bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmentally Delayed Epigenetic Reprogramming Underlying the Pathogenesis of Preeclampsia
Authors: He Wei , Wei Yuan , Gong Xiaoli , Chang Luyuan , Jin Wan , Liu Ke , Wang Xinghuan , Xiao Yu , Zhang Wenjing , Chen Qiong , Wu Kai , Liang Lili , Liu Jia , Chen Yawen , Guo Huanhuan , Chen Wenhao , Yang Jiexia , Qi Yiming , Dong Wei , Fu Meng , Li Xiaojuan , Liu Jiusi , Zhang Yi , Yin Aihua
Published: May 2020

Preeclampsia, a life-threatening pregnancy complication characterized by hypertension and multiorgan damage, affects 2-5% of pregnancies and causes 76,000 deaths per year. Most preeclampsia associated syndromes immediately dispel after removal of placenta, indicating a casual role of placenta in the pathogenesis. Failed transformation of spiral artery due to insufficient invasion and excessive apoptosis of trophoblast suggested developmental defects in preeclampsia placenta. However, the underlying molecular mechanisms that affected placenta development in preeclampsia remained elusive. Here we show that, in preeclampsia placenta, the epigenetic landscape formed during extraembryonic tissue differentiation was disrupted: dramatic chromatin accessibility shift affected known and novel genes implicated in preeclampsia. DNA methylation defects in preeclampsia affected lineage-defining PcG-controlled loci in trophectoderm. LTR12 retrotransposons associated with VCT/SCT-specific genes were hypermethylated. Meanwhile, hundreds of PcG-regulated EVT-specific gene promoters, which otherwise undergone post-ZGA extraembryonic-tissue-specificde novomethylation, were hypomethylated and hyper-activated. Together, these epigenetic defects resulted in placenta developmental delay in preeclampsia. The defective methylation pattern could be detected in serum cfDNA, and could be used to accurately predict preeclampsia at early pregnancy weeks in independent validation cohorts. Our data suggests that the preeclampsia placenta represents a stalled state of epigenetic reprogrammingen routeof development from trophectoderm to normal placenta.
Deep learning models for COVID-19 infected area segmentation in CT images
Authors: Voulodimos Athanasios , Protopapadakis Eftychios , Katsamenis Iason , Doulamis Anastasios , Doulamis Nikolaos
Published: May 2020

Recent studies indicated that detecting radiographic patterns on CT chest scans can yield high sensitivity and specificity for COVID-19 detection. In this work, we scrutinize the effectiveness of deep learning models for semantic segmentation of pneumonia infected area segmentation in CT images for the detection of COVID-19. We explore the efficacy of U-Nets and Fully Convolutional Neural Networks in this task using real-world CT data from COVID-19 patients. The results indicate that Fully Convolutional Neural Networks are capable of accurate segmentation despite the class imbalance on the dataset and the man-made annotation errors on the boundaries of symptom manifestation areas, and can be a promising method for further analysis of COVID-19 induced pneumonia symptoms in CT images.

Impact Statement

Fully Convolutional Neural Networks appear to be an accurate segmentation method in CT scans for COVID-19 pneumonia and could assist in the detection as a fast and cost-effective option.
Age-stratified model of the COVID-19 epidemic to analyze the impact of relaxing lockdown measures: nowcasting and forecasting for Switzerland
Authors: Balabdaoui F. , Mohr D.
Published: May 2020

Compartmental models enable the analysis and prediction of an epidemic including the number of infected, hospitalized and deceased individuals in a population. They allow for computational case studies on non-pharmaceutical interventions thereby providing an important basis for policy makers. While research is ongoing on the transmission dynamics of the SARS-CoV-2 coronavirus, it is important to come up with epidemic models that can describe the main stages of the progression of the associated COVID-19 respiratory disease. We propose an age-stratified discrete compartment model as an alternative to differential equation based S-I-R type of models. The model captures the highly age-dependent progression of COVID-19 and is able to describe the day-by-day advancement of an infected individual in a modern health care system. The fully-identified model for Switzerland not only predicts the overall histories of the number of infected, hospitalized and deceased, but also the corresponding age-distributions. The model-based analysis of the outbreak reveals an average infection fatality ratio of 0.4% with a pronounced maximum of 9.5% for those aged ≥80 years. The predictions for different scenarios of relaxing the soft lockdown indicate a low risk of overloading the hospitals through a second wave of infections. However, there is a hidden risk of a significant increase in the total fatalities (by up to 200%) in case schools reopen with insufficient containment measures in place.
US Primary Care in 2029: A Delphi Survey on the Impact of Machine Learning
Authors: Blease Charlotte , Kharko Anna , Locher Cosima , DesRoches Catherine M. , Mandl Kenneth D.
Published: May 2020

Objective

To solicit leading health informaticians’ predictions about the impact of AI/ML on primary care in the US in 2029.

Design

A three-round online modified Delphi poll.

Participants

Twenty-nine leading health informaticians.

Methods

In September 2019, health informatics experts were selected by the research team, and invited to participate the Delphi poll. Participation in each round was anonymous, and panelists were given between 4-8 weeks to respond to each round. In Round 1 open-ended questions solicited forecasts on the impact of AI/ML on: (1) patient care, (2) access to care, (3) the primary care workforce, (4) technological breakthroughs, and (5) the long-future for primary care physicians. Responses were coded to produce itemized statements. In Round 2, participants were invited to rate their agreement with each item along 7-point Likert scales. Responses were analyzed for consensus which was set at a predetermined interquartile range of ≤ 1. In Round 3 items that did not reach consensus were redistributed.

