Zaia Joseph
Published: March 2020

Influenza A virus (IAV) mutates rapidly, resulting in antigenic drift and poor year-to-year vaccine effectiveness. One challenge in designing effective vaccines is that genetic mutations frequently cause amino acid variations in IAV envelope protein hemagglutinin (HA) that create newN-glycosylation sequons; resultingN-glycans cause antigenic shielding, allowing viral escape from adaptive immune responses. Vaccine candidate strain selection currently involves correlating antigenicity with HA protein sequence among circulating strains, but quantitative comparison of site-specific glycosylation information may likely improve the ability to design vaccines with broader effectiveness against evolving strains. However, there is poor understanding of the influence of glycosylation on immunodominance, antigenicity, and immunogenicity of HA, and there are no well-tested methods for comparing glycosylation similarity among virus samples. Here, we present a method for statistically rigorous quantification of similarity between two related virus strains that considers the presence and abundance of glycopeptide glycoforms. We demonstrate the strength of our approach by determining that there was a quantifiable difference in glycosylation at the protein level between wild-type IAV HA from A/Switzerland/9715293/2013 (SWZ13) and a mutant strain of SWZ13, even though noN-glycosylation sequons were changed. We determined site-specifically that WT and mutant HA have varying similarity at the glycosylation sites of the head domain, reflecting competing pressures to evade host immune response while retaining viral fitness. To our knowledge, our results are the first to quantify changes in glycosylation state that occur in related proteins of considerable glycan heterogeneity. Our results provide a method for understanding how changes in glycosylation state are correlated with variations in protein sequence, which is necessary for improving IAV vaccine strain selection. Understanding glycosylation will be especially important as we find new expression vectors for vaccine production, as glycosylation state depends greatly on the host species.