bluuebunny/crossref_metadata_2025 huggingface dataset:
The transcriptomic profiling of COVID-19 compared to SARS, MERS, Ebola, and H1N1
Authors: Alsamman Alsamman M. , Zayed Hatem
Published: May 2020

COVID-19 pandemic is a global crisis that threatens our way of life. As of April 29, 2020, COVID-19 has claimed more than 200,000 lives, with a global mortality rate of ~7% and recovery rate of ~30%. Understanding the interaction of cellular targets to the SARS-CoV2 infection is crucial for therapeutic development. Therefore, the aim of this study was to perform a comparative analysis of transcriptomic signatures of infection of COVID-19 compared to different respiratory viruses (Ebola, H1N1, MERS-CoV, and SARS-CoV), to determine unique anti-COVID1-19 gene signature. We identified for the first time molecular pathways for Heparin-binding, RAGE, miRNA, and PLA2 inhibitors, to be associated with SARS-CoV2 infection. TheNRCAMandSAA2that are involved in severe inflammatory response, andFGF1andFOXO1genes, which are associated with immune regulation, were found to be associated with a cellular gene response to COVID-19 infection. Moreover, several cytokines, most significantly theIL-8,IL-6, demonstrated key associations with COVID-19 infection. Interestingly, the only response gene that was shared between the five viral infections wasSERPINB1. The PPI study sheds light on genes with high interaction activity that COVID-19 shares with other viral infections. The findings showed that the genetic pathways associated with Rheumatoid arthritis, AGE-RAGE signaling system, Malaria, Hepatitis B, and Influenza A were of high significance. We found that the virogenomic transcriptome of infection, gene modulation of host antiviral responses, and GO terms of both COVID-19 and Ebola are more similar compared to SARS, H1N1, and MERS. This work compares the virogenomic signatures of highly pathogenic viruses and provides valid targets for potential therapy against COVID-19.
Myocardial characteristics as the prognosis for COVID-19 patients
Authors: Zhang Jianguo , Ding Daoyin , Cao Can , Zhang Jinhui , Huang Xing , Fu Peiwen , Liang Guoxin , Xu Wenrong , Tao Zhimin
Published: May 2020

Background

Amid the crisis of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), front-line clinicians in collaboration with backstage medical researchers analyzed clinical characteristics of COVID-19 patients and reported the prognosis using myocardial data records upon hospitalization.

Methods

We reported 135 cases of laboratory-confirmed COVID-19 patients admitted in The First People’s Hospital of Jiangxia District in Wuhan, China. Demographic data, medical history, and laboratory parameters were taken from inpatient records and compared between patients at the Intensive Care Unit (ICU) and non-ICU isolation wards for prognosis on disease severity. In particular, survivors and non-survivors upon ICU admission were compared for prognosis on disease mortality.

Results

For COVID-19 patients, blood test results showed more significantly deranged values in the ICU group than those in non-ICU. Among those parameters for ICU patients, myocardial variables including troponin T, creatine kinase isoenzymes, myoglobin, were found significantly higher in non-survivors than in survivors.

Conclusions

Upon hospitalization abnormal myocardial metabolism in COVID-19 patients could be prognostic indicators of a worsened outcome for disease severity and mortality.
Optimal upper respiratory tract sampling time for novel coronavirus pneumonia suspects
Authors: Zhou Jing , Chen Lin , Zhang Dehe , Chen Haijun , Sheng Qiyue , Deng Hongsheng , Zhang Yang , Ni Shunlan , Luo Shengnan , Ren Binbin
Published: May 2020

Objective

Explore best upper respiratory tract sampling time of suspected novel coronavirus pneumonia cases.

Methods

We collected dates of patients from Hangzhou, Shenzhen, Jinhua city and so on who had the clear exposure history of a novel coronavirus pneumonia(COVID-19). We retrospected demographic data, exposure time, onset time, visiting time and positive time for novel coronavirus nucleic acid detection in respiratory specimens. There were 256 patients from January 20,2020-February 12,2020 from eight cities included in our study. 106 cases appeared symptoms before January 25th and 150 after.

Results

There were 136(53.1%)male infected cases. The mean age of all patients was 43.80±14.85. The median time from exposure to onset was 5(3,8) days. The median time of the first time of positive nucleic acid detection was 11(9,14)days and mode number was 13. The median time from onset to the first time of positive nucleic acid detection was 6(4,8)days and mode number was 5. The time from onset to definite diagnosis was 5(3,7) days before January 25th while it was 7.5(5,10)days after which was significantly shorter before January 25th(U=3885.5,P<0.001). The time from exposure to definite diagnosis was 11(9,14)days and 11(9,14)days before January 25th and after and without significant difference. The time from exposure to definite diagnosis was 11(9,13)days in first-tier cities and 13(11,15)days in second and third-tier cities. The difference was significantly shorter of first-tier cities(U=1355.5, P=0.039). And also the time was short from visiting to definite diagnosis which was 2(2,3)days in first-tier cities and 3(2,4)days in second and third-tier cities but without significant difference(U=842.5, P=0.054).