Results

A total of 16 experts participated in Round 1 (16/29, 55%). Of these experts 13/16 (response rate, 81%), and 13/13 (response rate, 100%), responded to Rounds 2 and 3, respectively. As a result of developments in AI/ML by 2029 experts anticipated workplace changes including incursions into the disintermediation of physician expertise, and increased AI/ML training requirements for medical students. Informaticians also forecast that by 2029 AI/ML will increase diagnostic accuracy especially among those with limited access to experts, minorities and those with rare diseases. Expert panelists also predicted that AI/ML-tools would improve access to expert doctor knowledge.

Conclusions

This study presents timely information on informaticians’ consensus views about the impact of AI/ML on US primary care in 2029. Preparation for the near-future of primary care will require improved levels of digital health literacy among patients and physicians.
Negative nasopharyngeal SARS-CoV-2 PCR conversion in Response to different therapeutic interventions
Authors: Shabrawishi Mohammed Hassan , Naser Abdallah Y , Alwafi Hassan , Aldobyany Ahmad Mansoor , Touman Abdelfattah Ahmed
Published: May 2020

BACKGROUND

Despite lack of convincing evidence of the efficacy of hydroxychloroquine, it has been suggested to be used for the treatment of SARS-CoV-2 to accelerate the negative virus conversion. We aimed to explore the association between negative nasopharyngeal SARS-CoV-2 PCR clearance and different therapeutic interventions.

METHODOLOGY

This was a retrospective cohort study of 93 patients who were admitted to medical ward with a PCR confirmed diagnosis of COVID-19 and met the inclusion criteria in a tertiary hospital in Mecca, Saudi Arabia. There were three interventional subgroups (group A (n=45): who received antimalarial drug only classified as (A1), combined with azithromycin (A2) or combined with antiviral drugs (A3)), and one supportive care group (group B) (n=48). The primary and secondary endpoints of the study were achieving negative SARS-CoV-2 nasopharyngeal PCR sample within five days or less from the start of the intervention and 12 days or less from the diagnose, respectively.

RESULTS

The mean age of the patients was 43.9 years (SD:15.9). A median time of 3.00 days (IQR:2.00-6.50) needed from the time of starting the intervention/supportive care to the first negative PCR sample. There was no statistically significant difference neither between the percentage of patients in the interventional group and the supportive care group who achieved the primary or the secondary endpoint, nor in the median time needed to achieve the first negative PCR sample (p>0.05).

CONCLUSION

Prescribing antimalarial medications was not shown to shorten the disease course nor to accelerate the negative PCR conversion rate.
Prediction of 2019-nCov in Italy based on PSO and inversion analysis
Authors: Siyi Sun , Yangping Zheng
Published: May 2020

Novel coronavirus (2019-nCov) has swept the world, and all of the world have been harmful. This article makes prediction and suggestions for the Italy. Up to March 11, 2020, 2019-nCov thoroughly broke out in Italy with over 10,000 confirmed cases notwithstanding the gradually block of the country since March 9, 2020. Estimation of possible infection population and prospective suggestion of handling spread based on exist data are of crucial importance. Considering of the biology parameters obtained based on Chinese clinical data in Wuhan, other scholars’ work and real spread feature of 2019-nCov in Italy, we built a more applicable model called SEIJR with log-normal distributed time delay to forecast the trend of spreading. Adopting Particle Swarm Optimization (PSO), we estimated the early period average spreading velocity (α0) and conducted inversion analysis of time point (T0) when the virus first hit the Italy. Based on fixed α0 and T0, we then obtained the average spreading velocity α1 after the lock by PSO. For the aim of offering expeditious advice, we generated the prediction trends with different α which we considered would be helpful in addressing the infection. Not only solved the complex, nondifferentiable equation of epidemic model, our research also performs well in inversion analysis based on PSO which conveys informative outcomes for further discussion on precatious action. To conclude, the first day of spread is around February 1, 2020 with the early period average spreading velocity α0=0.330 which is higher than most cities in China except Wuhan. After locking the country and attaching great attention to public precaution, the α1 sharply descended to 0.278, indicting the effectiveness of these measures. Furthermore, in order to cope the disease before mid-April, take actions to control the under 0.25 is necessary. Code can be freely downloaded from https://github.com/Summerwork/2019-nCov-Prediction.
Genome-wide association study of school grades identifies a genetic overlap between language ability, psychopathology and creativity
Authors: Rajagopal Veera M. , Ganna Andrea , Coleman Jonathan R. I. , Allegrini Andrea G. , Voloudakis Georgios , Grove Jakob , Als Thomas D. , Horsdal Henriette T. , Petersen Liselotte , Appadurai Vivek , Schork Andrew , Buil Alfonso , Bulik Cynthia M. , Bybjerg-Grauholm Jonas , Bækvad-Hansen Marie , Hougaard David M. , Mors Ole , Nordentoft Merete , Werge Thomas ,   iPSYCH-Broad Consortium, Mortensen Preben Bo , Breen Gerome , Roussos Panos , Plomin Robert , Agerbo Esben , Børglum Anders D. , Demontis Ditte
Published: May 2020

