bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutation landscape of SARS-CoV-2 reveals five mutually exclusive clusters of leading and trailing single nucleotide substitutions
Authors: Mishra Akhilesh , Pandey Ashutosh Kumar , Gupta Parul , Pradhan Prashant , Dhamija Sonam , Gomes James , Kundu Bishwajit , Vivekanandan Perumal , Menon Manoj B.
Published: May 2020

The COVID-19 pandemic has spread across the globe at an alarming rate. However, unlike any of the previous global outbreaks the availability of a large number of SARS-CoV-2 sequences provides us with a unique opportunity to understand viral evolution in real time. We analysed 1448 full-length (>29000 nt) sequences available and identified 40 single-nucleotide substitutions occurring in >1% of the genomes. Majority of the substitutions were C to T or G to A. We identify C/Gs with an upstream TTT trinucleotide motif as hotspots for mutations in the SARS-CoV-2 genome. Interestingly, three of the 40 substitutions occur within highly conserved secondary structures in the 5’ and 3’ regions of the genomic RNA that are critical for the virus life cycle. Furthermore, clustering analysis revealed unique geographical distribution of SARS-CoV-2 variants defined by their mutation profile. Of note, we observed several co-occurring mutations that almost never occur individually. We define five mutually exclusive lineages (A1, B1, C1, D1 and E1) of SARS-CoV-2 which account for about three quarters of the genomes analysed. We identify lineage-defining leading mutations in the SARS-CoV-2 genome which precede the occurrence of sub-lineage defining trailing mutations. The identification of mutually exclusive lineage-defining mutations with geographically restricted patterns of distribution has potential implications for diagnosis, pathogenesis and vaccine design. Our work provides novel insights on the temporal evolution of SARS-CoV-2.

Importance

The SARS-CoV-2 / COVID-19 pandemic has spread far and wide with high infectivity. However, the severeness of the infection as well as the mortality rates differ greatly across different geographic areas. Here we report high frequency mutations in the SARS-CoV-2 genomes which show the presence of linage-defining, leading and trailing mutations. Moreover, we propose for the first time, five mutually exclusive clusters of SARS-CoV-2 which account for 75% of the genomes analysed. This will have implications in diagnosis, pathogenesis and vaccine design
Knowledge, attitude and practice of secondary school students toward COVID-19 epidemic in Italy: a cross selectional study
Authors: Souli Dafni , Dilucca Maddalena
Published: May 2020

The coronavirus disease (COVID-19) is a highly transmittable and pathogenic viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which emerges in December 2019 in Wuhan, China and spreads around the world at the beginning of 2020. The World Health Organization declares the outbreak a Public Health Emergency of International Concern on the 30th of January, and a pandemic on the 11th of March. On the 4th of March, the Italian government orders the full closure of all schools and universities nationwide.

The aim of this study is to investigate the knowledge, practice and attitudes (KAP) of secondary school at the time of COVID-19 pandemic in Italy. In this cross-sectional, web-based survey, conducted among the high school student population with age ranging from 14 to 19 years old, a questionnaire with 19 items regarding the KAP toward COVID-19 is asked. Study participants are recruited from several secondary schools of different areas. Frequencies and histograms are computed for descriptive purposes. Statistical analysis is computed with Chi square test, utilized to depict relevant difference between geender. Among a total of 2380 students who answers the questionnaire, 40.7% are male and 59.3% are female.

Level of knowledge about generical characteristics of COVID-19 is quite similar among gender. Students present a good level of knowledge about the clinical presentation of the disease, the basic hygiene principles, the modes of transmission and the method of protection against virus transmission. The knowledge about number of this pandemia and easy scientific correlation with COVID-19 is quite confused. The most frequently reported source of knowledge about COVID-19 is television, whereas the less is the school. Our findings suggest that student population shows appropriate practice, and positive attitude towards COVID-19 at the time of its outbreak.

More emphasis should be placed on education of the student partecipants about biological meaning of this infection and relative preventive or future measures.
The real time effective reproductive number for COVID-19 in the United States
Authors: Zhang Yue , Keegan Lindsay T , Yuqing Qiu , Samore Matthew H
Published: May 2020

none.
SARS-CoV-2 activates lung epithelia cell proinflammatory signaling and leads to immune dysregulation in COVID-19 patients by single-cell sequencing
Authors: Chen Huarong , Liu Weixin , Liu Dabin , Zhao Liuyang , Yu Jun
Published: May 2020

Objective

The outbreak of Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection has become a global health emergency. We aim to decipher SARS-CoV-2 infected cell types, the consequent host immune response and their interplay in the lung of COVID-19 patients.

Design

We analyzed single-cell RNA sequencing (scRNA-seq) data of lung samples from 17 subjects (6 severe COVID-19 patients, 3 mild patients who recovered and 8 healthy controls). The expression of SARS-CoV-2 receptors (ACE2 and TMPRSS2) was examined among different cell types in the lung. The immune cells infiltration patterns, their gene expression profiles, and the interplay of immune cells and SARS-CoV-2 target cells were further investigated.

Results

Compared to healthy controls, the overall ACE2 (receptor of SARS-CoV-2) expression was significantly higher in lung epithelial cells of COVID-19 patients, in particular in ciliated cell, club cell and basal cell. Comparative transcriptome analysis of these lung epithelial cells of COVID-19 patients and healthy controls identified that SARS-CoV-2 infection activated pro-inflammatory signaling including interferon pathway and cytokine signaling. Moreover, we identified dysregulation of immune response in patients with COVID-19. In severe COVID-19 patients, significantly higher neutrophil, but lower T and NK cells in lung were observed along with markedly increased cytokines (CCL2, CCL3, CCL4, CCL7, CCL3L1 and CCL4L2) compared with healthy controls as well as mild patients who recovered. The cytotoxic phenotypes were shown in lung T and NK cells of severe patients as evidenced by enhanced ifnγ, Granulysin, Granzyme B and Perforin expression. Moreover, SARS-CoV-2 infection altered the community interplay of lung epithelial cells and immune cells: the interaction between epithelial cells with macrophage, T and NK cell was stronger, but their interaction with neutrophils was lost in COVID-19 patients compared to healthy controls.

Conclusions

SARS-CoV-2 infection activates pro-inflammatory signaling in lung epithelial cells expressing ACE2 and causes dysregulation of immune response to release more pro-inflammatory cytokines. Moreover, SARS-CoV-2 infection breaks the interplay of lung epithelial cells and immune cells.
HDAC inhibitors decrease TLR7/9-mediated human plasmacytoid dendritic cell activation by interfering with IRF-7 and NF-κB signaling
Authors: Descalzi-Montoya Dante B. , Dai Jihong , Singh Sukhwinder , Fitzgerald-Bocarsly Patricia
Published: May 2020

Histone deacetylase inhibitors (HDACi) are epigenome modulating molecules that target histone and non-histone proteins and have been successfully used to target many types of cancer and immunological disorders. While HDACi’s effects on nuclear histone deacetylases are well characterized, their effect on non-nuclear, cytoplasmic molecules requires further investigation. In the current study we characterized the effects of class I/II HDACi, specifically, TSA, MS-275, and SAHA, on plasmacytoid dendritic cell (pDC) biology upon viral activation via the TLR7/9 pathway. TSA, MS-275, and SAHA, down-modulated the induction of IFN-α and TNF-α upon Influenza A virus (IAV; TLR7 signaling) and Herpes Simplex 1 (HSV-1; TLR9 signaling) stimulation in primary pDC. The HDACi inhibitory effect was more prominent for IAV-mediated responses than for HSV-1. While IFN-α induction was not associated with inhibition of IRF-7 upregulation in the presence of TSA or MS-275, IRF-7 upregulation was affected by SAHA, but only for IAV. Furthermore, TSA, but not MS-275, inhibited TLR7/9-induced expression of maturation markers, CD40, and CD86, but not CD40. In addition, HDACi treatment increased virally-induced shedding of CD62L. Mechanistically, TSA, MS-275, SAHA significantly decreased early IRF-7 and NF-κB nuclear translocation, which was preceded by a decline in phosphorylation of IRF-7 at Ser477/479 and NF-κB p-p65, except for MS-275. In summary, we propose that broad HDACi, but not class I HDACi, treatment can negatively impact early TLR7/9-mediated signaling, namely, the disruption of IRF-7 and NF-κB activation and translocation that lead to deleterious effects on pDC function.
COVID-19 peak estimation and effect of nationwide lockdown in India
Authors: Belfin R V , Bródka Piotr , Radhakrishnan B L , Rejula V
Published: May 2020

There was a fury of the pandemic because of novel coronavirus (2019-nCoV/SARS-CoV-2) that happened in Wuhan, Hubei province, in China in December 2019. Since then, many model predictions on the COVID-19 pandemic in Wuhan and other parts of China have been reported. The first incident of coronavirus disease 2019 (COVID-19) in India was reported on 30 January 2020, which was a student from Wuhan. The number of reported cases has started to increase day by day after 30 February 2020. The purpose of this investigation is to provide a prediction of the epidemic peak for COVID-19 in India by utilizing real-time data from 30 February to 14 April 2020. We apply the well-known epidemic compartmental model “SEIR” to predict the epidemic peak of COVID-19, India. Since we do not have the complete detail of the infective population, using the available infected population data, we identify the R0 by using polynomial regression. By using the third-order polynomial equation, we estimate that the basic reproduction number for the epidemic in India is R0 = 3.3 (95%CI, 3.1–3.5), and the epidemic peak could be reached by September 2020.
Timing of non-pharmaceutical interventions to mitigate COVID-19 transmission and their effects on mobility: A cross-country analysis
Authors: Summan Amit , Nandi Arindam
Published: May 2020

Non-pharmaceutical interventions (NPIs) that encourage physical distancing can decrease and delay the transmission of COVID-19. They have been implemented globally during the pandemic, however, the specific NPIs implemented and the timing of interventions has varied widely. We validated two published datasets on the implementation of NPIs globally. The health and socioeconomic factors associated with delay in implementation of NPIs was analyzed using fractional logit and probit models, and beta regression models. The probability of timely NPI implementation by a country was analyzed using a probit model. The effects of these interventions on mobility changes using Google social mobility reports, were analyzed with propensity score matching methods. Three NPIs were analyzed: national school closure, national lockdown, and global travel ban. Countries with higher incomes, larger populations, and better health preparedness measures had greater delays in implementation. Countries with greater population density, more democratic political systems, lower case detection capacity, and later arrival of first cases were more likely to implement NPIs. Implementation of lockdowns significantly reduced physical mobility. Mobility was further reduced when lockdowns were enforced with curfews or fines, or were more strictly defined. National school closures did not significantly change mobility. The implementation of NPIs is a global public good during pandemics, and the international community needs to address constraints and design incentives so countries implement NPIs in a timely manner. Further analysis is needed on the effect of NPI variations on mobility and transmission, and their associated costs.
SARS-CoV-2 receptor networks in diabetic and COVID-19 associated kidney disease
Authors: Menon Rajasree , Otto Edgar A. , Sealfon Rachel , Nair Viji , Wong Aaron K. , Theesfeld Chandra L. , Chen Xi , Wang Yuan , Boppana Avinash S. , Luo Jinghui , Yang Yingbao , Kasson Peter M. , Schaub Jennifer A. , Berthier Celine C. , Eddy Sean , Lienczewski Chrysta C. , Godfrey Bradley , Dagenais Susan L. , Sohaney Ryann , Hartman John , Fermin Damian , Subramanian Lalita , Looker Helen C. , Harder Jennifer L. , Mariani Laura H. , Hodgin Jeffrey B. , Sexton Jonathan Z. , Wobus Christiane E. , Naik Abhijit S. , Nelson Robert G. , Troyanskaya Olga G. , Kretzler Matthias
Published: May 2020

COVID-19 morbidity and mortality is increased in patients with diabetes and kidney disease via unknown mechanisms. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into host cells. Since ACE2 is a susceptibility factor for infection, we investigated how diabetic kidney disease (DKD) and medications alter ACE2 receptor expression in kidneys. Single cell RNA profiling of healthy living donor (LD) and DKD kidney biopsies revealed ACE2 expression primarily in proximal tubular epithelial cells (PTEC). This cell specific localization was confirmed by in situ hybridization. ACE2 expression levels were unaltered by exposures to renin angiotensin aldosterone system inhibitors in DKD. Bayesian integrative analysis of a large compendium of public -omics datasets identified molecular network modules induced in ACE2-expressing PTEC in DKD (searchable at hb.flatironinstitute.org/covid-kidney) that were linked to viral entry, immune activation, endomembrane reorganization, and RNA processing. The DKD ACE2-positive PTEC module overlapped with expression patterns seen in SARS-CoV-2 infected cells. Similar cellular programs were seen in ACE2-positive PTEC obtained from urine samples of 13 COVID-19 patients who were hospitalized, suggesting a consistent ACE2-coregulated PTEC expression program that may interact with the SARS-CoV-2 infection processes. Thus SARS-CoV-2 receptor networks can seed further research into risk stratification and therapeutic strategies for COVID-19 related kidney damage.

Translational statement

To understand the overwhelming burden of kidney disease in COVID-19, we mapped the expression of the SARS-CoV-2 receptor, ACE2, in healthy kidney, early diabetic (DKD) and COVID-19 associated kidney diseases. Single cell RNA sequencing of 111035 cells identified ACE2 predominantly in proximal tubular epithelial cells. ACE2 upregulation was observed in DKD, but was not associated with RAAS inhibition, arguing against an increased risk of COVID-19 among patients taking RAAS inhibitors. Molecular network analysis linked ACE2 expression to innate immune response and viral entry machinery, thereby revealing potential therapeutic strategies against COVID-19.
COVID-Classifier: An automated machine learning model to assist in the diagnosis of COVID-19 infection in chest x-ray images
Authors: Zargari Khuzani Abolfazl , Heidari Morteza , Shariati Ali
Published: May 2020

Chest-X ray (CXR) radiography can be used as a first-line triage process for non-COVID-19 patients with pneumonia. However, the similarity between features of CXR images of COVID-19 and pneumonia caused by other infections make the differential diagnosis by radiologists challenging. We hypothesized that machine learning-based classifiers can reliably distinguish the CXR images of COVID-19 patients from other forms of pneumonia. We used a dimensionality reduction method to generate a set of optimal features of CXR images to build an efficient machine learning classifier that can distinguish COVID-19 cases from non-COVID-19 cases with high accuracy and sensitivity. By using global features of the whole CXR images, we were able to successfully implement our classifier using a relatively small dataset of CXR images. We propose that our COVID-Classifier can be used in conjunction with other tests for optimal allocation of hospital resources by rapid triage of non-COVID-19 cases.
The Coronavirus 2019 pandemic in Canada: the impact of public health interventions on the course of the outbreak in Alberta and other provinces
Authors: Mahsin Mohamed , Lee Seungwon , Vickers David , Guigue Alexis , Williamson Tyler , Quan Hude , Quinn Robert Ross , Ravani Pietro
Published: May 2020

Background: The SARS-CoV-2 disease 2019 (COVID-19) pandemic has spread across the world with varying impact on health systems and outcomes. We assessed how the type and timing of public- health interventions impacted the course of the outbreak in Alberta and other Canadian provinces.
Methods: We used publicly-available data to summarize rates of laboratory data and mortality in relation to measures implemented to contain the outbreak and testing strategy. We estimated the transmission potential of SARS-CoV-2 before the state of emergency declaration for each province (R0) and at the study end date (Rt).
Results: The first cases were confirmed in Ontario (January 25) and British Columbia (January 28). All provinces implemented the same health-policy measures between March 12 and March 30. Alberta had a higher percentage of the population tested (3.8%) and a lower mortality rate (3/100,000) than Ontario (2.6%; 11/100,000) or Quebec (3.1%; 31/100,000). British Columbia tested fewer people (1.7%) and had similar mortality as Alberta. Data on provincial testing strategies were insufficient to inform further analyses. Mortality rates increased with increasing rates of lab- confirmed cases in Ontario and Quebec, but not in Alberta. R0 was similar across all provinces, but varied widely from 2.6 (95% confidence intervals 1.9-3.4) to 6.4 (4.3-8.5), depending on the assumed time interval between onset of symptoms in a primary and a secondary case (serial interval). The outbreak is currently under control in Alberta, British Columbia and Nova Scotia (Rt <1).
Interpretation: COVID-19-related health outcomes varied by province despite rapid implementation of similar health-policy interventions across Canada. Insufficient information about provincial testing strategies and a lack of primary data on serial interval are major limitations of existing data on the Canadian COVID-19 outbreak.
Comparison of Operative Time and Blood Loss with the FFX® Device Versus Pedicle Screw Fixation During Surgery for Lumbar Spinal Stenosis: A Retrospective Cohort Study
Authors: Srour Robin
Published: May 2020

Objective: Pedicle screw (PS) placement to facilitate stability and spinal fusion following lumbar decompression surgery is associated with significant soft tissue damage and blood loss. The present study evaluated differences in operative time and blood loss between PS fixation and the use of new implantable facet fusion device (FFX®) during surgeries of patients with lumbar spinal stenosis (LSS).
Methods: Patients from a single institution who underwent posterior lumbar fusion surgery for LSS with either PS fixation or the FFX device were included in this non-randomized, retrospective study. The PS group consisted of patients with LSS operated on in 2016 and the FFX group included patients operated on in 2018. Both groups excluded patients whose procedures were combined with additional implanted devices. All procedures were performed by the same surgeon. Select patient demographics, number of levels operated on, operative time and estimated operative blood loss were collected retrospectively. Differences between the two groups were assessed using the unpaired Wilcoxon two-sample test.
Results: Of the 70 patients undergoing fusion surgery included in the study, there were 28 in the PS arm and 42 in the FFX arm. Mean age for the PS group was 67.5 ± 9.3 years (range 42.7 to 87.5) compared to 70.4 ± 11.5 years (range 49.7 to 86.6) for the FFX group. The PS group had a greater percentage of females (57.1%) compared to the FFX group (31.0%). The mean number of levels operated were similar between the PS and FFX groups (2.3 ± 1.1 vs. 2.2 ± 1.0, respectively). Mean operative time was significantly longer for the PS group versus the FFX group (152.5 ± 39.4 vs. 99.4 ± 44.0 minutes; p<0.001). Mean operative blood loss was also significantly greater for the PS group compared to the FFX group (446.5 ± 272.0 vs. 251.0 ± 315.9 mL; p<0.001). Differences were independent of the number of levels operated on.
Conclusion: The use of the FFX device is associated with a significant reduction in both operative time and blood loss compared to PS fixation in LSS patients undergoing spinal fusion surgery.
Brazil Health Care System preparation against COVID-19
Authors: Silva Lincoln Luís , de Carvalho Dutra Amanda , Iora Pedro Henrique , Ramajo Guilherme Luiz Rodrigues , Messias Gabriel Antônio Fernandes , Gualda Iago Amado Peres , Scheidt Joao Felipe Hermann Costa , Amaral Pedro Vasconcelos Maia do , Staton Catherine , Rocha Thiago Augusto Hernandes , Andrade Luciano de , Vissoci João Ricardo Nickenig
Published: May 2020

Background

The coronavirus disease outbreak from 2019 (COVID-19) is associated with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly contagious virus that claimed thousands of lives around the world and disrupted the health system in many countries. The assessment of emergency capacity in every country is a necessary part of the COVID-19 response efforts. Thus, it is extremely recommended to evaluate the health care system to prepare the country to tackle COVID-19 challenges.

Methods and Findings

A retrospective and ecological study was performed with data retrieved from the public national healthcare database (DATASUS). Numbers of intensive care unit and infirmary beds, general or intensivists physicians, nurses, nursing technicians, and ventilators from each Regional Health Unity were extracted, and the beds per health professionals and ventilators per population rates were assessed. The accessibility to health services was also performed using a spatial overlay approach to verify regions that lack assistance. It was found that Brazil lacks equity, integrity, and may struggle to assist with high complexity for the COVID-19 patients in many regions of the country.

Conclusions

Brazil’s health system is insufficient to tackle the COVID-19 in some regions of the country where the coronavirus may be responsible for high rates of morbidity and mortality.
Molecular Docking studies of Phytocompounds ofRheum emodiWall with proteins responsible for antibiotic resistance in bacterial and fungal pathogens:In silicoapproach to enhance the bio-availability of antibiotics
Authors: Rolta Rajan , Kumar Vikas , Sourirajan Anuradha , Dev Kamal
Published: May 2020

Rheum emodiWall. (Himalayan rhubarb) has been used to cure many human diseases. Literature survey demonstrated that it has many pharmacological activities such as antioxidant, antimicrobial, antiviral, anticancer and wound healing. The present study was aimed to understand if major phytocompounds ofRheum emodicould bind proteins responsible for antibiotic resistance in bacterial and fungal pathogens and enhance the potency of antibiotics. The major phytocompounds ofR. emodi(emodin, rhein-13c6 and chrysophenodimethy ether) were retrieved from Pubchem and target proteins were retrieved from RCSB protein data bank. The docking study was performed with Hex 8.0.0 software and molinspiration, swiss ADME servers were used for determination of Lipinski rule of 5, drug-likeness prediction respectively, whereas, admetSAR and Protox-II tools were used for toxicity prediction. Among all the selected phytocompounds, emodin showed the best binding energy of −235.82 Kcal mol-1and −245 Kcal mol-1with cytochrome P450 14 alpha-sterol demethylase (PDB ID: 1EA1) andN-myristoyl transferase (PDB ID: 1IYL) receptors, respectively, which is more than that of fluconazole (−224.12 kcalmol-1and −161.14 kcal mol-1). Similarly, with Penicillin binding protein 3 (PDB ID: 3VSL) receptor, emodin and Chrysophanol dimethyl ether showed highest binding energy of - 216.68 Kcal mol-1and −215.58 kcal mol-1which is comparable to erythromycin (−263.63 kcal mol-1), chloramphanicol (−217.34 kcal mol-1) and tetracycline (−263.63 kcal mol-1). All the selected phytocompounds also fulfill Lipinski rule, non-carcinogenic and non-cytotoxic in nature. These compounds also showed high LD50value showing non-toxicity of these phytocompounds.

Graphical abstract
Semi-automatic model revision of Boolean regulatory networks: confronting time-series observations with (a)synchronous dynamics
Authors: Gouveia Filipe , Lynce Inês , Monteiro Pedro T.
Published: May 2020

Motivation

Complex cellular processes can be represented by biological regulatory networks. Computational models of such networks have successfully allowed the reprodution of known behaviour and to have a better understanding of the associated cellular processes. However, the construction of these models is still mainly a manual task, and therefore prone to error. Additionally, as new data is acquired, existing models must be revised. Here, we propose a model revision approach of Boolean logical models capable of repairing inconsistent models confronted with time-series observations. Moreover, we account for both synchronous and asynchronous dynamics.

Results

The proposed tool is tested on five well known biological models. Different time-series observations are generated, consistent with these models. Then, the models are corrupted with different random changes. The proposed tool is able to repair the majority of the corrupted models, considering the generated time-series observations. Moreover, all the optimal solutions to repair the models are produced.

Contact

{filipe.gouveia@tecnico.ulisboa.pt,pedro.tiago.monteiro@tecnico.ulisboa.pt}
Overexpression of Orange (OR) and OR mutant protein inChlamydomonas reinhardtiienhances carotenoid and ABA accumulation and increases resistance to abiotic stress
Authors: Yazdani Mohammad , Croen Michelle G. , Fish Tara L. , Thannhauser Theodore W. , Ahner Beth A.
Published: May 2020

The carotenoid content of plants can be increased by overexpression of the regulatory protein ORANGE (OR) or a mutant variant known as the ‘golden SNP’. In the present study, transgenic lines of the microalgaeChlamydomonas reinhardtiiwere generated to overexpress either wild typeCrOR(CrORWT) or a mutatedCrOR(CrORHis) containing a single histidine substitution for a conserved arginine. Overexpression of bothCrORWTandCrORHisdramatically enhanced the accumulation of several different carotenoids, including β-cartotene, α-carotene, lutein and violaxanthin, inC. reinhardtiiand, in contrast to higher plants, upregulated the transcript abundance of several relevant carotenoid biosynthetic genes. In addition, microscopic analysis revealed that theORtransgenic cells were larger than control cells and exhibited larger chloroplasts with a disrupted morphology. Moreover, bothCrORWTandCrORHiscell lines showed increased tolerance to salt and paraquat stress. The levels of endogenous phytohormone abscisic acid (ABA) were also increased inCrORWTandCrORHislines, not only in normal growth conditions but also in growth medium supplemented with paraquat. Together these results offer new insights regarding the role of the OR protein in regulating carotenoid biosynthesis and accumulation in microalgae, and establish a new functional role forORto modulate oxidative stress tolerance mediated by ABA.
Impaired state-dependent potentiation of GABAergic synaptic currents triggers seizures in an idiopathic generalized epilepsy model
Authors: Zhang Chun-Qing , Catron Mackenzie A. , Ding Li , Hanna Caitlyn M. , Gallagher Martin J. , Macdonald Robert L. , Zhou Chengwen
Published: May 2020

Idiopathic generalized epilepsy(IGE) patients have genetic causes and their seizure onset mechanisms particularly during sleep remain elusive. Here we proposed that sleep-like slow-wave oscillations(0.5 Hz SWOs) potentiated excitatory or inhibitory synaptic currents in layer V cortical pyramidal neurons from wild-type(wt) mouseex vivobrain slices. In contrast, SWOs potentiated excitatory, not inhibitory, currents in cortical neurons from heterozygous(het) knock-in(KI) IGE mice(GABAAreceptor γ2 subunitGabrg2Q390Xmutation), creating an imbalance between evoked excitatory and inhibitory currents to effectively prompt neuronal action potentials. Similarly, more physiologically similar up/down-state(present during slow-wave sleep) induction in cortical neurons could potentiate excitatory synaptic currents within slices from wt/hetGabrg2Q390XKI mice. Consequently, SWOs or up/down-state inductionin vivo(using optogenetic method) could trigger epileptic spike-wave discharges(SWDs) in hetGabrg2Q390XKI mice. To our knowledge, this is the first operative mechanism to explain why epileptic SWDs preferentially happen during non-REM sleep or quiet-wakefulness in human IGE patients.
Machine Learning and Deep Learning challenges for building 2′O site prediction
Authors: Mostavi Milad , Huang Yufei
Published: May 2020

2′-O-methylation (2′O) is one of the abundant post-transcriptional RNA modifications which can be found in all types of RNA. Detection and functional analysis of 2′O methylation have become challenging problems for biologists ever since its discovery. This paper addresses computational challenges for building Machine Learning and Deep Learning models for predicting 2′O sites. In particular, the impact of sequence length containing 2′O site, embedding method and the type of predictive model are each investigated separately. 30 different predictive models are built and each showed the impact of the mentioned parameters. The area under the precision-recall and receiving operating characteristics curves are utilized to test imbalanced case scenarios in the real world. By comparing the performance of these models, it is shown that embedding methods are crucial for Machine Learning models. However, they do not improve the performance of Deep Learning models. Furthermore, the best predictive model was further investigated to extract significant nucleotides surrounding 2′O sites. Interestingly, based on the significant score matrix achieved by all 2′O samples, it is depicted that model pays the highest attention at the location that the dominant 2′O motifs exist. Dataset and all of the codes are available athttps://github.com/MMostavi/2_O_Me_sitePred
Object-based attentional selection emerges late in visual cortical hierarchy for objects of varying perceptual strengths
Authors: Al-Janabi Shahd , Strommer Nofar , Gabay Shai , Greenberg Adam S.
Published: May 2020

Object-based attention (OBA) can - in addition to acting upon explicit object representations - act upon occluded and illusory objects. It remains unknown, however, whether or not the selection of such object representations is detectable at the same level within visual cortex. This study examined the level within visual cortex (V1-V3, LOC) at which object-based selection is observed for explicit, occluded and illusory objects. During fMRI acquisition, participants identified a target preceded by a predictive arrow cue in the double-rectangle cueing paradigm. We independently localized retinotopically-specific regions of cortex corresponding to all possible target locations to examine neural fluctuations at each level of the visual cortical hierarchy. We found, after cue onset, that activity along visual cortex was not greater for representations of cued than of uncued same object locations. In contrast, we found that activity in V3 was enhanced at retinotopic representations that correspond to uncued same than different object locations. These results, together, support attentional spreading. Additionally, when the target appeared at either the cued or uncued locations, we found higher activation in areas representing uncued same object versus cued locations. This effect emerged along the visual cortical hierarchy. Further, when the target appeared on either the cued or uncued object, we found that activation in V3 transiently increased at uncued same than different object locations. This effect was also detectable upstream in LOC. These results index attentional re-orienting between locations/objects. Effects emerged regardless of object type: explicit or completed. Thus, the gating of object information proceeds completion.

Significance Statement

We investigated the level within visual cortex (V1-V3, LOC) that object-based selection is observed for explicit objects and those requiring perceptual completion. We showed that activity along visual cortex was similar for representations of locations on a cued object, which may indicate attention spreads evenly to all locations on an object marked as relevant by the cue. We also showed that activity in late visual areas was greater for representations of uncued same than different object locations, which may indicate that attention enhances the cued object. These findings support the attentional spreading account. Object selection may, thus, be instantiated by even engagement of locations within a cued, and/or suppression of locations within an uncued, object - independent of its type.
A Continuously Active Antimicrobial Coating effective against Human Coronavirus 229E
Authors: Ikner Luisa A. , Torrey Jason R. , Gundy Patricia M. , Gerba Charles P.
Published: May 2020

The disinfection of high-contact surfaces is seen as an infection control practice to prevent the spread of pathogens by fomites. Unfortunately, recontamination of these surfaces can occur any time after the use of common disinfectants. We recently reported on a novel continuously active antimicrobial coating which was shown to reduce the spread of healthcare acquired infections in hospitals. We evaluated a modified coating that demonstrated a residual efficacy against viruses. The coated surfaces were found to be effective against human coronavirus (HCoV) 229E, reducing the concentration of these viruses by greater than 90% in 10 minutes and by greater than 99.9% after two hours of contact. The coating formulation when tested in suspension yielded a greater than 99.99% reduction of HCoV 229E within ten minutes of contact. This outcome presents an opportunity for controlling the transmission of COVID-19 from contaminated fomites.
Processing of a spoken narrative in the human brain is shaped by family cultural background
Authors: Hakonen M. , Ikäheimonen A. , Hultèn A. , Kauttonen J. , Koskinen M. , Lin F-H. , Lowe A. , Sams M. , Jääskelainen I. P.
Published: May 2020

Using neuroimaging, we studied influence of family cultural background on processing of an audiobook in human brain. The audiobook depicted life of two young Finnish men, one with the Finnish and the other with the Russian family background. Shared family cultural background enhanced similarity of narrative processing in the brain at prelexical, word, sentence, and narrative levels. Similarity was also enhanced in brain areas supporting imagery. The cultural background was further reflected as semantic differences in word lists by which the subjects described what had been on their minds when they heard the audiobook during neuroimaging. Strength of social identity shaped word, sentence, and narrative level processing in the brain. These effects might enhance mutual understanding between persons who share family cultural background and social identity and, conversely, deteriorate between-group mutual understanding in modern multicultural societies wherein native speakers of a language may assume highly similar understanding.
In-silico screening of drug candidates for thermoresponsive liposome formulations
Authors: Balouch Martin , Šrejber Martin , Šoltys Marek , Janská Petra , Štěpánek František , Berka Karel
Published: May 2020

Liposomal formulations can be advantageous in a number of scenarios such as targeted delivery to reduce the systemic toxicity of highly potent Active Pharmaceutical Ingredients (APIs), to increase drug bioavailability by prolonging systemic circulation, to protect labile APIs from degradation in the gastrointestinal tract, or to improve skin permeation in dermal delivery. However, not all APIs are suitable for encapsulation in liposomes. Some of the issues are too high permeability of the API across the lipid bilayer, which may lead to premature leakage, too low permeability, which may hinder the drug release process, or too strong membrane affinity, which may reduce the overall efficacy of drug release from liposomes. Since the most reliable way to test API encapsulation and release from liposomes so far has been experimental, anin silicomodel capable of predicting API transport across the lipid bilayer might accelerate formulation development. In this work, we demonstrate a newin silicoapproach to compute the temperature dependent permeability of a set of compounds across the bilayer of virtual liposomes constructed by molecular dynamics simulation. To validate this approach, we have conducted a series of experiments confirming the model predictions using a homologous series of fluorescent dyes. Based on the performance of individual molecules, we have defined a set of selection criteria for identifying compatible APIs for stable encapsulation and thermally controlled release from liposomes. To further demonstrate thein silico-based methodology, we have screened the DrugBank database, identified potent drugs suitable for liposome encapsulation and successfully carried out the loading and thermal release of one of them - an antimicrobial compound cycloserine.
Visual stimulus-specific habituation of innate defensive behaviour in mice
Authors: Tafreshiha Azadeh , van den Burg Sven A. , Smits Kato , Blömer Laila A. , Heimel J. Alexander
Published: May 2020

Innate defensive responses such as freezing or escape are essential for animal survival. Mice show defensive behaviour to stimuli sweeping overhead, like a bird cruising the sky. Here, we found that mice reduced their defensive freezing after sessions with a stimulus passing overhead repeatedly. This habituation is stimulus-specific, as mice freeze again to a novel shape. This allows us to investigate the invariances in the mouse visual system. The mice generalize over retinotopic location and over size and shape, but distinguish objects when they differ in both size and shape. Innate visual defensive responses are thus strongly influenced by previous experience as mice learn to ignore specific stimuli. This form of learning occurs at the level of a location-independent representation.
ODDPub – a Text-Mining Algorithm to Detect Data Sharing in Biomedical Publications
Authors: Riedel Nico , Kip Miriam , Bobrov Evgeny
Published: May 2020

Open research data are increasingly recognized as a quality indicator and an important resource to increase transparency, robustness and collaboration in science. However, no standardized way of reporting Open Data in publications exists, making it difficult to find shared datasets and assess the prevalence of Open Data in an automated fashion.

We developed ODDPub (Open Data Detection in Publications), a text-mining algorithm that screens biomedical publications and detects cases of Open Data. Using English-language original research publications from a single biomedical research institution (n=8689) and randomly selected from PubMed (n=1500) we iteratively developed a set of derived keyword categories. ODDPub can detect data sharing through field-specific repositories, general-purpose repositories or the supplement. Additionally, it can detect shared analysis code (Open Code).

To validate ODDPub, we manually screened 792 publications randomly selected from PubMed. On this validation dataset, our algorithm detected Open Data publications with a sensitivity of 0.74 and specificity of 0.97. Open Data was detected for 11.5% (n=91) of publications. Open Code was detected for 1.4% (n=11) of publications with a sensitivity of 0.73 and specificity of 1.00. We compared our results to the linked datasets found in the databases PubMed and Web of Science.

Our algorithm can automatically screen large numbers of publications for Open Data. It can thus be used to assess Open Data sharing rates on the level of subject areas, journals, or institutions. It can also identify individual Open Data publications in a larger publication corpus. ODDPub is published as an R package on GitHub.
COTAN: Co-expression Table Analysis for scRNA-seq data
Authors: Galfrè S. G. , Morandin F. , Pietrosanto M. , Cremisi F. , Helmer-Citterich M.
Published: May 2020

Estimating co-expression of cell identity factors in single-cell transcriptomes is crucial to decode new mechanisms of cell state transition. Due to the intrinsic low efficiency of single-cell mRNA profiling, novel computational approaches are required to accurately infer gene co-expression in a cell population. We introduce COTAN, a statistical and computational method to analyze the co-expression of gene pairs at single cell level, providing the foundation for single-cell gene interactome analysis.
Ca2+-Dependent Regulation by the Cyclic AMP Pathway of Primary Cilium Length in LLC-PK1 Renal Epithelial Cells
Authors: Scarinci Noelia , Perez Paula L. , del Rocío Cantero María , Cantiello Horacio F.
Published: May 2020

The primary cilium is a sensory organelle projecting from the apical surface of renal epithelial cells. Dysfunctional cilia have been linked to a number of genetic diseases known as ciliopathies, which include autosomal dominant polycystic kidney disease (ADPKD). Previous studies have determined that renal epithelial primary cilia express both the polycystin-2 (PC2, TRPP2) channel and the type-2 vasopressin receptor (V2R), coupled to local cAMP production. However, little is known as to how Ca2+and cAMP signals lead to changes in the length of the primary cilium. Here, we explored how cAMP signals regulate the length of the primary cilium in wild type LLC-PK1 renal epithelial cells. Primary cilia length was determined by immunocytochemical labeling of the ciliary axoneme. Treatment of cells with the cAMP analog 8-Br-cAMP (1 mM) in normal external Ca2+(1.2 mM) produced a 25.3% increase (p < 0.0001) in the length of the primary cilium, a phenomenon also observed in cells exposed to high external Ca2+(6.2 mM). However, exposure of cells to vasopressin (AVP, 10 μM), which also increases cAMP in primary cilia of LLC-PK1 cells, mimicked the effect of 8-Br-cAMP in normal, but not in high Ca2+. Further, specific gene silencing of PC2 expression further increased primary cilium length after 8-Br-cAMP treatment, in normal, but not high Ca2+. The encompassed data indicate a crosstalk between the cAMP and Ca2+signals to modulate the length of the primary cilium, in a phenomenon that implicates the expression of PC2.

Significance Statement

Morphological changes in primary cilia have been linked to genetic disorders, including autosomal dominant polycystic kidney disease (ADPKD), a major cause of kidney disease. Both cAMP and Ca2+are universal second messengers that regulate polycystin-2 (PC2, TRPP2), a Ca2+permeable non-selective cation channel implicated in ADPKD, and expressed in the primary cilium of renal epithelial cells. Despite current interest, little is known as to how second messenger systems and how aberrant regulation of PC2 may link primary cilium structure with cyst formation in ADPKD. Here we determined that both the cAMP analog 8-Br-cAMP and vasopressin increase the length of the primary cilium in renal epithelial cells. However, this phenomenon depends of external Ca2+andPKD2gene silencing. Proper cAMP signaling may be essential in the control of the primary cilium of renal epithelial cells, and the onset of cyst formation in ADPKD.
A small molecule that binds an RNA repeat expansion stimulates its decay via the exosome complex
Authors: Angelbello Alicia J. , Benhamou Raphael I. , Rzuczek Suzanne G. , Choudhary Shruti , Tang Zhenzhi , Chen Jonathan L. , Roy Madhuparna , Wang Kye Won , Yildirim Ilyas , Jun Albert S. , Thornton Charles A. , Disney Matthew D.
Published: May 2020

We describe the design of a small molecule that binds the structure of a r(CUG) repeat expansion [r(CUG)exp] and reverses molecular defects in two diseases mediated by the RNA - myotonic dystrophy type 1 (DM1) and Fuchs endothelial corneal dystrophy (FECD). Thus, a single structure-specific ligand has potential therapeutic benefit for multiple diseases, in contrast to oligonucleotide-based modalities that are customized for each disease by nature of targeting the gene that harbors the repeat. Indeed, the small molecule binds the target with nanomolar affinity and >100-fold specificity vs. many other RNAs and DNA. Interestingly, the compound’s downstream effects are different in the two diseases, owing to the location of the repeat expansion. In DM1, r(CUG)expis harbored in the 3’ untranslated region (UTR) of and mRNA, and the compound has no effect on the RNA’s abundance. In FECD, however, r(CUG)expis located in an intron, and the small molecule, by binding the repeat expansion, facilitates excision of the intron, which is then degraded by the exosome complex exonuclease, hRRP6. Thus, structure-specific, RNA-targeting small molecules can act disease-specifically to affect biology, either by disabling its gain-of-function mechanism (DM1) or by stimulating quality control pathways to rid a disease-affected cell of a toxic RNA (FECD).

Significance statement

Many different diseases are caused by toxic structured RNAs. Herein, we designed a lead small molecule that binds a toxic structure and rescues disease biology. We show that a structure-specific small molecule can improve disease-associated defects in two diseases that share the common toxic RNA structure. In one disease, the toxic structure is harbored in an intron and causes its retention. The compound facilitates processing of a retained intron, enabling the disease-affected cell to remove the toxic RNA.
Uptake of monoaromatic hydrocarbons during biodegradation by FadL channel-mediated lateral diffusion
Authors: Somboon Kamolrat , Doble Anne , Bulmer David , Baslé Arnaud , Khalid Syma , van den Berg Bert
Published: May 2020

In modern societies, biodegradation of hydrophobic pollutants generated by industry is important for environmental and human health. In Gram-negative bacteria, biodegradation depends on facilitated diffusion of the pollutant substrates into the cell, mediated by specialised outer membrane (OM) channels. Here we show, via a combined experimental and computational approach, that the uptake of monoaromatic hydrocarbons such as toluene inPseudomonas putidaF1 (PpF1) occurs via lateral diffusion through FadL channels. Contrary to classical diffusion channels via which polar substrates move directly into the periplasmic space, PpF1 TodX and CymD direct their hydrophobic substrates into the OM via a lateral opening in the channel wall, bypassing the polar barrier formed by the lipopolysaccharide leaflet on the cell surface. Our study suggests that lateral diffusion of hydrophobic molecules is themodus operandiof all FadL channels, with potential implications for diverse areas such as biodegradation, quorum sensing and gut biology.