bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineering Transcriptional Interference through RNA Polymerase Processivity Control
Authors: O’Connor Nolan J. , Bordoy Antoni E. , Chatterjee Anushree 
Published: September 2020

ABSTRACTAntisense transcription is widespread in all kingdoms of life and has been shown to influence gene expression through transcriptional interference (TI), a phenomenon in which one transcriptional process negatively influences anotherin cis. The processivity, or uninterrupted transcription, of an RNA Polymerase (RNAP) is closely tied to levels of antisense transcription in bacterial genomes, but its influence on TI, while likely important, is not well-characterized. Here we show that TI can be tuned through processivity control via three distinct antitermination strategies: the antibiotic bicyclomycin, phage protein Psu, and ribosome-RNAP coupling. We apply these methods toward TI and tune ribosome-RNAP coupling to produce 38-fold gene repression due to RNAP collisions. We then couple protein roadblock and RNAP collisions to design minimal genetic NAND and NOR logic gates. Together these results show the importance of processivity control for strong TI and demonstrate the potential for TI to create sophisticated switching responses.
Detection of SARS-CoV-2 within the healthcare environment: a multicentre study conducted during the first wave of the COVID-19 outbreak in England
Authors: Moore Ginny , Rickard Helen , Stevenson David , Bou Paz Aranega , Pitman James , Crook Ant , Davies Katherine , Spencer Antony , Burton Chris , Easterbrook Linda , Love Hannah E. , Summers Sian , Welch Stephen R. , Wand Nadina , Thompson Katy-Anne , Pottage Thomas , Richards Kevin S. , Dunning Jake , Bennett Allan 
Published: September 2020

AbstractUnderstanding how Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is spread within the hospital setting is essential if staff are to be adequately protected, effective infection control measures are to be implemented and nosocomial transmission is to be prevented.The presence of SARS-CoV-2 in the air and on environmental surfaces around hospitalised patients, with and without respiratory symptoms, was investigated. Environmental sampling was carried out within eight hospitals in England during the first wave of the COVID-19 outbreak. Samples were analysed using reverse transcription polymerase chain reaction (RT-PCR) and virus isolation assays.SARS-CoV-2 RNA was detected on 30 (8.9%) of 336 environmental surfaces. Ct values ranged from 28·8 to 39·1 equating to 2·2 × 105 to 59 genomic copies/swab. Concomitant bacterial counts were low, suggesting the cleaning performed by nursing and domestic staff across all eight hospitals was effective. SARS-CoV-2 RNA was detected in four of 55 air samples taken <1 m from four different patients. In all cases, the concentration of viral RNA was low and ranged from <10 to 460 genomic copies per m3 of air. Infectious virus was not recovered from any of the PCR positive samples analysed.Effective cleaning can reduce the risk of fomite (contact) transmission but some surface types may facilitate the survival, persistence and/or dispersal of SARS-CoV-2. The presence of low or undetectable concentrations of viral RNA in the air supports current guidance on the use of specific PPE ensembles for aerosol and non-aerosol generating procedures.
Over-the-counter Analgesics in Pregnancy and Offspring Neonatal Outcomes: A Retrospective Cohort Study
Authors: Zafeiri Aikaterini , Raja Edwin A. , Mitchell Rod T. , Hay David C. , Bhattacharya Sohinee , Fowler Paul A. 
Published: September 2020

AbstractObjectiveTo identify associations between in utero exposure to 5 over-the-counter (OTC) analgesics and adverse neonatal outcomes.DesignRetrospective cohort studySettingAberdeen UKPopulation151,141 singleton deliveries, 1985 to 2015MethodsSelf-reported, non-prescription, consumption of paracetamol, aspirin, ibuprofen, diclofenac and naproxen during pregnancy and neonatal outcomes were obtained from the Aberdeen Maternity and Neonatal Databank (AMND). Univariable and multivariable regression analyses were performed to investigate associations between analgesic use and offspring neonatal outcomes. Crude (cORs) and adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were reported, indicating the strength of association.Main Outcome MeasuresPremature delivery (<37 weeks), stillbirth, neonatal death, birthweight, standardised birthweight score, neonatal unit admission, APGAR score at 1 and 5 minutes, cryptorchidism, neural tube and amniotic band defects, hypospadias and gastroschisis.ResultsPregnancies exposed to at least one of the 5 analgesics were significantly independently associated with increased odds for premature delivery <37 weeks (aOR=1.50, 95%CI 1.43-1.58), stillbirth (aOR=1.33, 95%CI 1.15-1.54), neonatal death (aOR=1.56, 95%CI 1.27-1.93), birthweight <2500g (aOR=1.28, 95%CI 1.20-1.37), birthweight >4000g (aOR=1.09, 95%CI 1.05-1.13), admission to neonatal unit (aOR=1.57, 95%CI 1.51-1.64), APGAR score <7 at 1 minute (aOR=1.18, 95%CI 1.13-1.23) and 5 minutes (aOR=1.48, 95%CI 1.35-1.62), neural tube defects (aOR=1.64, 95%CI 1.08-2.47) and hypospadias (aOR=1.27, 95%CI 1.05-1.54 males only).ConclusionsThere was a high prevalence of OTC analgesics use during pregnancy, which steeply increased during the 30-year study period. Analgesic consumption was independently associated with multiple adverse neonatal offspring outcomes. The use of paracetamol in combination with other NSAIDs conferred the highest risk.FundingBiotechnology and Biological Sciences Research council (BBSRC) funding under the EASTBIO doctoral training programme.
EXTENDING THE SUSCEPTIBLE-EXPOSED-INFECTED-REMOVED (SEIR) MODEL TO HANDLE THE HIGHfaLSEnEGATIVE RATE ANDsyMPTOM-BASED ADMINISTRATION OF COVID-19 DIAGNOSTIC TESTS:SEIR-fansy
Authors: Bhaduri Ritwik , Kundu Ritoban , