bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic performance of multifocal photopic negative response, pattern electroretinogram and optical coherence tomography in glaucoma
Authors: Al-Nosairy Khaldoon O. , Thieme Hagen , Hoffmann Michael B.
Published: March 2020

Objectives

To optimize stimulation parameters for electroretionographic recordings of the multifocal photopic negative response (mfPhNR) for the detection of glaucoma and to compare the diagnostic accuracy of electrophysiological, structural and functional measures of glaucoma.

Methods

In 24 healthy controls, 10 glaucoma suspects (GLAS) and 16 glaucoma participants (GLAG), mfPhNR for 6 different stimulation rates were assessed to compare their discrimination performance. Subsequently, a cross-modal comparison of the mfPhNR/b-wave ratio was performed with pattern electroretinogram (PERG), and peripapillary retinal nerve fiber layer (pRNFL) thickness. These analyses were based on area under curves (AUC) obtained from receiver-operating-characteristics (ROC) analyses and step-wise regression analyses.

Results

Compared to the other mfPhNR-conditions, the PhNR/b-wave ratio for the fastest stimulation condition had the highest AUC for GLAS(0.84, P = 0.008, 95%CI: 0.71-0.98); the other modalities, i.e., PERG-amplitude and pRNFL had AUCs of 0.77, and 0.74 respectively. pRNFL was the significant predictor for mfPhNR/b-wave ratio [t (48) = 4, P 0.0002].

Conclusions

Fast mfPhNR protocols outperform other mf-protocols in the identification of glaucomatous damage especially for GLASand thus aid the early detection of glaucoma.

Significance

mfPhNR recordings might serve as surrogate marker of ganglion cell dysfunction especially in glaucoma suspects.
Estimating Preventable COVID-19 Infections Related to Elective Outpatient Surgery in Washington State: A Quantitative Model
Authors: Zhang Yuemei , Cheng Sheng-Ru
Published: March 2020

Background

As the number of suspected and confirmed COVID-19 cases in the US continues to rise, the US surgeon general, Centers for Disease Control and Prevention, and several specialty societies have issued recommendations to consider canceling elective surgeries. However, these recommendations have also faced controversy and opposition.

Methods

Using previously published information and publicly available data on COVID-19 infections, we calculated a transmission rate and generated a mathematical model to predict a lower bound for the number of healthcare-acquired COVID-19 infections that could be prevented by canceling or postponing elective outpatient surgeries in Washington state.

Results

Our model predicts that over the course of 30 days, at least 75.9 preventable patient infections and at least 69.3 preventable healthcare worker (HCW) infections would occur in WA state alone if elective outpatient procedures were to continue as usual.

Conclusion

Canceling elective outpatient surgeries during the COVID-19 pandemic could prevent a large number of patient and healthcare worker infections.
Chinese Public Attention to COVID-19 Epidemic: Based on Social Media
Authors: Zhao Yuxin , Xu Huilan
Published: March 2020

Background

Since the new coronavirus epidemic in China in December 2019, information and discussions about COVID-19 have spread rapidly on the Internet and have quickly become the focus of worldwide attention, especially on social media.

Objective

This study aims to investigate and analyze the public’s attention to COVID-19-related events in China at the beginning of the COVID-19 epidemic in China (December 31, 2019, to February 20, 2020) through the Sina Microblog hot search list.

Methods

We collected topics related to the COVID-19 epidemic on the Sina Microblog hot search list from December 31, 2019, to February 20, 2020 and described the trend of public attention on COVID-19 epidemic-related topics. ROST CM6.0 (ROST Content Mining System Version 6.0) was used to analyze the collected text for word segmentation, word frequency, and sentiment analysis. We further described the hot topic keywords and sentiment trends of public attention. We used VOSviewer to implement a visual cluster analysis of hot keywords and build a social network of public opinion content.

Results

The study has four main findings. First, we analyzed the changing trend of the public’s attention to the COVID-19 epidemic, which can be divided into three stages. Second, the hot topic keywords of public attention at each stage are slightly different. In addition, the emotional tendency of the public toward the COVID-19 epidemic-related hot topics has changed from negative to neutral, with negative emotions weakening and positive emotions increasing as a whole. Finally, we divided the COVID-19 topics with the most public concern into five categories: new COVID-19 epidemics and their impact; (2) frontline reporting of the epidemic and prevention and control measures; (3) expert interpretation and discussion on the source of infection; (4) medical services on the frontline of the epidemic; and (5) focus on the global epidemic and the search for suspected cases.

Conclusions

This is the first study of public attention on the COVID-19 epidemic using a Chinese social media platform (i.e., Sina Microblog). Our study found that social media (e.g., Sina Microblog) can be used to measure public attention to public health emergencies. During the epidemic of the novel coronavirus, a large amount of information about the COVID-19 epidemic was disseminated on Sina Microblog and received widespread public attention. We have learned about the hotspots of public concern regarding the COVID-19 epidemic. These findings can help the government and health departments better communicate with the public on health and translate public health needs into practice to create targeted measures to prevent and control the spread of COVID-19.
Age-Sex based estimates of risk of death from COVID Infection in Adult Cancer Patients
Authors: Williams Matt , Mi Ella , Calvez Kerlann Le , Chen Jiarong , Pakzad-Shahabi Lillie , Dadhania Seema , Wang James , L.K.Ho Andrew , Rabinowicz Simon
Published: March 2020

Background

During the coronavirus disease 2019 (COVID) pandemic, various organisations have produced management guidance for cancer patients and the delivery of cytotoxic chemotherapy, but none offer estimates of risk, or the potential impact across populations.