Conclusions

From our study we found that the best upper respiratory tract sampling time for novel coronavirus pneumonia suspects was 13days after exposure. The time from onset to definite diagnosis was shorter after January 25th. The patients were diagnosed faster in the first-tier cities after exposure.
PROGNOSTIC FACTORS FOR CLINICAL COURSE OF PATIENTS WITH COVID-19: PROTOCOL FOR A RAPID LIVING SYSTEMATIC REVIEW
Authors: Rocha-Filho César Ramos , Pinto Ana Carolina Pereira Nunes , Rocha Aline Pereira da , Milby Keilla Martins , de Assis Reis Felipe Sebastião , Civile Vinicius Tassoni , Junior Nelson Carvas , Santos Rodolfo Rodrigo Pereira , Ramalho Gabriel Sodré , Trevisani Giulia Fernandes Moça , Ferla Laura Jantsch , Puga Maria Eduarda dos Santos , Trevisani Virgínia Fernandes Moça , Atallah Alvaro Nagib
Published: May 2020

CONTEXT AND OBJECTIVE

Determining prognostic factors in a context of health crises such as the COVID-19 scenario may provide the best possible care for patients and optimize the management and the resource utilization of the health system. Thus, we aim to systematically review the prognostic factors for different outcomes of patients with COVID-19. DESIGN AND SETTING: Protocol for a rapid living systematic review methodology following the recommendations proposed by the Cochrane Handbook. METHODS: We will include cohorts and case-control studies. We will search Medline via PubMed, Embase via Elsevier, Cochrane Library - Cochrane Central Register of Controlled Trials (CENTRAL), Portal Regional BVS-LILACS, Scopus and WebofScience to identify studies. No language restrictions will be applied. We will perform the critical appraisal of included studies with the Quality in Prognosis Studies (QUIPS) tool and the certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE).
Preexisting Comorbidities Predicting Severe Covid-19 in Older Adults in the UK Biobank Community Cohort
Authors: Atkins Janice L , Masoli Jane AH , Delgado Joao , Pilling Luke C , Kuo Chia-Ling , Kuchel George A , Melzer David
Published: May 2020

Background

Older COVID-19 hospitalized patients frequently have hypertension, diabetes or coronary heart disease (CHD), but whether these are more common than in the population is unclear. During the initial epidemic in England, virus testing for older adults was restricted to symptomatic hospitalized patients. We aimed to estimate associations between pre-existing diagnoses and COVID-19 status, in a large community cohort.

Methods

UK Biobank (England) participants assessed 2006 to 2010, followed in hospital discharge records to 2017. Demographic and pre-existing common diagnoses association tested with COVID-19 status (16th March to 14th April 2020) in logistic models, adjusted for demographics, study site and other diagnoses.

Results

There were 274,356 participants aged 65+, including 448 (0.16%) hospitalized COVID-19 patients. Common co-morbidities in patients were hypertension (58.5%), coronary heart disease (CHD, 21.1%), history of fall or fragility fractures (30.6%), and type 2 diabetes (19.6%). However, in adjusted models, COVID-19 patients were more likely than other participants to have pre-existing dementia (OR=3.07 95% CI 1.71 to 5.50), COPD (OR= 1.82 CI 1.33 to 2.49), depression (OR=1.81 CI 1.36 to 2.40), type 2 diabetes (OR=1.70 CI 1.30 to 2.21), chronic kidney disease and atrial fibrillation. Hypertension was modestly associated (OR=1.29 CI 1.04 to 1.59), but CHD (OR=0.92 CI 0.71 to 1.20) prevalence was similar in COVID-19 patients and other participants.

Conclusion

Specific co-morbidities are disproportionally common in older adults who develop severe COVID-19. Tailored interventions may be needed, as these results do not support simple age-based targeting to prevent severe COVID-19 infection.
Spatial Network based model forecasting transmission and control of COVID-19
Authors: Sharma Natasha , Verma Atul Kumar , Gupta Arvind Kumar
Published: May 2020

The SARS-CoV-2 driven infectious novel coronavirus disease (COVID-19) has been declared a pandemic by virtue of its brutal impact on the world in terms of loss on human life, health, economy, and other crucial resources. With the aim to explore more about its aspects, we adopted the SEIQRD (Susceptible-Exposed-Infected-Quarantine-Recovered-Death) pandemic spread with a time delay on the heterogeneous population and geography in this work. Focusing on the spatial heterogeneity, the entire population of interest in a region is divided into small distinct geographical sub regions, which interact by means of migration networks across boundaries. Utilizing the estimations of the time delay differential equations based model, we analyzed the spread dynamics of disease in a region and its sub regions. The model based numerical outcomes are validated from real time available data for India. We computed the approximate peak infection in forward time and relative timespan when disease outspread halts. To further evaluate the influence of the delay on the long term system dynamics, the sensitivity analysis is performed on time delay. The most crucial parameter, basic reproduction number R0 and its time-dependent generalization, has been estimated at both regional and sub regional levels. The impact of the most significant lockdown measure that has been implemented in India to contain the pandemic spread has been extensively studied by considering no lockdown scenario. A suggestion based on outcomes, for a bit relaxed lockdown, followed by an extended period of strict social distancing as one of the most effective control measures to manage COVID-19 spread is provided for India.
Cast away on Mindoro island: lack of space limits population growth of the endangered tamaraw (Bubalus mindorensis)
Authors: Bonenfant C. , Rutschmann A. , Burton J. , Boyles R. , García F. , Tilker A. , Schütz E.
Published: May 2020

Endangered species, despite often living at low population densities, may undergo unexpected density-dependent feedbacks in the case of successful recovery or marked reduction in range. Because density-dependence dynamics can increase risk of extinction, these effects can hamper conservation efforts. In this study, we analyse the dynamics of the largest population of the tamaraw (Bubalus mindorensis), a critically endangered ungulate species endemic to Mindoro island, Philippines. The population is located within a < 3,000 ha area in Mounts Iglit-Baco Natural Park, with limited expansion possibilities. We took advantage of a 21 year time series of tamaraw counts to estimate annual population growth rate and possible density-dependence, accounting for sampling errors in the counts. The tamaraw population has been increasing at an average rate of +5% per year, as would be expected given its protected status by law. Population growth showed strong spatial structuring, with a population growth close to +10% in the core area of protection, and a reduction of abundance of −5% at the periphery of its range, inside the protected area. This range constriction is concerning because our best population dynamics model suggests significant negative density-dependence (Bayes factor = 0.9). The contraction of tamaraw range is likely caused by anthropogenic pressures forcing the species to live at relatively high densities in the core zone where protection is most effective, creating source-sink dynamics. Our study highlights the fact that, despite the continuous population growth over the last two decades, the long-term viability of the Mounts Iglit-Baco Natural Park tamaraw population remains uncertain.
Prevalence and phenology of mycorrhizal colonization across populations ofLycopodiella inundata
Authors: Kowal Jill , Arrigoni Elena , Serra Jordi , Bidartondo Martin
Published: May 2020

Mycorrhizal fungi are critical components of terrestrial habitats and agroecosystems. Recently, Mucoromycotina fine root endophyte (MucFRE) fungi were found to engage in nutritional mutualism with the rare plantLycopodiella inundata(‘marsh clubmoss’), one of the earliest vascular plant lineages known to associate with MucFRE. The extent to which this mutualism plays a role in resilient plant populations can only be understood by examining its occurrence rate and phenological patterns.

To test for prevalence and seasonality in colonization, we examined 1,297 individualL. inundataroots collected during spring and autumn 2019 from 11 semi-natural heathlands in Britain and the Netherlands. We quantified presence/absence of MucFRE-like hyphae and vesicles and explored possible relationships between temperature and precipitation in the months immediately before sampling.

MucFRE-like hyphae were the dominant mycorrhizal fungi observed in all of the examined heathlands. However, we found significant differences in colonization between the two seasons at every site. Overall, 14% ofL. inundataroots were colonised in spring (2.4% with vesicles) compared with 86% in autumn (7.6% with vesicles). Colonization levels between populations were also significantly different, and correlated with temperature and precipitation, suggesting some local environments may be more conducive to hyphal growth.

These marked seasonal differences in host-plant colonization suggest that results about mycorrhizal status - typically drawn from single time point collections - should be carefully interpreted. Our findings are directly relevant to habitat restoration, species conservation plans, agricultural bio-inoculation nutrient enhancement treatments, microbial diversity and functional studies of host plants and symbionts.
Exploiting collateral sensitivity controls growth of mixed culture of sensitive and resistant cells and decreases selection for resistant cells
Authors: Kornél Grolmusz Vince , Chen Jinfeng , Emond Rena , Cosgrove Patrick A. , Pflieger Lance , Nath Aritro , Moos Philip J. , Bild Andrea H.
Published: May 2020

Background

CDK4/6 inhibitors such as ribociclib are becoming widely used targeted therapies in hormone-receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, cancers can advance due to drug resistance, a problem in which tumor heterogeneity and evolution are key features.

Methods

Ribociclib-resistant HR+/HER2-CAMA-1 breast cancer cells were generated through long-term ribociclib treatment. Characterization of sensitive and resistant cells were performed using RNA sequencing and whole exome sequencing. Lentiviral labeling with different fluorescent proteins enabled us to track the proliferation of sensitive and resistant cells under different treatments in a heterogeneous, 3D spheroid coculture system using imaging microscopy and flow cytometry.

Results

Transcriptional profiling of sensitive and resistant cells revealed the downregulation of the G2/M checkpoint in the resistant cells. Exploiting this acquired vulnerability; resistant cells exhibited collateral sensitivity for the Wee-1 inhibitor, adavosertib (AZD1775). The combination of ribociclib and adavosertib achieved additional antiproliferative effect exclusively in the cocultures compared to monocultures, while decreasing the selection for resistant cells.

Conclusions

Our results suggest that optimal antiproliferative effects in heterogeneous cancers can be achieved via an integrative therapeutic approach targeting sensitive and resistant cancer cell populations within a tumor, respectively.
No Evidence for a Difference in 2D:4D Ratio between Youth with Elevated Prenatal Androgen Exposure due to Congenital Adrenal Hyperplasia and Controls
Authors: Nave Gideon , Koppin Christina M. , Manfredi Dylan , Richards Gareth , Watson Steven J. , Geffner Mitchell E. , Yong Jillian E. , Kim Robert , Ross Heather M. , Serrano-Gonzalez Monica , Kim Mimi S.
Published: May 2020

The second-to-fourth digit ratio (2D:4D) has been associated with sexual dimorphism, with a lower 2D:4D in males. A large body of research has relied on the 2D:4D as a proxy for prenatal androgen exposure, and includes reports of relationships between 2D:4D and a wide range of human traits. Here, we examine the validity of the 2D:4D proxy by studying the association between 2D:4D and classical Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency, a condition characterized by excessive prenatal exposure to androgens during most of the gestational period. To this end, we retrospectively examine 513 serial radiographs of the left hand obtained clinically in 90 youth with classical CAH (45 female) and 70 control youth (31 female). Replicating previous reports, we observe associations of the 2D:4D with sex (lower 2D:4D in males) and age (increase of 2D:4D through development). However, we find no evidence for differences in 2D:4D between CAH and controls (full sample: □ = -0.001 (−0.008, 0.006)]; females: □ = -0.004 [-0.015, 0.007]; males: □ = 0.001, [-0.008, 0.011]). Although our findings do not rule out a small association between the 2D:4D and CAH, they cast doubt on the usefulness of the 2D:4D as a biomarker for prenatal androgen exposure in behavioral research.
Genome-wide Studies Reveal the Essential and Opposite Roles of ARID1A in Controlling Human Cardiogenesis and Neurogenesis from Pluripotent Stem Cells
Authors: Liu Juli , Liu Sheng , Gao Hongyu , Han Lei , Chu Xiaona , Sheng Yi , Wang Yue , Shou Weinian , Liu Yunlong , Wan Jun , Yang Lei
Published: May 2020

Background

Early human heart and brain development simultaneously occur during embryogenesis. Notably, in human newborns, congenital heart defects strongly associate with neurodevelopmental abnormalities, suggesting a common gene/complex underlying both cardiogenesis and neurogenesis. However, due to lack ofin vivostudies, the molecular mechanisms that govern both early human heart and brain development remain elusive.

Results

Here, we report ARID1A, which is a DNA-binding-subunit of the SWI/SNF epigenetic complex, controls both neurogenesis and cardiogenesis from human embryonic stem cells (hESCs) via employing distinct mechanisms. Knockout of ARID1A (ARID1A-/-) led to spontaneous differentiation of neural cells together with globally enhanced expression of neurogenic genes in undifferentiated hESCs. Additionally, when compared with WT hESCs, cardiac differentiation from ARID1A-/-hESCs was prominently suppressed, whereas neural differentiation was significantly promoted. Whole genome-wide scRNA-seq, ATAC-seq, and ChIP-seq analyses revealed that ARID1A was required to open chromatin accessibility on promoters of essential cardiogenic genes, and temporally associated with key cardiogenic transcriptional factors T and MEF2C during early cardiac development. However, during early neural development, transcription of most essential neurogenic genes was dependent on ARID1A, which could interact with a known neural restrictive silencer factor REST/NRSF.

Conclusions

We uncovered the opposite roles by ARID1A to govern both early cardiac and neural development from pluripotent stem cells. Global chromatin accessibility on cardiogenic genes is dependent on ARID1A, whereas transcriptional activity of neurogenic genes is under control by ARID1A, possibly through ARID1A-REST/NRSF interaction.
Coarse-grained molecular simulations of the binding of the SARS-CoV-2 spike protein RBD to the ACE2 receptor
Authors: De Sancho David , Gavira José A. , Pérez-Jiménez Raul
Published: May 2020

Since it was first observed, the COVID-19 pandemic has created a global emergency for national health systems due to millions of confirmed cases and hundreds of thousands of deaths. At a molecular level, the bottleneck for the infection is the binding of the receptor binding domain (RBD) of the viral spike protein to ACE2, an enzyme exposed on human cell membranes. Several experimental structures of the ACE2:RBD complex have been made available, however they offer only a static description of the arrangements of the molecules in either the free or bound states. In order to gain a dynamic description of the binding process that is key to infection, we use molecular simulations with a coarse grained model of the RBD and ACE2. We find that binding occurs in an all-or-none way, without intermediates, and that even in the bound state, the RBD exhibits a considerably dynamic behaviour. From short equilibrium simulations started in the unbound state we provide snapshots that result in a tentative mechanism of binding. Our findings may be important for the development of drug discovery strategies that target the RBD.
Development and validation of the COVID-19 severity index (CSI): a prognostic tool for early respiratory decompensation
Authors: Haimovich Adrian , Ravindra Neal G. , Stoytchev Stoytcho , Young H. Patrick , Wilson Francis Perry , van Dijk David , Schulz Wade L. , Taylor R. Andrew
Published: May 2020

Objective

The goal of this study was to create a predictive model of early hospital respiratory decompensation among patients with COVID-19.

Design

Observational, retrospective cohort study.

Setting

Nine-hospital health system within the Northeastern United States.

Populations

Adult patients (≥ 18 years) admitted from the emergency department who tested positive for SARS-CoV-2 (COVID-19) up to 24 hours after initial presentation. Patients meeting criteria for respiratory critical illness within 4 hours of arrival were excluded.

Main outcome and performance measures

We used a composite endpoint of critical illness as defined by oxygen requirement (greater than 10 L/min by low-flow device, high-flow device, non-invasive, or invasive ventilation) or death within the first 24 hours of hospitalization. We developed models predicting our composite endpoint using patient demographic and clinical data available within the first four hours of arrival. Eight hospitals (n= 932) were used for model development and one hospital (n= 240) was held out for external validation. Area under receiver operating characteristic (AU-ROC), precision-recall curves (AU-PRC), and calibration metrics were used to compare predictive models to three illness scoring systems: Elixhauser comorbidity index, qSOFA, and CURB-65.

Results

During the study period from March 1, 2020 to April 27,2020, 1,792 patients were admitted with COVID-19. Six-hundred and twenty patients were excluded based on age or critical illness within the first 4 hours, yielding 1,172 patients in the final cohort. Of these patients, 144 (12.3%) met the composite endpoint within the first 24 hours. We first developed a bedside quick COVID-19 severity index (qCSI), a twelve-point scale using nasal cannula flow rate, respiratory rate, and minimum documented pulse oximetry. We then created a machine-learning gradient boosting model, the COVID-19 severity index (CSI), using twelve additional variables including inflammatory markers and liver chemistries. Both the qCSI (AU-ROC mean [95% CI]: 0.90 [0.85-0.96]) and CSI (AU-ROC: 0.91 [0.86-0.97]) outperformed the comparator models (qSOFA: 0.76 [0.69-0.85]; Elixhauser: 0.70 [0.62-0.80]; CURB-65: AU-ROC 0.66 [0.58-0.77]) on cross-validation and performed well on external validation (qCSI: 0.82, CSI: 0.76, CURB-65: 0.50, qSOFA: 0.59, Elixhauser: 0.61). We find that a qCSI score of 0-3 is associated with a less than 5% risk of critical respiratory illness, while a score of 9-12 is associated with a 57% risk of progression to critical illness.