Individuals with psychiatric disorders perform differently in school compared to the general population. Genetic factors contribute substantially to such differences. It is however unclear if differential performance is seen across all cognitive domains such as math and language. Here we report a genome-wide association study (GWAS) of school grades in 30,982 individuals (18,495 with and 12,487 without one or more of six major psychiatric disorders) and a replication study in 4,547 individuals. GWAS of overall school performance yielded results that were highly similar to the results of a previous GWAS of educational attainment. Analyzing subject specific grades, we observed that math performance was severely affected whereas language performance (Danish and English) was relatively unaffected or enhanced in those with psychiatric disorders compared to controls. We found that the genetic variants associated with poor math performance, but better language performance were also associated with increased risk for multiple psychiatric disorders. The same variants were also associated with creativity, which we show through a polygenic score analysis of 2953 creative professionals and 164,622 controls. The results overall suggest that risk for psychiatric disorders, language ability and creativity might have overlapping genetic roots.
Identification and genetic diversity analysis of a male-sterile gene (MS1) in Japanese cedar (Cryptomeria japonicaD. Don)
Authors: Hasegawa Yoichi , Ueno Saneyoshi , Wei Fu-Jin , Matsumoto Asako , Uchiyama Kentaro , Ujino-Ihara Tokuko , Hakamata Tetsuji , Fujino Takeshi , Kasahara Masahiro , Bino Takahiro , Yamaguchi Katsushi , Shigenobu Shuji , Tsumura Yoshihiko , Moriguchi Yoshinari
Published: May 2020

Identifying causative genes for a target trait in conifer reproduction is challenging for species lacking whole-genome sequences. In this study, we searched for the male-sterility gene (MS1) inCryptomeria japonica, aiming to promote marker-assisted selection (MAS) of male-sterileC. japonicato reduce the pollinosis caused by pollen dispersal from artificialC. japonicaforests in Japan. We searched for mRNA sequences expressed in male strobili and found the gene CJt020762, coding for a lipid transfer protein containing a 4-bp deletion specific to male-sterile individuals. We also found a 30-bp deletion by sequencing the entire gene of another individual with thems1. All nine breeding materials with the allelems1had either a 4-bp or 30-bp deletion in gene CJt020762, both of which are expected to result in faulty gene transcription and function. Furthermore, the 30-bp deletion was detected from three of five individuals in the Ishinomaki natural forest. From our findings, CJt020762 was considered to be the causative gene ofMS1. Thus, by performing MAS using two deletion mutations as a DNA marker, it will be possible to find novel breeding materials ofC. japonicawith the allelems1adapted to the unique environment of each region of the Japanese archipelago.
Generating Artificial Sensations with Spinal Cord Stimulation in Primates and Rodents
Authors: Yadav Amol P. , Li Shuangyan , Krucoff Max O. , Lebedev Mikhail A. , Abd-El-Barr Muhammad M. , Nicolelis Miguel A.L.
Published: May 2020

For patients who have lost sensory function due to a neurological injury such as spinal cord injury (SCI), stroke, or amputation, spinal cord stimulation (SCS) may provide a mechanism for restoring somatic sensations via an intuitive, non-visual pathway. Inspired by this vision, here we trained rhesus monkeys and rats to detect and discriminate patterns of epidural SCS. Thereafter, we constructed psychometric curves describing the relationship between different SCS parameters and the animal’s ability to detect SCS and/or changes in its characteristics. We found that the stimulus detection threshold decreased with higher frequency, longer pulse-width, and increasing duration of SCS. Moreover, we found that monkeys were able to discriminate temporally- and spatially-varying patterns (i.e. variations in frequency and location) of SCS delivered through multiple electrodes. Additionally, sensory discrimination of SCS-induced sensations in rats obeyed Weber’s law of just noticeable differences. These findings suggest that by varying SCS intensity, temporal pattern, and location different sensory experiences can be evoked. As such, we posit that SCS can provide intuitive sensory feedback in neuroprosthetic devices.
Protein stability and functional activity during nebulization: A comparative study of three nebulizer!
Authors: Singh Niti , Yadav Preeti , Gaur Prekcha , Gaur Manish , Yadav Awadh Bihari
Published: May 2020

Delivery of therapeutics protein to the lung offers effective treatments of lungs disease. Efficacy of delivered therapeutics molecules depends on integrity and stability of protein during nebulization. In this study, we compared three nebulizers: compressed air nebulizer (CAN), ultrasonic nebulizer (USN) and mesh nebulizer (MAN) to deliver aerosol dose, stability and functional activity of a model protein lysozyme. Lysozyme/BSA delivered dose assessed by indirect and direct method. It was shown CAN deliver 0.142±0.027 to 0.632± 0.09 ml of protein, USN deliver 0.511±0.119 to 1.688±0.173 ml and MAN deliver 0.238±0.006 to 0.731±0.013 ml of protein in the same time. Integrity of nebulized proteins were assessed by gel electrophoresis and circular diochorism. It was found integrity of lysozyme compromised in all three nebulizer maximum in CAN and minimum with MAN. The functional activity of protein was assessed after nebulization by turbidometry assay. The functional activity was compromised by all three nebulizer upto some extent. In conclusion, nebulization compromise protein stability: this impact depend on nebulization techniques as well as nature of protein. The CAN deliver protein more precisely in small amount in comparison to the other nebulizer.

Abstract Figure

Graphical Abstract
Somatostatin receptor subtypes 1 and 4 redundantly regulate neprilysin, the major amyloid-beta degrading enzyme in brain
Authors: Nilsson Per , Sörgjerd Karin , Kakiya Naomasa , Sasaguri Hiroki , Watamura Naoto , Shimozawa Makoto , Tsubuki Satoshi , Zhou Zhulin , Loera-Valencia Raul , Takamura Risa , Sekiguchi Misaki , Petrich Aline , Schulz Stefan , Saito Takashi , Winblad Bengt , Saido Takaomi C.
Published: May 2020

Alzheimer’s disease (AD) brains are characterized by increased levels of the pathogenic amyloid beta (Aβ) peptide, which accumulates into extracellular plaques. Finding a way to lower Aβ levels is fundamental for the prevention and treatment of AD. Neprilysin is the major Aβ degrading enzyme which is regulated by the neuropeptide somatostatin. Here we used a combination ofin vitroandin vivoapproaches to identify the subtype specificity of the five somatostatin receptors (SSTs) expressed in the brain, involved in the regulation of neprilysin. Using a battery ofSstdouble knockout (dKO) mice we show that neprilysin is regulated by SST1and SST4in a redundant manner.Sst1andSst4dKO mice exhibit a specific decrease of presynaptic neprilysin in the Lacunosum molecular layer. Moreover, a genetic deficiency ofSst1andSst4in amyloid beta precursor protein (App) knock-in mice, an AD mouse model, aggravates the Aβ pathology in the hippocampus. As a first proof of concept towards an Aβ-lowering strategy involving neprilysin, we demonstrate that treatment with an agonist selective for SST1and SST4ameliorates the Aβ pathology and improves cognition in theAppknock-in AD mouse model.
Isolation of full-length IgG antibodies from combinatorial libraries expressed in the cytoplasm ofEscherichia coli
Authors: Robinson Michael-Paul , Cox Emily C. , Li Mingji , Jaroentomeechai Thapakorn , Zheng Xiaolu , Chang Matthew , Berkmen Mehmet , DeLisa Matthew P.
Published: May 2020

We describe a facile and robust genetic selection for isolating full-length IgG antibodies from combinatorial libraries expressed in the cytoplasm of the genetically engineeredEscherichia colistrain, SHuffle. The method is based on the transport of a bifunctional substrate comprised of an antigen fused to chloramphenicol acetyltransferase, which allows positive selection of bacterial cells co-expressing cytoplasmic IgGs called ‘cyclonals’ that specifically capture the chimeric antigen and sequester the antibiotic resistance marker in the cytoplasm. The selective power of this approach was demonstrated by facile isolation of novel complementarity-determining regions for a cyclonal that specifically recognized the basic-region leucine zipper domain of the yeast transcriptional activator protein Gcn4.
Meta-Signer: Metagenomic Signature Identifier based on Rank Aggregation of Features
Authors: Reiman Derek , Metwally Ahmed A. , Sun Jun , Dai Yang
Published: May 2020

Background

The advance of metagenomic studies provides the opportunity to identify microbial taxa that are associated to human diseases. Multiple methods exist for the association analysis. However, the results could be inconsistent, presenting challenges in interpreting the host-microbiome interactions. To address this issue, we introduce Meta-Signer, a novelMetagenomicSignature Identifiertool based on rank aggregation of features identified from multiple machine learning models including Random Forest, Support Vector Machines, LASSO, Multi-Layer Perceptron Neural Networks, and our recently developed Convolutional Neural Network framework (PopPhy-CNN). Meta-Signer generates ranked taxa lists by training individual machine learning models over multiple training partitions and aggregates them into a single ranked list by an optimization procedure to represent the most informative and robust microbial features. Meta-Signer can rank taxa using two input forms of the data: the relative abundances of the original taxa and taxa from the populated taxonomic trees generated from the original taxa. The latter form allows the evaluation of the association of microbial features at different taxonomic levels to the disease, which is attributed to our novel model of PopPhy-CNN.

Results

We evaluate Mega-Signer on five different human gut-microbiome datasets. We demonstrate that the features derived from Meta-Signer were more informative compared to those obtained from other available feature ranking methods. The highly ranked features are strongly supported by published literature.

Conclusion

Meta-Signer is capable of deriving a robust set of microbial features at multiple taxonomic levels for the prediction of host phenotype. Meta-Signer is user-friendly and customizable, allowing users to explore their datasets quickly and efficiently.
Evolutionary and Functional Lessons from Human-Specific Amino-Acid Substitution Matrices
Authors: Shauli Tair , Brandes Nadav , Linial Michal
Published: May 2020

The characterization of human genetic variation in coding regions is fundamental to our understanding of protein function, structure, and evolution. Amino-acid (AA) substitution matrices such as BLOSUM (BLOcks SUbstitution Matrix) and PAM (Point Accepted Mutations) encapsulate the stochastic nature of such proteomic variation and are used in studying protein families and evolutionary processes. However, these matrices were constructed from protein sequences spanning long evolutionary distances and are not designed to reflect polymorphism within species. To accurately represent proteomic variation within the human population, we constructed a set of human-centric substitution matrices derived from genetic variations by analyzing the frequencies of >4.8M single nucleotide variants (SNVs). These human-specific matrices expose short-term evolutionary trends at both codon and AA resolution and therefore present an evolutionary perspective that differs from that implicated in the traditional matrices. Specifically, our matrices consider the directionality of variants, and uncover a set of AA pairs that exhibit a strong tendency to substitute in a specific direction. We further demonstrate that the substitution rates of nucleotides only partially determine AA substitution rates. Finally, we investigate AA substitutions in post-translational modification (PTM) and ion-binding sites. We confirm a strong propensity towards conservation of the identity of the AA that participates in such functions. The empirically-derived human-specific substitution matrices expose purifying selection over a range of residue-based protein properties. The new substitution matrices provide a robust baseline for the analysis of protein variations in health and disease. The underlying methodology is available as an open-access to the biomedical community.
Universal MS/MS Visualization and Retrieval with the Metabolomics Spectrum Resolver Web Service
Authors: Bittremieux Wout , Chen Christopher , Dorrestein Pieter C. , Schymanski Emma L. , Schulze Tobias , Neumann Steffen , Meier Rene , Rogers Simon , Wang Mingxun
Published: May 2020

The growth of online mass spectrometry metabolomics resources, including data repositories, spectral library databases, and online analysis platforms has created an environment of online/web accessibility. Here, we introduce the Metabolomics Spectrum Resolver (https://metabolomics-usi.ucsd.edu/), a tool that builds upon these exciting developments to allow for consistent data export (in human and machine-readable forms) and publication-ready visualisations of tandem mass spectrometry spectra. This tool supports the Human Proteome Organization – Proteomics Standards Initiative’s Universal Spectrum Identifier (USI) specification, which has been extended to deal with the metabolomics use cases. To date, this resource already supports data formats from GNPS, MassBank, MS2LDA, MassIVE, MetaboLights, and Metabolomics Workbench and is integrated into several of these resources.
Mitogen-activated protein kinases are carbon dioxide receptors in plants
Authors: Gałgańska Hanna , Gałgański Łukasz
Published: May 2020

The amount of CO2in the atmosphere is increasing continuously in the industrial era, posing a threat to the ecological balance on Earth. There are two ways to reduce elevated CO2concentrations ([CO2]high): reducing human emissions or increasing their absorption by oceans and plants. However, in response to [CO2]high, plants diminish gas exchange and CO2uptake by closing stomata. Surprisingly, we do not know how plants sense CO2in their environment, and the basic mechanisms of the plant response to [CO2]highare very poorly understood. Here, we show that mitogen-activated protein kinases (MAPKs) are plant CO2receptors. We demonstrate that MPK4, a prominent MAPK that is known to be involved in the stomatal response to [CO2]high1–3, is capable of binding CO2and is directly activated by a very low increase in [CO2]in vivoandin vitro. Unlike MPK4 activation by infections4, stress and hormones within known MAPK signalling cascades, [CO2]high-induced MPK4 activation is independent of the upstream regulators MKK1 and MKK2. Moreover, once activated, MPK4 is prone to inactivation by bicarbonate. The identification of stress-responsive MPK4 as a CO2receptor sheds new light on the integration of various environmental signals in guard cells, setting up MPK4 as the main hub regulating CO2availability for photosynthesis. This result could help to find new ways to increase CO2uptake by plants.
Multiple introductions, regional spread and local differentiation during the first week of COVID-19 epidemic in Montevideo, Uruguay
Authors: Salazar Cecilia , Díaz-Viraqué Florencia , Pereira-Gómez Marianoel , Ferrés Ignacio , Moreno Pilar , Moratorio Gonzalo , Iraola Gregorio
Published: May 2020

Background

After its emergence in China in December 2019, the new coronavirus disease (COVID-19) caused by SARS-CoV-2, has rapidly spread infecting more than 3 million people worldwide. South America is among the last regions hit by COVID-19 pandemic. In Uruguay, first cases were detected on March 13th2020 presumably imported by travelers returning from Europe.

Methods

We performed whole-genome sequencing of 10 SARS-CoV-2 from patients diagnosed during the first week (March 16thto 19th) of COVID-19 outbreak in Uruguay. Then, we applied genomic epidemiology using a global dataset to reconstruct the local spatio-temporal dynamics of SARS-CoV-2.

Results

Our phylogeographic analysis showed three independent introductions of SARS-CoV-2 from different continents. Also, we evidenced regional circulation of viral strains originally detected in Spain. Introduction of SARS-CoV-2 in Uruguay could date back as early as Feb 20th. Identification of specific mutations showed rapid local genetic differentiation.

Conclusions

We evidenced early independent introductions of SARS-CoV-2 that likely occurred before first cases were detected. Our analysis set the bases for future genomic epidemiology studies to understand the dynamics of SARS-CoV-2 in Uruguay and the Latin America and the Caribbean region.
Neuropathic Pain Linked to Defective Dopaminergic Inhibition in Anterior Cingulate Cortex
Authors: Lançon Kevin , Navratilova Edita , Porreca Frank , Séguéla Philippe
Published: May 2020

Pyramidal neurons in the anterior cingulate cortex (ACC), a prefrontal region involved in processing the affective components of pain, display hyperexcitability in chronic neuropathic conditions and their silencing abolishes hyperalgesia in rodents. We show here that dopamine, through D1-like receptor signaling, inhibits layer 2/3 pyramidal neurons of mouse ACC. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control the firing activity of these pyramidal neurons. Through Gs-coupled D1-like receptors, dopamine induces the opening of HCN channels at physiological membrane potentials, driving a significant decrease in input resistance and excitability. Systemic L-DOPA rescues HCN channel activity, pyramidal excitability in ACC as well as sensory phenotype in neuropathic mice while microinjection of a selective D1-like agonist in ACC induces relief of ongoing pain in neuropathic animals. We conclude that decreased dopaminergic inhibition in ACC plays a critical role in an abnormal top-down modulation leading to neuropathic pain.
Transcriptome analysis reveals the genetic basis underlying the development of skin appendages and immunity in hedgehog (Atelerix albiventris)
Authors: Li Hui-Ming , Yang Bi-Ze , Zhang Xiu-Juan , Jiang Hai-Ying , Li Lin-Miao , Ahmad Hafiz Ishfaq , Chen Jin-Ping
Published: May 2020

The expression of hair features is an evolutionary adaptation resulting from interactions between many organisms and their environment. Elucidation of the mechanisms that underlie the expression of such traits is a topic in evolutionary biology research. Therefore, we assessed thede novotranscriptome ofAtelerix albiventrisat three developmental stages and compared gene expression profiles between abdomen hair and dorsal spine tissues. We identified 328,576 unigenes in our transcriptome, among which 3,598 were differentially expressed between hair- and spine-type tissues. Dorsal and abdomen skin tissues 5 days after birth were compared and the resulting differentially expressed genes were mainly enriched in keratin filament, epithelium cell differentiation, and epidermis development based on GO enrichment analysis, and tight junction, p53, and cell cycle signaling pathways based on KEGG enrichment analysis. Expression variations ofMBP8, SFN, Wnt10, KRT1,andKRT2may be the main factors regulating hair and spine differentiation for the hedgehog. Strikingly, DEGs in hair-type tissues were also significantly enriched in immune-related terms and pathways with hair-type tissues exhibiting more upregulated immune genes than spine-type tissues. Thus, we propose that spine development was an adaptation that provided protection against injuries or stress and reduced hedgehog vulnerability to infection.
Notch1 switches progenitor competence in inducing medulloblastoma
Authors: Ballabio Claudio , Gianesello Matteo , Lago Chiara , Okonechnikov Konstantin , Anderle Marica , Aiello Giuseppe , Antonica Francesco , Zhang Tingting , Gianno Francesca , Giangaspero Felice , Hassan Bassem A. , Pfister Stefan M. , Tiberi Luca
Published: May 2020

The identity of the cell of origin is a key determinant of cancer subtype, progression and prognosis. Group 3 Medulloblastoma (MB) is a malignant childhood brain cancer with poor prognosis and unknown cell of origin. We overexpressed the Group 3 MB genetic drivers MYC and Gfi1 in different candidate cells of origin in the postnatal mouse cerebellum. We found that S100b+cells are competent to initiate Group 3 MB, while Math1+, Sox2+or Ascl1+cells are not. We noted that S100b+cells have higher levels of Notch1 pathway activity compared to Math1+cells. Interestingly, we found that additional activation of Notch1 in Math1+cells was sufficient to induce Group 3 MB upon MYC/Gfi1 expression. Taken together, our data suggest that the MB cell of origin competence depends on the cellular identity, which relies on Notch1 activity.

Graphical Abstract
Fronto-parietal, cingulo-opercular and striatal contributions to learning and implementing control policies
Authors: Bhandari Apoorva , Badre David
Published: May 2020

Efficient task performance requires co-ordination of internal cognitive processes by implementing control policies adapted to the dynamic structure of task demands. The cognitive and neural basis of control policy implementation remains poorly characterized, in part because it is typically confounded with implementing new stimulus-response rules. To disambiguate these processes, we asked participants to perform multiple novel variants of a working memory control task. Each variant had a unique, novel sequential trial structure, but all shared common stimulusresponse rules, enabling us to test control policy implementation separate from rule learning. Behaviorally, we found evidence for two adaptive processes tied to control policy implementation. One process was reflected in slower responses on the first trial with a novel sequential trial structure, followed by rapid speeding on subsequent trials. A second process was reflected in the diminishing size of the first trial cost as participants accommodated different variants of the task over many blocks. Using fMRI, we observed that the striatum and a cingulo-opercular cortical network increased activity to the first trial, tracking the fast adjustment. This pattern of activity dissociated these regions from a fronto-parietal network including dorsolateral PFC, inferior frontal junction, inferior parietal sulcus, and rostrolateral PFC, which showed a slower decline in activity across trials, mirroring findings in rule implementation studies, but in the absence of rule implementation demands. Our results reveal two adaptive processes underlying the implementation of efficient, generalizable control policies, and suggest a broader account of the role of a cortico-striatal network in control policy implementation.

Significance statement

Rapid adaptation to novel tasks is a hallmark of human behavior. Understanding how human brains achieve this is of critical importance in neuroscience. Here we broaden the scope of this problem, going beyond task rules to more broadly consider the cognitive control demands produced by novel task dynamics. We propose that humans rely on two adaptive processes to rapidly implement efficient, generalizable control policies as task dynamics change, even when task rules remain unchanged. One process unfolds rapidly and underlies efficient adaptation. A second process unfolds slowly with experience across task conditions and underlies generalization of control policies. Using fMRI, we identify cingulo-opercular cortex, fronto-parietal cortex and striatum as dissociable components of a cortico-striatal network that contribute to control implementation.
Aging markers in human urine: A comprehensive, non-targeted LC-MS study
Authors: Teruya Takayuki , Goga Haruhisa , Yanagida Mitsuhiro
Published: May 2020

Metabolites in human biofluids document individual physiological status. We conducted comprehensive, non-targeted, non-invasive metabolomic analysis of urine from 27 healthy human subjects, comprising 13 youths (30±3 yr) and 14 seniors (76±4 yr). Quantitative analysis of 99 metabolites revealed 55 that were linked to aging, displaying significant differences in abundance between the two groups. These include 13 standard amino acids, 5 methylated, 4 acetylated, and 9 other amino acids, 6 nucleosides, nucleobases, and derivatives, 4 sugar derivatives, 5 sugar phosphates, 4 carnitines, 2 hydroxybutyrates, 1 choline, and 1 ethanolamine derivative, and glutathione disulfide. Abundances of 53 compounds decreased, while 2 increased in elderly people. Many age-linked markers were highly correlated; 42 of 55 compounds, showed Pearson’s correlation coefficients larger than 0.70. As metabolite profiles of urine and blood are quite different, age-related information in urine components offer yet more valuable insights into aging mechanisms of endocrine system and related organ systems.
Heparan sulfate proteoglycans as attachment factor for SARS-CoV-2
Authors: Liu Lin , Chopra Pradeep , Li Xiuru , Bouwman Kim M. , Tompkins S. Mark , Wolfert Margreet A. , de Vries Robert P. , Boons Geert-Jan
Published: May 2020

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is causing an unprecedented global pandemic demanding the urgent development of therapeutic strategies. Microarray binding experiments using an extensive heparan sulfate (HS) oligosaccharide library showed that the receptor binding domain (RBD) of the spike of SARS-CoV-2 can bind HS in a length-and sequence-dependent manner. Hexa- and octa-saccharides composed of IdoA2S-GlcNS6S repeating units were identified as optimal ligands. Surface plasma resonance (SPR) showed the SARS-CoV-2 spike protein binds with much higher affinity to heparin (KD = 55 nM) compared to the RBD (KD = 1 μM) alone. We also found that heparin does not interfere in angiotensin-converting enzyme 2 (ACE2) binding or proteolytic processing of the spike. Our data supports a model in which HS functions as the point of initial attachment for SARS-CoV-2 infection. Tissue staining studies using biologically relevant tissues indicate that heparan sulfate proteoglycan (HSPG) is a critical attachment factor for the virus. Collectively, our results highlight the potential of using HS oligosaccharides as a therapeutic agent by inhibiting SARS-CoV-2 binding to target cells.
Performance of aerialBacillus thuringiensisvar.israelensisapplications in mixed saltmarsh-mangrove systems and use of affordable unmanned aerial systems to identify problematic levels of canopy cover
Authors: Johnson Brian J. , Manby Russell , Devine Gregor J.
Published: May 2020

BACKGROUND

In the Australian southeast, the saltmarsh mosquitoAedes vigilax(Skuse) is the focus of area-wide larviciding campaigns employing the biological agentBacillus thuringiensisvar.israelensis (Bti). Although generally effective, frequent inundating tides and considerable mangrove cover can make control challenging. Here, we describe the efficacy and persistence of an aqueousBtisuspension (potency: 1200 International Toxic Units; strain AM65-52) within a mixed saltmarsh-mangrove system and the use of affordable unmanned aerial systems (UAS) to identify and map problematic levels of mangrove canopy cover.

RESULTS

High mangrove canopy density (>40% cover) reduced product deposition by 74.5% (0.013± 0.002 μl/cm2vs. 0.051± 0.006 μl/cm2), larval mortality by 27.7% (60.7± 4.1% vs. 84.0± 2.4%), and ground levelBticoncentrations by 32.03% (1144 ± 462.6 vs. 1683 ± 447.8 spores ml−1) relative to open saltmarsh. Persistence of product post-application was found to be low (80.6% loss at 6 h) resulting in negligible additional losses to tidal inundation 24 h post-application. UAS surveys accurately identified areas of high mangrove cover using both standard and multispectral imagery, although derived index values for this vegetation class were only moderately correlated with ground measurements (R2=0.17-0.38) at their most informative scales.

CONCLUSION

These findings highlight the complex operational challenges that affect coastal mosquito control in heterogeneous environments. The problem is exacerbated by continued mangrove transgression into saltmarsh habitat in the region. Emerging UAS technology can help operators optimize treatments by accurately identifying and mapping challenging canopy cover using both standard and multispectral imaging.
Environmental RNA interference in two-spotted spider mite,Tetranychus urticae, reveals dsRNA processing requirements for efficient RNAi response
Authors: Bensoussan Nicolas , Dixit Sameer , Tabara Midori , Letwin David , Milojevic Maja , Antonacci Michele , Jin Pengyu , Arai Yuka , Bruinsma Kristie , Suzuki Takeshi , Fukuhara Toshiyuki , Zhurov Vladimir , Geibel Sven , Nauen Ralf , Grbic Miodrag , Grbic Vojislava
Published: May 2020

Comprehensive understanding of pleiotropic roles of RNAi machinery highlighted the conserved chromosomal functions of RNA interference. The consequences of the evolutionary variation in the core RNAi pathway genes are mostly unknown, but may lead to the species-specific functions associated with gene silencing. The two-spotted spider mite,Tetranychus urticae, is a major polyphagous chelicerate pest capable of feeding on over 1,100 plant species and developing resistance to pesticides used for its control. A well annotated genome, susceptibility to RNAi and economic importance, makeT. urticaean excellent candidate for development of an RNAi protocol that enables high-throughput genetic screens and RNAi-based pest control. Here, we show that the length of the exogenous dsRNA critically determines its processivity and ability to induce RNAiin vivo. A combination of the long dsRNAs and the use of dye to trace the ingestion of dsRNA enabled the identification of genes involved in membrane transport and 26S proteasome degradation as sensitive RNAi targets. Our data demonstrate that environmental RNAi can be an efficient reverse genetics and pest control tool inT. urticae. In addition, the species-specific properties together with the variation in the components of the RNAi machinery makeT. urticaea potent experimental system to study the evolution of RNAi pathways.
Germline mutagenesis ofNasonia vitripennisthrough ovarian delivery of CRISPR-Cas9 ribonucleoprotein
Authors: Chaverra-Rodriguez Duverney , Benetta Elena Dalla , Heu Chan C. , Rasgon Jason L. , Ferree Patrick M. , Akbari Omar S.
Published: May 2020

CRISPR/Cas9 gene editing is a powerful technology to study the genetics of rising model organisms, such as the jewel waspNasonia vitripennis. However, current methods involving embryonic microinjection of CRISPR reagents are challenging. Delivery of Cas9 ribonucleoprotein into female ovaries is an alternative that has only been explored in a small handful of insects, such as mosquitoes and whiteflies. Here, we developed a simple protocol for germline gene editing by injecting Cas9 ribonucleoprotein in adultN. vitripennisfemales using either ReMOT control (Receptor-Mediated Ovary Transduction of Cargo) or BAPC (Branched Amphiphilic Peptide Capsules) as ovary delivery methods. We demonstrate efficient delivery of protein cargo such as EGFP and Cas9 into developing oocytes via P2C peptide and BAPC. Additionally, somatic and germline gene editing have been demonstrated. This approach will greatly facilitate CRISPR-applied genetic manipulation in this and other rising model organisms.
Predictions of COVID-19 dynamics in the UK: short-term forecasting and analysis of potential exit strategies
Authors: Keeling Matt J. , Hill Edward M. , Gorsich Erin E. , Penman Bridget , Guyver-Fletcher Glen , Holmes Alex , Leng Trystan , McKimm Hector , Tamborrino Massimiliano , Dyson Louise , Tildesley Michael J.
Published: May 2020

Background

Efforts to suppress transmission of SARS-CoV-2 in the UK have seen non-pharmaceutical interventions being invoked. The most severe measures to date include all restaurants, pubs and cafes being ordered to close on 20th March, followed by a “stay at home” order on the 23rd March and the closure of all non-essential retail outlets for an indefinite period. Government agencies are presently analysing how best to develop an exit strategy from these measures and to determine how the epidemic may progress once measures are lifted. Mathematical models are currently providing short and long term forecasts regarding the future course of the COVID-19 outbreak in the UK to support evidence-based policymaking.

Methods

We present a deterministic, age-structured transmission model that uses real-time data on confirmed cases requiring hospital care and mortality to provide up-to-date predictions on epidemic spread in ten regions of the UK. The model captures a range of age-dependent heterogeneities, reduced transmission from asymptomatic infections and produces a good fit to the key epidemic features over time. We simulated a suite of scenarios to assess the impact of differing approaches to relaxing social distancing measures from 7th May 2020, on the estimated number of patients requiring inpatient and critical care treatment, and deaths. With regard to future epidemic outcomes, we investigated the impact of reducing compliance, ongoing shielding of elder age groups, reapplying stringent social distancing measures using region based triggers and the role of asymptomatic transmission.

Findings

We find that significant relaxation of social distancing measures from 7th May onwards can lead to a rapid resurgence of COVID-19 disease and the health system being quickly overwhelmed by a sizeable, second epidemic wave. In all considered age-shielding based strategies, we projected serious demand on critical care resources during the course of the pandemic. The reintroduction and release of strict measures on a regional basis, based on ICU bed occupancy, results in a long epidemic tail, until the second half of 2021, but ensures that the health service is protected by reintroducing social distancing measures for all individuals in a region when required.

Discussion

Our work confirms the effectiveness of stringent non-pharmaceutical measures in March 2020 to suppress the epidemic. It also provides strong evidence to support the need for a cautious, measured approach to relaxation of lockdown measures, to protect the most vulnerable members of society and support the health service through subduing demand on hospital beds, in particular bed occupancy in intensive care units.
Influences and aspirations in the production of national projects in Lebanon and Kuwait
Authors: Mazzetto Silvia , El-Khoury Roula
Published: May 2020

Purpose

By looking at a selection of iconic modern projects designed by or commissioned to the prominent but not well-examined architect Sami Abdul Baki both in Lebanon and Kuwait during his most productive years in the 50s, this paper attempts to identify first main trends, influences and ideologies that shaped these works at the peak of modern architectural development in the region. Through these examples, the paper then aims at retracing predominant trajectories of intellectual capital exchange and transfer of knowledge between Lebanon and Kuwait. These can go far beyond their territorial boundaries, without claiming a single grand-narrative that describes the modern architectural development in any of the two countries.

Design/methodology/approach

The data collected from discourse analysis, interviews and biographical notes were mapped into a schematic diagram illustrating a complex network of connections and multidisciplinary involvement in projects.

Findings

However, the outcome did not generate a dominant theme for the projects or expertise of the architect.

Originality/value

It is very likely that Sami Abdul Baki's strong political dimension and quality as a mediator or facilitator in addition to his strong network of contacts played a significant role in the project commissions that he has won as an architect/engineer in Kuwait, Lebanon, Germany and other countries.