Methods

We combine data from four countries to produce pooled age-banded Case Fatality Rates (CFRs), calculate the sex-difference in survival and use data from four recent studies to convert CFRs into age-sex stratified Infection Fatality Rates (IFRs). We estimate the additional risk of death in cancer patients, and in those receiving chemotherapy. We illustrate the impact of these by considering the impact on a national incident cancer cohort and present some clinical scenarios.

Results

We obtained data based on 412,985 cases and 41,854 deaths. The pooled estimate for IFR was 0.92%. Age-related IFRs for patients with cancer range from 0.01% to 29%, and higher in patients receiving chemotherapy. The risk is significantly higher in men than women. 40% of all male and 32% of all female patients with a new diagnosis of cancer this year have an IFR of ≥ 5%.

Conclusions

Older male patients are at a higher risk of death with COVID infection. Patients with cancer are also at higher risk, as are those who have recently received chemotherapy. We provide well-founded estimates to allow patients and clinicians to better balance these risks, and illustrate the wider impact in a national incident cohort.

FUNDING & DISCLOSURES

MW receives funding from the Imperial/ NIHR BRC; SD receives funding from the IC/ICR CRUK Major Centre; LPS receives funding from Brain Tumour Research and the Brain Tumour Research Campaign. JC is supported by the Guangdong International Young Research Talents Training Programme for Postdoctoral Researchers. The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Code, data and appendicies are available at:https://gitlab.com/computational.oncology/covidcancerrisk

HIGHLIGHTS

We report case and infection fatality rates based on a large multi-national cohort

We provide sex and age-specific estimates of risk

We provide estimates of additional risk for patients with cancer to allow patients and clinicians to balance risk and benefit
Virome of New York Presbyterian Hospital pediatric emergency
Authors: Ud-Dean Minhaz , Filip Ioan , Galanti Marta , Birger Ruthie , Comito Devon , Freyer Gregory , Ibrahim Sadiat , Lane Benjamin , Ligon Chanel , Matienzo Nelsa , Morita Haruka , Shittu Atinuke , Tagne Eudosie , Dayan Peter , Shaman Jeffrey
Published: March 2020

Background

Viral infection of the respiratory tract is one of the major causes of hospital visits for young children. In this study, we report the occurrence and co-occurrence of different virus types and subtypes among the patients arriving at the pediatric emergency room of New York Presbyterian Hospital, a major urban hospital.

Methods

We collected nasal swabs from the patients and their accompanying persons. We also recorded the levels (None, Mild, High, and Severe) of their symptoms (Fever, Chill, Muscle Pain, Watery Eye, Runny Nose, Sneezing, Sore throat and Cough). The collected swabs were tested for the presence of common viruses infecting the respiratory tract.

Results

Human Rhinovirus was the most common virus among the patients, followed Influenza and Respiratory Syncytial Virus. Human Rhinovirus was most common in summer, autumn and spring. In contrast, influenza was more common in winter. Further, Influenza A virus was more likely to co-occur with Corona Virus 229E. In comparison, Influenza was less likely to co-occur with Human Rhinovirus. Moreover, Influenza, Parainfluenza and Corona virus were associated with more severe symptoms, while Human Rhinovirus was associated with less severe symptoms. In addition, we observed that Influenza and Respiratory Syncytial Virus were more likely to infect a patient when these viruses also infected the accompanying person. We also found that it was difficult to distinguish among viruses based on the symptoms. The inability to distinguish among different virus types and subtypes is explained by the fact that multiple viruses lead to similar symptoms.

Conclusions

The findings of this study provide a better understanding of respiratory viral infections in small children presenting at a pediatric emergency room in New York.
Assessing the Global Tendency of COVID-19 Outbreak
Authors: Liu Qinghe , Liu Zhicheng , Zhu Junkai , Zhu Yuhao , Li Deqiang , Gao Zefei , Zhou Liuling , Tang Yuanbo , Zhang Xiang , Yang Junyan , Wang Qiao
Published: March 2020

COVID-19 is now widely spreading around the world as a global pandemic. In this report, we estimate the global tendency of COVID-19 and analyze the associated global epidemic risk, given that the status quo is continued without further measures being taken.