Conclusions

A significant proportion of admitted COVID-19 patients decompensate within 24 hours of hospital presentation and these events are accurately predicted using bedside respiratory exam findings within a simple scoring system.
The Leipzig Catalogue of Vascular Plants (LCVP) – An improved taxonomic reference list for all known vascular plants
Authors: Freiberg Martin , Winter Marten , Gentile Alessandro , Zizka Alexander , Muellner-Riehl Alexandra Nora , Weigelt Alexandra , Wirth Christian
Published: May 2020

The lack of comprehensive and standardized taxonomic reference information is an impediment for robust plant research, e.g. in systematics, biogeography or macroecology. Here we provide an updated and much improved reference list of 1,315,479 scientific plant taxa names for all described vascular plant taxa names globally. The Leipzig Catalogue of Vascular Plants (LCVP; version 1.0.2) contains 351.176 accepted species (plus 6.160 natural hybrids), within 13.422 genera, 561 families and 84 orders. The LCVP a) contains more information on the taxonomic status of global plant names than any other similar resource and b) significantly improves the reliability of our knowledge by e.g. resolving the taxonomic status of ∼184.000 taxa names compared to The Plant List, the up to date most commonly used plant name resource. We used ∼4500 publications, existing relevant databases and available studies on molecular phylogenetics to construct a robust reference backbone. For easy access and integration into automated data processing pipelines, we provide an ‘R’-package (lcvplants) with the LCVP.
Efficacy of a novel iodine complex solution, CupriDyne, in inactivating SARS-CoV-2
Authors: Mantlo Emily , Evans Alex , Patterson-Fortin Laura , Boutros Jenny , Smith Richard , Paessler Slobodan
Published: May 2020

The coronavirus known as SARS-CoV-2, which causes COVID-19 disease, is presently responsible for a global pandemic wherein more than 3.5 million people have been infected and more than 250,000 killed to-date. There is currently no vaccine for COVID-19, leaving governments and public health agencies with little defense against the virus aside from advising or enforcing best practices for virus transmission prevention, which include hand-washing, physical distancing, use of face covers, and use of effective disinfectants. In this study, a novel iodine complex called CupriDyne®was assessed for its ability to inactivate SARS-CoV-2. CupriDyne was shown to be effective in inactivating the virus in a time-dependent manner, reducing virus titers by 99% (2 logs) after 30 minutes, and reducing virus titers to below the detection limit after 60 minutes. The novel iodine complex tested herein offers a safe and gentle alternative to conventional disinfectants for use on indoor and outdoor surfaces.
YTHDF1 drives intestinal immune response against bacterial infection
Authors: Zong Xin , Xiao Xiao , Shen Bin , Jiang Qin , Wang Hong , Lu Zeqing , Wang Fengqin , Jing Minliang , Wang Yizhen
Published: May 2020

Invasion of pathogenic bacteria is a serious threat to intestinal health. Recent emerging evidence has demonstrated that N6-methyladenosine (m6A) is closely associated with innate immunity; however, the underlying mechanism remains unclear. Herein, we aim to explore the function and mechanism of m6A modification in the regulation of innate immune responses against bacterial pathogens in the intestine. Ribo-seq and m6A-seq data have demonstrated that YTHDF1, an m6A reader, directs the translation of tumor necrosis factor receptor-associated factor 6 (TRAF6) mRNA to regulate immune responses via modulation of m6A methylation near stop codon. Furthermore, we have identified a unique mechanism that the interaction between YTHDF1 and the host factor DDX60 are critical in regulating intestinal immune response against bacterial infection by recognizing TRAF6 target transcripts. Additionally, our results provide novel insights as to why YTHDF1 could recognize its unique targets using the same domain as other YTHDF proteins. This work identifies YTHDF1 as a key driver of intestinal immune responses and provides an avenue for development of novel strategies to modulate intestinal immune response against bacterial infection.
Whole Genome Sequences ofAedes aegypti(Linn.) Field Isolates from Southern India
Authors: Bernard Venitha , Moudgalya Sanjana , Reegan Daniel , Sreekanthreddy Peddagangannagari , Mohan Abhilash , Subramanya Hosahalli S , Vembar Shruthi Sridhar , Ghosh Sanjay
Published: May 2020

Aedes spp. mosquitoes are a major health concern as they transmit several viral pathogens resulting in millions of deaths annually around the world. This is compounded by the emergence of insecticide-resistant strains and global warming, which could expose more than half of the world's population to Aedes-borne diseases in the future. Therefore, a comprehensive understanding of vector biology and the genomic basis of phenotypes such as insecticide resistance in natural populations are of paramount importance. Here, we sequenced the genome of Aedes aegypti mosquitos sampled from dengue-endemic areas and investigated the genetic variations between the previously reported laboratory-reared strain and our field isolates. The mosquito genomic DNA was used for paired-end sequencing using the Illumina platform. The reads were used for template-based assembly and mapped to the Aedes aegypti reference genome. Stringent parameters and multiple variant calling methods were used to identify unique single nucleotide variants (SNVs) and insertions-deletions (indels) and mapped to the Aedes chromosomes to create a draft consensus genome. Gene Ontology analyses was performed on the variant-enriched genes while two gene families involved in insecticide resistance were used for comparative sequence and phylogenetic analyses. Comparative sequence variant analyses showed that the majority of the high-quality variants in our samples mapped to non-coding regions of the genome, while gene ontology analyses of genic variants revealed enrichment of terms relevant to drug binding and insecticide resistance. Importantly, one mutation implicated in pyrethroid resistance was found in one Aedes sample. This is the first report of genome sequences of A. aegypti field isolates from India which reveals variants specific to the wild population. This is a useful resource which will facilitate development of robust integrated vector control strategies for management of Aedes-borne diseases through genetic manipulation of local mosquito populations.
The non-typeableHaemophilus influenzaemajor adhesin Hia is a dual function lectin that binds to human-specific respiratory tract sialic acid glycan receptors
Authors: Atack John M , Day Christopher J , Poole Jessica , Brockman Kenneth L. , Timms Jamie R L , Winter Linda E. , Haselhorst Thomas , Bakaletz Lauren O , Barenkamp Stephen J , Jennings Michael P
Published: May 2020

NTHi is a human-adapted pathogen that colonises the human respiratory tract. Strains of NTHi express multiple adhesins, however there is a unique, mutually exclusive relationship between the major adhesins Hia and HMW1/2. Approximately 25% of NTHi strains express Hia, a phase-variable autotransporter protein, and which has a critical role in colonisation of the host nasopharynx. The remaining 75% of strains express HMW1/2. Previous work has shown that the HMW1 and HMW2 proteins mediate binding to 2,3- and 2,6-linked sialic acid glycans found in the human respiratory tract. Here we show that that the high affinity binding domain of Hia, binding domain 1 (BD1) is responsible for binding to α2,6-sialyllactosamine glycans. BD1 is highly specific for glycans that incorporate the form of sialic acid expressed by humans,N-acetylneuraminic acid (Neu5Ac). We further show that Hia has lower affinity binding activity for 2,3-linked sialic acid and that this binding activity is mediated via a distinct domain. Thus, Hia with its dual binding activities functionally mimics the combined activities of the HMW1 and 2 adhesins. In addition, we show that Hia has a role in biofilm formation by strains of NTHi that express the adhesin. Knowledge of the binding affinity of a major NTHi adhesin, and putative vaccine candidate, will direct and inform development of future vaccines and therapeutic strategies for this important pathogen.

Importance

Host-adapted bacterial pathogens like NTHi have evolved specific mechanisms to colonize their restricted host niche. Relatively few of the adhesins expressed by NTHi have been characterized as regards their binding affinity at the molecular level. In this work we show that the major NTHi adhesin, Hia, preferentially binds to Neu5Ac-α2,6-sialyllactosamine, the form of sialic acid expressed in humans. The receptors targeted by Hia in the human airway mirror those targeted by influenza A virus and indicates the broad importance of sialic acid glycans as receptors for airway pathogens.
Comparison of SARS-CoV-2 spike protein binding to human, pet, farm animals, and putative intermediate hosts ACE2 and ACE2 receptors
Authors: Zhai Xiaofeng , Sun Jiumeng , Yan Ziqing , Zhang Jie , Zhao Jin , Zhao Zongzheng , Gao Qi , He Wan-Ting , Veit Michael , Su Shuo
Published: May 2020

The emergence of a novel coronavirus, SARS-CoV-2, resulted in a pandemic. Here, we used recently released X-ray structures of human ACE2 bound to the receptor-binding domain (RBD) of the spike protein (S) from SARS-CoV-2 to predict its binding to ACE2 proteins from different animals, including pets, farm animals, and putative intermediate hosts of SARS-CoV-2. Comparing the interaction sites of ACE2 proteins known to serve or not serve as receptor allows to define residues important for binding. From the 20 amino acids in ACE2 that contact S up to seven can be replaced and ACE2 can still function as the SARS-CoV-2 receptor. These variable amino acids are clustered at certain positions, mostly at the periphery of the binding site, while changes of the invariable residues prevent S-binding or infection of the respective animal. Some ACE2 proteins even tolerate the loss or the acquisition of N-glycosylation sites located near the S-interface. Of note, pigs and dogs which are not or not effectively infected, respectively, have only a few changes in the binding site have relatively low levels of ACE2 in the respiratory tract. Comparison of the RBD of S of SARS-CoV-2 with viruses from bat and pangolin revealed that the latter contains only one substitution, whereas the bat virus exhibits five. However, ACE2 of pangolin exhibit seven changes relative to human ACE2, a similar number of substitutions is present in ACE2 of bats, raccoon, and civet suggesting that SARS-CoV-2 may not especially adapted to ACE2 of any of its putative intermediate hosts. These analyses provide new insight into the receptor usage and animal source/origin of SARS-COV-2.

IMPORTANCE

SARS-CoV-2 is threatening people worldwide and there are no drugs or vaccines available to mitigate its spread. The origin of the virus is still unclear and whether pets and livestock can be infected and transmit SARS-CoV-2 are important and unknown scientific questions. Effective binding to the host receptor ACE2 is the first prerequisite for infection of cells and determines the host range. Our analysis provides a framework for the prediction of potential hosts of SARS-CoV-2. We found that ACE2 from species known to support SARS-CoV-2 infection tolerate many amino acid changes indicating that the species barrier might be low. However, the lower expression of ACE2 in the upper respiratory tract of some pets and livestock means more research and monitoring should be done to explore the animal source of infection and the risk of potential cross-species transmission. Finally, the analysis also showed that SARS-CoV-2 may not specifically adapted to any of its putative intermediate hosts.
AI334 and AQ806 antibodies recognize the spike S protein from SARS-CoV-2 by ELISA
Authors: Hammel Philippe , Marchetti Anna , Lima Wanessa C. , Lau Kelvin , Pojer Florence , Hacker David , Cosson Pierre
Published: May 2020