The results show that the global R0, excluding China, is estimated to be 2.49 (95% CI: 2.15 – 2.92). The United States, Germany, Italy and Spain have peak values over 100,000. According to dynamical model and cluster analysis, we category the globe into four type regional epicenters of the outbreak: Southeast Asia extending southward to Oceania, the Middle East, Western Europe and North America. Among them, Western Europe will become the major center of the outbreak. The peak values in Germany, Italy and Spain are estimated to be 105,903, 127,283 and 152,539, respectively. The United States is the country with the most serious outbreak trend. Based on the current control measures by Mar. 27, 2020, the peak value in the United States will reach 400,892. Above all, if the current control measures are maintained, the cumulative number of patients worldwide will be 1,442,523 (95% CI: 1,052,577 – 8,981,440). We also estimated the diagnosis rate, recovery rate and infection degree of each country or region, and use clustering algorithm to retrieve countries or regions with similar epidemic characteristics. Different suggestions are proposed for countries or regions in different clusters.
Socio-economic and environmental patterns behind H1N1 spreading in Sweden
Authors: Bóta András , Holmberg Martin , Gardner Lauren , Rosvall Martin
Published: March 2020

The first influenza pandemic in our century started in 2009, spreading from Mexico to the rest of the world, infecting a noticeable fraction of the world population. The outbreak reached Europe in late April, and eventually, almost all countries had confirmed H1N1 cases. On 6 May, Swedish authorities reported the first confirmed influenza case. By the time the pandemic ended, more than 10 thousand people were infected in the country. In this paper, we aim to discover critical socio-economic, travel, and environmental factors contributing to the spreading of H1N1 in Sweden covering six years between 2009 and 2015, focusing on 1. the onset and 2. the peak of the epidemic phase in each municipality.

We apply the Generalized Inverse Infection Method (GIIM) to identify these factors. GIIM represents an epidemic spreading process on a network of nodes corresponding to geographical objects, connected by links indicating travel routes, and transmission probabilities assigned to the links guiding the infection process. The GIIM method uses observations on a real-life outbreak as a training dataset to estimate these probabilities and construct a simulated outbreak matching the training data as close as possible.

Our results show that the influenza outbreaks considered in this study are mainly driven by the largest population centers in the country. Also, changes in temperature have a noticeable effect. Other socio-economic factors contribute only moderately to the epidemic peak and have a negligible effect on the epidemic onset. We also demonstrate that by training our model on the 2009 outbreak, we can predict the timing of the epidemic onset in the following five seasons with good accuracy.

The model proposed in this paper provides a real-time decision support tool advising on resource allocation and surveillance. Furthermore, while this study only considers H1N1 outbreaks, the model can be adapted to other influenza strains or diseases with a similar transmission mechanism.
CMTM6 drives cisplatin resistance in OSCC by regulating AKT mediated Wnt signaling
Authors: Mohapatra Pallavi , Shriwas Omprakash , Mohanty Sibasish , Kaushik Sandeep Rai , Arya Rakesh , Rath Rachna , Majumdar Saroj Kumar Das , Muduly Dillip Kumar , Nanda Ranjan K , Dash Rupesh
Published: March 2020

Chemoresistance is one of the important factors for treatment failure in OSCC, which can culminate in progressive tumor growth and metastatic spread. Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance, which can be achieved by identifying the causative factors for acquired chemoresistance. In this study, to explore the key cisplatin resistance triggering factors, we performed global proteomic profiling of OSCC lines representing with sensitive, early and late cisplatin-resistant patterns. The top ranked up-regulated protein appeared to be CMTM6. We found CMTM6 to be elevated in both early and late cisplatin-resistant cells with respect to the sensitive counterpart. Analyses of OSCC patient samples indicate that CMTM6 expression is upregulated in chemotherapy-non-responder tumors as compared to chemotherapy-naïve tumors. Stable knockdown of CMTM6 restores cisplatin-mediated cell death in chemoresistant OSCC lines. Similarly, upon CMTM6 overexpression in CMTM6KD lines, the cisplatin resistant phenotype was efficiently rescued. Mechanistically, it was found that CMTM6 interacts with membrane bound Enolase-1 and stabilized its expression, which in turn activates the AKT-GSK3β mediated Wnt signaling. CMTM6 triggers the translocation of β-catenin into the nucleus, which elevates the Wnt target pro-survival genes like Cyclin D, c-Myc and CD44. Moreover, incubation with lithium chloride, a Wnt signaling activator, efficiently rescued the chemoresistant phenotype in CMTM6KD OSCC lines. In a patient-derived cell xenograft model of chemoresistant OSCC, knock-down of CMTM6 restores cisplatin induced cell death and results in significant reduction of tumor burden. CMTM6 has recently been identified as a stabilizer of PD-L1 and henceforth it facilitates immune evasion by tumor cells. Herewith for the first time, we uncovered another novel role of CMTM6 as one of the major driver of cisplatin resistance.
Host shifting and host sharing in a genus of specialist flies diversifying alongside their sunflower hosts
Authors: Hippee Alaine C. , Beer Marc A. , Bagley Robin K. , Condon Marty A. , Kitchen Andrew , Lisowski Edward A. , Norrbom Allen L. , Forbes Andrew A.
Published: March 2020

Congeneric parasites are unlikely to specialize on the same tissues of the same host species, likely because of strong multifarious selection against niche overlap. Exceptions where multiple congeneric species overlap on the same tissues may therefore reveal important insights into the ecological factors underlying the origins and maintenance of diversity. Larvae of sunflower maggot flies in genusStrauziafeed on the pith of plants in the family Asteraceae. AlthoughStrauziatend to be host specialists, some species overlap in their host use. To resolve the origins of host sharing among these specialist flies, we used reduced representation genomic sequencing to infer the first multi-locus phylogeny of genusStrauzia.Our results show thatHelianthus tuberosusandHelianthus grosseserratuseach host three different fly species, and that the flies co-occurring on a host are not one another’s closest relatives. Though this pattern implies that host sharing is most likely the result of host shifts, these may not be host shifts in the conventional sense of an insect moving onto an entirely new plant. Many hosts ofStrauziabelong to a young (1-2 MYA) clade of perennial sunflowers noted for their frequent introgression and hybrid speciation events. In at least one case, flies may have converged upon a host after their respective ancestral host plants hybridized to form a new sunflower species (H. tuberosus). Broadly, we suggest that rapid and recent adaptive introgression and speciation in this group of plants may have instigated the diversification of their phytophagous fly associates, including the convergence of >1 species onto the same shared host plants.
Direct Measurement of Trunk Volume in Forest Trees: Focus on White Pine and Comparison to a Statistical Method
Authors: Leverett Robert T. , Ruskin David N. , Masino Susan A.
Published: March 2020

Accurate measurement of tree volume and associated carbon storage are necessary to determine ongoing sequestration as well as site productivity and changes in growth of individual tree species. Standard statistical methods vary their estimations of tree volume, and thus carbon storage and sequestration, particularly in larger, older trees in a forest setting. Here, we describe a detailed direct measurement method that combines traditional trunk taper models with state-of-the-art instrumentation and the best mathematical models for producing more accurate measurements of trunk volume. A stand-grown Eastern White Pine (Pinus strobus) is used as an example; the method is compared with a commonly used statistics-based Forest Service method. This latter method is shown to over- or underestimate volume if the trunk form factor deviates sufficiently from the average value for this species. Direct measurement modeling can be used to validate or choose among existing simple statistical volume models, especially for local applications. It can also assist in widespread recalibration of other standards and models used to estimate volume and carbon storage over time.
Detecting Tumor Specific Antigen-Reactive T cells from Tumor Infiltrating Lymphocytes via Interaction Dependent Fucosyl-biotinylation
Authors: Liu Zilei , Li Jie P. , Chen Mingkuan , Wu Mengyao , Shi Yujie , Li Wei , Teijaro John R. , Wu Peng
Published: March 2020

Re-activation and clonal expansion of tumor specific antigen (TSA)-reactive T cells are critical to the success of checkpoint blockade and adoptive transfer of tumor-infiltrating lymphocyte (TIL) based therapies. There are no reliable markers to specifically identify the repertoire of TSA-reactive T cells due to their heterogeneous composition. Here we introduce FucoID as a general platform to detect endogenous antigen-specific T cells and study their biology. Through this interaction dependent labeling approach, TSA-reactive T cells can be detected and separated from bystander T cells in primary tumor digests based on their cell-surface enzymatic fucosyl-biotinylation. Compared to bystander TILs, TSA-reactive TILs possess a distinct TCR repertoire and unique gene features. Though exhibiting a dysfunctional phenotype, this subset of TILs possesses substantial capabilities of proliferation and tumor specific killing. FucoID features genetic manipulation-free procedures and a quick turnover cycle, and therefore should have the potential of accelerating the pace of personalized cancer treatment.

Highlights

Interaction dependent fucosylation enables the detection and isolation ofbona fideintratumoral tumor specific antigen-reactive T cells

Tumor specific antigen-reactive CD8+T cells possess capabilities to be expanded and adoptively transferred for tumor control

Tumor specific antigen-reactive CD8+T cells feature oligoclonal expansion and upregulate genes for the steroid biosynthesis and metabolic process

Intratumoral bystander CD8+T cells can be separated into two groups based on PD-1 expression that feature distinct gene modules
Austropuccinia psidii, causing myrtle rust, has a gigabase-sized genome shaped by transposable elements
Authors: Tobias Peri A , Schwessinger Benjamin , Deng Cecilia H , Wu Chen , Dong Chongmei , Sperschneider Jana , Jones Ashley , Lou Zhenyan , Zhang Peng , Sandhu Karanjeet , Smith Grant R , Tibbits Josquin , Chagné David , Park Robert F
Published: March 2020

Austropuccinia psidii, originating in South America, is a globally invasive fungal plant pathogen that causes rust disease on Myrtaceae. Several biotypes are recognized, with the most widely distributed pandemic biotype spreading throughout the Asia-Pacific and Oceania regions over the last decade.Austropuccinia psidiihas a broad host range with more than 480 myrtaceous species. Since first detected in Australia in 2010, the pathogen has caused the near extinction of at least three species and negatively affected commercial production of several Myrtaceae. To enable molecular and evolutionary studies intoA. psidiipathogenicity, we assembled a highly contiguous genome for the pandemic biotype. With an estimated haploid genome size of just over 1 Gb (gigabases), it is the largest assembled fungal genome to date. The genome has undergone massive expansion via distinct transposable element (TE) bursts. Over 90% of the genome is covered by TEs predominantly belonging to the Gypsy superfamily. These TE bursts have likely been followed by deamination events of methylated cytosines to silence the repetitive elements. This in turn led to the depletion of CpG sites in transposable elements and a very low overall GC content of 33.8%. The overall gene content is highly conserved, when compared to other closely related Pucciniales, yet the intergenic distances are increased by an order of magnitude indicating a general insertion of TEs between genes. Overall, we show how transposable elements shaped the genome evolution ofA. psidiiand provide a greatly needed resource for strategic approaches to combat disease spread.
Intracellular Delivery of NanoparticlesviaMicroelectrophoresis Technique: Feasibility demonstration
Authors: Han Mengke , Zhao Jiangbo , Fabian Joseph Mahandas , Mustafa Sanam , Ruan Yinlan , Wiederman Steven , Ebendorff-Heidepriem Heike
Published: March 2020

Nanoparticles with desirable properties and functions have been actively developed for various bio-medical research, such asin vivoandin vitrosensors, imaging agents and delivery vehicles of therapeutics. However, an effective method to deliver nanoparticles into the intracellular environment is a major challenge and critical to many biological studies. Current techniques, such as intracellular uptake, electroporation and microinjection, each have their own set of benefits and associated limitations (e.g., aggregation and endosomal degradation of nanoparticles, high cell mortality and low throughput). Here, the well-established microelectrophoresis technique is applied for the first time to deliver nanoparticles into target cells, which overcomes some of these delivery difficulties. Semiconductive quantum dots, with average hydrodynamic diameter of 24.4 nm, have been successfully ejectedviasmall electrical currents (−0.2 nA) through fine-tipped glass micropipettes as an example, into living human embryonic kidney cells (roughly 20 - 30μm in length). As proposed by previous studies, micropipettes were fabricated to have an average tip inner diameter of 206 nm for ejection but less than 500 nm to minimize the cell membrane damage and cell distortion. In addition, delivered quantum dots were found to stay monodispersed within the cells for approximately one hour. We believe that microelectrophoresis technique may serve as a simple and general strategy for delivering a variety of nanoparticles intracellularly in various biological systems.
Unsupervised inference of protein fitness landscape from deep mutational scan
Authors: Fernandez-de-Cossio-Diaz Jorge , Uguzzoni Guido , Pagnani Andrea
Published: March 2020

The recent technological advances underlying the screening of large combinatorial libraries in high-throughput mutational scans, deepen our understanding of adaptive protein evolution and boost its applications in protein design. Nevertheless, the large number of possible genotypes requires suitable computational methods for data analysis, the prediction of mutational effects and the generation of optimized sequences. We describe a computational method that, trained on sequencing samples from multiple rounds of a screening experiment, provides a model of the genotype-fitness relationship. We tested the method on five large-scale mutational scans, yielding accurate predictions of the mutational effects on fitness. The inferred fitness landscape is robust to experimental and sampling noise and exhibits high generalization power in terms of broader sequence space exploration and higher fitness variant predictions. We investigate the role of epistasis and show that the inferred model provides structural information about the 3D contacts in the molecular fold.
Reverse transcriptase enzyme and priming strategy affect quantification and diversity of environmental transcripts
Authors: Cholet Fabien , Ijaz Umer Z. , Smith Cindy J.
Published: March 2020

RT-Q-PCR, and RT-PCR amplicon sequencing, provide a convenient, target-specific, high-sensitivity approach for gene expression studies and are widely used in environmental microbiology. Yet, the effectiveness and reproducibility of the reverse transcription step has not been evaluated. Therefore, we tested a combination of four commercial reverse transcriptases with two priming techniques to faithfully transcribe16S rRNAandamoAtranscripts from marine sediments. Both enzyme and priming strategy greatly affected quantification of the exact same target with differences of up to 600-fold. Furthermore, the choice of RT system significantly changed the communities recovered. For16S rRNA, both enzyme and priming had a significant effect with enzyme having a stronger impact than priming. Inversely, foramoAonly the change in priming strategy resulted in significant differences between the same sample. Specifically, more OTUs and better coverage ofamoAtranscripts diversity were obtained with GS priming indicating this approach was better at recovering the diversity ofamoAtranscripts. Moreover, sequencing of RNA mock communities revealed that, even though transcript α diversities (i.e.OTU counts within a sample) can be biased by the RT, the comparison of β diversities (i.e.differences in OTU counts between samples) is reliable as those biases are reproducible between environments.

Originality-Significance Statement

Is the complementary DNA (cDNA) produced after Reverse Transcription (RT) a faithful representation of the starting RNA? This is a fundamental and important question for transcriptomic-based studies in environmental microbiology that aim to quantify and/or examine the diversity of transcripts via RT approaches. Yet little is known about the reliability and reproducibility of this step. Here, we evaluated the effect of the two main components of the RT reaction – the retro transcriptase enzyme and priming strategy (gene specific vs random priming), on the quantification and diversity of cDNA. We found that both have a significant impact. We further provide evidence to enable informed choices as to the enzyme and priming combinations to improve the performance of RT-PCR approaches. Taken together, this work will improve the reliability and reproducibility of transcript-based studies in environmental microbiology.
Plasticity of behavioural variability reflects conflicting selection in group-living and solitary desert locusts
Authors: Cooper Ben , Smith Jonathan M. , Matheson Tom , Ott Swidbert R.
Published: March 2020

Animals living in groups tend to express less variable behaviour than animals living alone. It is widely assumed that this difference reflects, at least in part, an adaptive response to contrasting selection pressures: group-living should favour the evolution of more uniform behaviour whereas lone-living should favour behaviour that is less predictable. Empirical evidence linking these contrasting selection pressures to intrinsic differences in behavioural variability is, however, largely lacking. The desert locust, Schistocerca gregaria, manifests in two very distinct eco-phenotypes, a lone-living cryptic “solitarious phase” and a swarming “gregarious phase” that aggregates into very large and dense groups. This “phase polyphenism” has evolved in response to contrasting selection pressures that change rapidly and unpredictably. Phase differences in mean behaviour are well-characterised, but no previous study has considered differences in variability. Here we used locust phase polyphenism to test the hypothesis that group living leads to the evolution of reduced intrinsic variability in behaviour. We measured two behaviours in both phenotypes: locomotor activity in the presence of conspecifics, and locomotor hesitation in approaching food when alone. We assayed each individual repeatedly and estimated variability relative to the mean in log-normal mixed-effects models that explicitly account for the means-variance dependency in the behavioural measures. Our results demonstrate that relative behavioural variability differs between the two phases in line with predictions from ecological theory: both within-individual and between-individual variability were lower in the group-living gregarious phenotype. This contrasts with previous studies on social niche construction in spiders and crickets, and highlights the importance of social ecology: in animals that form non-social collectives, such as locusts, reduced individual behavioural variability is key for coherent collective behaviour. The differences in variability persisted when gregarious locusts were tested in isolation and solitarious locusts were tested in groups, indicating that they arise not simply as flexible reactions to different social contexts, but are intrinsic to the individual animals of each phase. This “variance polyphenism” in locusts provides empirical evidence that evolutionary adaptation for group living has driven a reduction in within- and between-individual behavioural variability.
The genetic basis for PRC1 complex diversity emerged early in animal evolution
Authors: Gahan James M , Rentzsch Fabian , Schnitzler Christine E
Published: March 2020

Polycomb group proteins are essential regulators of developmental processes across animals. Despite their importance, studies on Polycomb are often restricted to classical model systems and, as such, little is known about the evolution of these important chromatin regulators. Here we focus on Polycomb Repressive Complex 1 (PRC1) and trace the evolution of core components of canonical and non-canonical PRC1 complexes in animals. Previous work suggested that a major expansion in the number of PRC1 complexes occurred in the vertebrate lineage. Here we show that the expansion of the PCGF protein family, an essential step for the establishment of the large diversity of PRC1 complexes found in vertebrates, predates the bilaterian-cnidarian ancestor. This means that the genetic repertoire necessary to form all major vertebrate PRC1 complexes emerged early in animal evolution, over 550 million years ago. We further show thatPCGF5, a gene conserved in cnidarians and vertebrates but lost in all other studied groups, is expressed in the nervous system in the sea anemoneNematostella vectensis, similar to its mammalian counterpart. Together this work provides an evolutionary framework to understand PRC1 complex diversity and evolution and establishesNematostellaas a promising model system in which this can be further explored.
Active Listening
Authors: Friston Karl J. , Sajid Noor , Quiroga-Martinez David Ricardo , Parr Thomas , Price Cathy J. , Holmes Emma
Published: March 2020

This paper introduces active listening, as a unified framework for synthesising and recognising speech. The notion ofactive listeninginherits from active inference, which considers perception and action under one universal imperative: to maximise the evidence for our (generative) models of the world. First, we describe a generative model of spoken words that simulates (i) how discrete lexical, prosodic, and speaker attributes give rise to continuous acoustic signals; and conversely (ii) how continuous acoustic signals are recognised as words. The ‘active’ aspect involves (covertly) segmenting spoken sentences and borrows ideas from active vision. It casts speech segmentation as the selection of internal actions, corresponding to the placement of word boundaries. Practically, word boundaries are selected that maximise the evidence for an internal model of how individual words are generated. We establish face validity by simulating speech recognition and showing how the inferred content of a sentence depends on prior beliefs and background noise. Finally, we consider predictive validity by associating neuronal or physiological responses, such as the mismatch negativity and P300, with belief updating under active listening, which is greatest in the absence of accurate prior beliefs about what will be heard next.
Computational vaccinology based development of multi-epitope subunit vaccine for protection against the Norovirus’ infections
Authors: Ahmad Irfan , Ali Syed Shujait , Shah Ismail , Khan Shahzeb , Khan Mazhar , Ullah Saif , Ali Shahid , Khan Jafar , Ali Mohammad , Khan Abbas , Wei Dong-Qing
Published: March 2020

Human Norovirus belong to familyCalciviridae, it was identified in the outbreak of gastroenteritis in Norwalk, due to its seasonal prevalence known as “winter vomiting disease”. Treatment of Norovirus infection is still mysterious because there is no effective antiviral drugs or vaccine developed to protect against the infection, to eradicate the infection an effective vaccine should be developed. In this study capsid protein (A7YK10), small protein (A7YK11) and polyprotein (A7YK09) were utilized. These proteins were subjected to B and T cell epitopes prediction by using reliable immunoinformatics tools. The antigenic and non-allergenic epitopes were selected for subunit vaccine, which can activate cellular and humoral immune responses. Linkers joined these epitopes together. The vaccine structure was modelled and validated by using Errat, ProSA and rampage servers. The modelled vaccine was docked with TLR-7. Stability of the docked complex was evaluated by MD simulation. In order to apply the concept in a wet lab, the reverse translated vaccine sequence was cloned in pET28a (+). The vaccine developed in this study requires experimental validation to ensure its effectiveness against the disease.
Revealing 29 sets of independently modulated genes inStaphylococcus aureus, their regulators and role in key physiological responses
Authors: Poudel Saugat , Tsunemoto Hannah , Seif Yara , Sastry Anand , Szubin Richard , Xu Sibei , Machado Henrique , Olson Connor , Anand Amitesh , Pogliano Joe , Nizet Victor , Palsson Bernhard O.
Published: March 2020

The ability ofStaphylococcus aureusto infect many different tissue sites is enabled, in part, by its Transcriptional Regulatory Network (TRN) that coordinates its gene expression to respond to different environments. We elucidated the organization and activity of this TRN by applying Independent Component Analysis (ICA) to a compendium of 108 RNAseq expression profiles from twoS. aureusclinical strains (TCH1516 and LAC). ICA decomposed theS. aureustranscriptome into 29 independently modulated sets of genes (i-modulons) that revealed (1) high confidence associations between 21 i-modulons and known regulators; (2) an association between an i-modulon and σS, whose regulatory role was previously undefined; (3) the regulatory organization of 65 virulence factors in the form of three i-modulons associated with AgrR, SaeR and Vim-3, (4) the roles of three key transcription factors (codY, Fur and ccpA) in coordinating the metabolic and regulatory networks; and (5) a low dimensional representation, involving the function of few transcription factors, of changes in gene expression between two laboratory media (RPMI, CAMHB) and two physiological media (blood and serum). This representation of the TRN covers 842 genes representing 76% of the variance in gene expression that provides a quantitative reconstruction of transcriptional modules inS. aureus, and a platform enabling its full elucidation.

Significance Statement

Staphylococcus aureusinfections impose an immense burden on the healthcare system. To establish a successful infection in a hostile host environment,S. aureusmust coordinate its gene expression to respond to a wide array of challenges. This balancing act is largely orchestrated by the Transcriptional Regulatory Network (TRN). Here, we present a model of 29 independently modulated sets of genes that form the basis for a segment of the TRN in clinical USA300 strains ofS. aureus. Using this model, we demonstrate the concerted role of various cellular systems (e.g. metabolism, virulence and stress response) underlying key physiological responses, including response during blood infection.
Pixel-based machine learning and image reconstitution for dot-ELISA pathogen serodiagnosis
Authors: Anastassopoulou Cleo , Tsakris Athanasios , Patrinos George P. , Manoussopoulos Yiannis
Published: March 2020

Serological methods serve as a direct or indirect means of pathogen infection diagnosis in plant and animal species, including humans. Dot-ELISA (DE) is an inexpensive and sensitive, solid-state version of the microplate enzyme-linked immunosorbent assay, with a broad range of applications in epidemiology. Yet, its applicability is limited by uncertainties in the qualitative output of the assay due to overlapping dot colorations of positive and negative samples, stemming mainly from the inherent color discrimination thresholds of the human eye. Here, we report a novel approach for unambiguous DE output evaluation by applying machine learning-based pattern recognition of image pixels of the blot using an impartial predictive model rather than human judgment. Supervised machine learning was used to train a classifier algorithm through a built multivariate logistic regression model based on the RGB (“Red”, “Green”, “Blue”) pixel attributes of a scanned DE output of samples of known infection status to a model pathogen (Lettuce big-vein associated virus). Based on the trained and cross-validated algorithm, pixel probabilities of unknown samples could be predicted in scanned DE output images which would then be reconstituted by pixels having probabilities above a cutoff that may be selected at will to yield desirable false positive and false negative rates depending on the question at hand, thus allowing for proper dot classification of positive and negative samples and, hence, accurate diagnosis. Potential improvements and diagnostic applications of the proposed versatile method that translates unique pathogen antigens to the universal basic color language are discussed.
Natural selection has preserved and enhanced the phase-separation properties of FUS during 160 million years of mammalian evolution
Authors: Dasmeh Pouria , Wagner Andreas
Published: March 2020