We tested 10 recombinant antibodies directed against the spike S protein from SARS-CoV-1. Among them, antibodies AI334 and AQ806 detect by ELISA the spike S protein from SARS-CoV-2.
The consensus Nglyco-X-S/T motif and a previously unknown Nglyco-N -linked glycosylation are necessary for growth and pathogenicity ofPhytophthora
Authors: Zhang Can , Chen Shanshan , Zhang Fan , Cui Tongshan , Xue Zhaolin , Wang Weizhen , Zhang Borui , Liu Xili
Published: May 2020

Asparagine (Asn, N) -linked glycosylation within the glycosylation motif (Nglyco-X-S/T; X≠P) is a ubiquitously distributed post-translational modification that participates in diverse eukaryotic cellular processes. However, little is known about the characteristic features and roles of N-glycosylation in oomycetes. In this work, it found that 2.5 μg/ml tunicamycin (N-glycosylation inhibitor) completely inhibitedPhytophthora sojaegrowth, suggesting that N-glycosylation is necessary for oomycete development. We conducted a glycoproteomic analysis ofP. sojaeto identify and map all N-glycosylated proteins and to quantify differentially expressed glycoproteins associated with mycelia, asexual cysts, and sexual oospores. A total of 355 N-glycosylated proteins were found, containing 496 glycosites that likely participate in glycan degradation, carbon metabolism, glycolysis, or other central metabolic pathways. To verify the glycoproteomic results and further examine the function of N-glycosylation inP. sojae, two proteins were selected for PNGase F deglycosylation assays and CRISPR/Cas9-mediated site-directed mutagenesis, including a GPI transamidase protein (GPI16) up-regulated in cysts, with the consensus Nglyco-X-S/T motif at Asn 94, and a heat shock protein 70 (HSP70) up-regulated in cysts and oospores with a previously unknown Nglyco-N motif at Asn 270. We demonstrated that the GPI16 and HSP70 are both N-glycosylated proteins, confirming that the Nglyco-N motif is a target site for asparagine - oligosaccharide N-glycosidic linkage. Glycosite mutations of Asn 94 in the GPI16 led to impaired cyst germination and pathogenicity, while HSP70 mutants exhibited decreased cyst germination and oospore production. This work describes an integrated map of oomycete N-glycoproteomes and advances our understanding of N-glycosylation in oomycetes. Moreover, we confirm that the consensus Nglyco-X-S/T and the Nglyco-N -linked glycosites are both essential for the growth ofPhytophthora sojae, indicating that there are multiple N-glycosylation motifs in oomycetes.
A Genetic Model Therapy Proposes a Critical Role for Liver Dysfunction in Mitochondrial Biology and Disease
Authors: Sabharwal Ankit , Wishman Mark D. , Cervera Roberto Lopez , Serres MaKayla R. , Anderson Jennifer L. , Treichel Anthony J. , Ichino Noriko , Liu Weibin , Yang Jingchun , Ding Yonghe , Deng Yun , Farber Steven A. , Clark Karl J. , Xu Xiaolei , Ekker Stephen C.
Published: May 2020

The clinical and largely unpredictable heterogeneity of phenotypes in patients with mitochondrial disorders demonstrates the ongoing challenges in the understanding of this semi-autonomous organelle in biology and disease. Here we present a new animal model that recapitulates key components of Leigh Syndrome, French Canadian Type (LSFC), a mitochondrial disorder that includes diagnostic liver dysfunction. LSFC is caused by allelic variations in the Leucine Rich Pentatricopeptide repeat-containing motif (LRPPRC) gene.LRPPRChas native functions related to mitochondrial mRNA polyadenylation and translation as well as a role in gluconeogenesis. We used the Gene-Breaking Transposon (GBT) cassette to create a revertible, insertional mutant zebrafish line in theLRPPRCgene.lrpprczebrafish homozygous mutants displayed impaired muscle development, liver function and lowered levels of mtDNA transcripts and are lethal by 12dpf, all outcomes similar to clinical phenotypes observed in patients. Investigations using anin vivolipidomics approach demonstrated accumulation of non-polar lipids in these animals. Transcript profiling of the mutants revealed dysregulation of clinically important nuclearly encoded and mitochondrial transcripts. Using engineered liver-specific rescue as a genetic model therapy, we demonstrate survival past the initial larval lethality, as well as restored normal gut development, mitochondrial morphology and triglyceride levels functionally demonstrating a critical role for the liver in the pathophysiology of this model of mitochondrial disease. Understanding the molecular mechanism of the liver-mediated genetic rescue underscores the potential to improve the clinical diagnostic and therapeutic developments for patients suffering from these devastating disorders.
Structural basis for histone variant H3tK27me3 recognition by PHF1 and PHF19
Authors: Dong Cheng , Nakagawa Reiko , Oyama Kyohei , Yamamoto Yusuke , Zhang Weilian , Li Yanjun , Yoshimura Yuriko , Kamiya Hiroyuki , Nakayama Jun-ichi , Ueda Jun , Min Jinrong
Published: May 2020

The PRC2 (Polycomb repressive complex 2) complex is a multi-component histone H3K27 methyltransferase, best known for silencingHoxgenes during embryonic development. The Polycomb-like proteins PHF1, MTF2 and PHF19 are critical components of PRC2 by stimulating its catalytic activity in embryonic stem (ES) cells. The Tudor domains of PHF1/19 have been previously shown to be readers of H3K36me3in vitro. However, some other studies suggest that PHF1 and PHF19 co-localize with the H3K27me3 mark, but not H3K36me3 in cells. Here, we provide further evidence that PHF1 co-localizes with H3tK27 in testis, and its Tudor domain preferentially binds to H3tK27me3 over canonical H3K27me3in vitro. Our complex structures of the Tudor domains of PHF1 and PHF19 with H3tK27me3 shed light on the molecular basis for preferential recognition of H3tK27me3 by PHF1 and PHF19 over canonical H3K27me3, implicating that H3tK27me3 might be a physiological ligand of PHF1/19.
Strong Effects of Population Density and Social Characteristics on Distribution of COVID-19 Infections in the United States
Authors: Rajan Kumar B. , Dhana Klodian , Barnes Lisa L. , Aggarwal Neelum T. , Evans Laura E. , McAninch Elizabeth A. , Weuve Jennifer , Wilson Robert S. , DeCarli Charles , Evans Denis A.
Published: May 2020

Background

Coronavirus disease 2019 (COVID-19) has devastated global populations and has had a large impact in the United States. The objective of this manuscript is to study the relation of population demographics, social characteristics, and social distancing on the number of infections and deaths in the US.

Methods

Data came from publicly available sources. Social distancing was measured by the change in the rate of human encounters per km2 relative to the pre-COVID-19 national average. A smooth generalized additive model for counts of total infections and deaths at US county-level included population demographics, social characteristics, and social distancing.

Results

The model strongly predicted the geo-spatial variations in COVID-19 infections and deaths, 97.2% of variation in infections and 99.3% of variation in deaths from March 15, 2020. US counties with higher population density, poverty index, civilian population, and minorities, especially African Americans, had a higher rate of infections and deaths, and social distancing was associated with a slower rate of infections and deaths. The number of people infected was increasing; however, the rate of increase of new infections was showing signs of plateauing from the second week of April. Our model estimates that 1,865,580 US residents will test positive for infections and 117,246 fatalities by June 1, 2020. Importantly, our model suggests significant social differences in the infections and deaths across US communities. Areas with a larger African American population and a higher poverty index are expected to show higher rates of infections and deaths.

Conclusion

Preventive steps, including social distancing and community closures, have been a cornerstone in slowing the transmission and potentially reducing the spread of the disease. Crucial knowledge of the role of social characteristics in disease transmission is essential to understand and predict current and future disease distribution and plan additional preventive steps.
CORRELATION BETWEEN CHEST COMPUTED TOMOGRAPHY AND LUNG ULTRASONOGRAPHY IN PATIENTS WITH CORONAVIRUS DISEASE 2019 (COVID-19)
Authors: Tung-Chen Yale , de Gracia Milagros Martí , Díez-Tascón Aurea , Agudo-Fernández Sergio , Alonso-González Rodrigo , Rodríguez-Fuertes Pablo , Parra-Gordo Luz , Ossaba-Vélez Silvia , Llamas-Fuentes Rafael
Published: May 2020

INTRODUCTION

There is growing evidence regarding the imaging findings of Coronavirus Disease 2019 (COVID-19), in chest X-ray and Computed Tomography scan (CT). At this moment, the role of Lung Ultrasonography (LUS) has yet to be explored.

OBJECTIVES

The main purpose of this study is to evaluate the correlation between LUS findings and chest CT in confirmed (positive RT-PCR) or clinically highly suspicious (dyspnea, fever, myasthenia, gastrointestinal symptoms, dry cough, ageusia or anosmia) of COVID-19 patients.

METHODS

Prospective study carried out in the emergency department (ED) of confirmed or clinically highly suspicious COVID-19 patients who were subjected to a chest CT and concurrent LUS exam. An experienced ED physician performed the LUS exam blind to the clinical history and results of the CT scan, which were reviewed by two radiologists in consensus for signs compatible with COVID-19 (bilateral ground-glass opacities in peripheral distribution). Compatible LUS exam was considered a bilateral pattern of B-lines, irregular pleural line and subpleural consolidations.

RESULTS

Between March and April 2020, fifty-one patients were consecutively enrolled. The indication for CT was a negative or indeterminate RT-PCR test (49.0%) followed by suspicion of pulmonary embolism (41.2%). Radiological signs compatible with COVID-19 were present in thirty-seven patients (72.5%) on CT scan and forty patients (78.4%) on LUS exam. The presence of LUS findings was correlated with a positive CT scan suggestive of COVID-19 (OR: 13.3, 95%CI: 4.539.6, p<0.001) with a sensitivity of 100.0% and a specificity of 78.6%, positive predictive value of 92.5% and negative of 100.0%. There was no missed diagnosis of COVID-19 with LUS compared to CT in our cohort. The LUS Score had a good correlation with CT total severity score (ICC 0.803, 95% CI 0.60-0.90, p<0.001).

CONCLUSION

LUS presents similar accuracy compared to chest CT to detect lung abnormalities in COVID-19 patients.

Summary Statement

LUS presents similar accuracy compared to chest CT to detect lung abnormalities in COVID-19 patients.

Key Results

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Common LUS findings mirror those previously described for CT: bilateral, peripheral, consolidation and/or ground glass opacities.

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LUS findings correlated with CT scan with a sensitivity of 100.0% and a specificity of 78.6%, positive predictive value of 92.5% and negative of 100.0%. The Lung score had a good correlation with CT total severity score (ICC 0.803, 95% CI 0.601-0.903, p < 0.001).

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There were no missed diagnosis of COVID-19 with LUS compared to CT in our cohort.