Protein phase separation is essential for the self-assembly of non-membraneous organelles. However, we know little about its ability to change in evolution. Here we studied the evolution of the mammalian RNA binding protein FUS, a protein whose prion-like domain (PLD) is essential for the formation of stress granules through liquid-liquid phase separation. Although the prion-like domain evolves three times as rapidly as the remainder of FUS, it harbors absolutely conserved tyrosine residues that are crucial for phase separation. Ancestral reconstruction shows that the phosphorylation sites within the PLD are subject to stabilizing selection. They toggle among a small number of amino acid states. One exception to this pattern are primates, where the number of such phosphosites has increased through positive selection. In addition, we find frequent glutamine to proline changes that help maintain the unstructured state of FUS that is necessary for phase separation. In summary, natural selection has stabilized the liquid-forming potential of FUS and minimized the propensity of cytotoxic liquid-to-solid phase transitions during 160 million years of mammalian evolution.
Rewiring of gene expression in circulating white blood cells is associated with pregnancy outcome in heifers (Bos taurus)
Authors: Moorey Sarah E. , Walker Bailey N. , Elmore Michelle F. , Elmore Joshua B. , Rodning Soren P. , Biase Fernando H.
Published: March 2020

Infertility is a challenging phenomenon in cattle that reduces the sustainability of beef production worldwide. Here, we tested the hypothesis that gene expression profiles of protein-coding genes expressed in peripheral white blood cells (PWBCs), and circulating micro RNAs in plasma, are associated with female fertility, measured by pregnancy outcome. We drew blood samples from 17 heifers on the day of artificial insemination and analyzed transcript abundance for 10496 genes in PWBCs and 290 circulating micro RNAs. The females were later classified as pregnant to artificial insemination, pregnant to natural breeding or not pregnant. We identified 1860 genes producing significant differential coexpression (eFDR<0.002) based on pregnancy outcome. Additionally, 237 micro RNAs and 2274 genes in PWBCs presented differential coexpression based on pregnancy outcome. Furthermore, using a machine learning prediction algorithm we detected a subset of genes whose abundance could be used for blind categorization of pregnancy outcome. Our results provide strong evidence that transcript abundance in circulating white blood cells is associated with fertility in heifers.
Regulatory Sharing Between Estrogen Receptor α Bound Enhancers
Authors: Carleton Julia B. , Ginley-Hidinger Matthew , Berrett Kristofer C. , Layer Ryan M. , Quinlan Aaron R. , Gertz Jason
Published: March 2020

The human genome encodes an order of magnitude more gene expression enhancers than promoters, suggesting that most genes are regulated by the combined action of multiple enhancers. We have previously shown that neighboring estrogen-responsive enhancers, which are approximately 5,000 basepairs apart, exhibit complex synergistic contributions to the production of an estrogenic transcriptional response. Here we sought to determine the molecular underpinnings of the observed enhancer cooperativity. We generated genetic deletions of individual estrogen receptor α (ER) bound enhancers and found that enhancers containing full estrogen response element (ERE) motifs control ER binding at neighboring sites, while enhancers with pre-existing histone acetylation/accessibility confer a permissible chromatin environment to the neighboring enhancers. Genome engineering revealed that a cluster of two enhancers with half EREs could not compensate for the lack of a full ERE site within the cluster. In contrast, two enhancers with full EREs produced a transcriptional response greater than the wild-type locus. By swapping genomic sequences between enhancers, we found that the genomic location in which a full ERE resides strongly influences enhancer activity. Our results lead to a model in which a full ERE is required for ER recruitment, but the presence of a pre-existing active chromatin environment within an enhancer cluster is also needed in order for estrogen-driven gene regulation to occur.
The impact of compound library size on the performance of scoring functions for structure-based virtual screening
Authors: Fresnais Louison , Ballester Pedro J.
Published: March 2020

Larger training datasets have been shown to improve the accuracy of Machine Learning (ML)-based Scoring functions (SFs) for Structure-Based Virtual Screening (SBVS). In addition, massive test sets for SBVS, known as ultra-large compound libraries, have been demonstrated to enable the fast discovery of selective drug leads with at least nanomolar potency. This proof-of-concept was carried out on two targets using a single docking tool along with its SF. It is thus unclear whether this high level of performance would generalise to other targets, docking tools and SFs.

We found that screening a larger compound library results in more potent actives being identified in all six additional targets using a different docking tool along with its classical SF. Furthermore, we established that a way to improve the potency of the retrieved molecules further is to rank them with more accurate ML-based SFs (we found this to be true in four of the six targets, the difference was not significant in the remaining two targets). A three-fold increase in average hit rate across targets was also achieved by the ML-based SFs. Lastly, we observed that classical and ML-based SFs often find different actives, which supports using both types of SFs on those targets.

Contact

pedro.ballester@inserm.fr

Supplementary information

an online-only supplementary results file is enclosed.

Biographical Note

L. Fresnais carried out a master research project directly supervised by P.J Ballester and he will soon be starting a PhD.

P.J Ballester has been working on virtual screening for over 15 years now. He is group leader and research scientist at cancer research centre of INSERM, the French National Institute of Health & Medical Research.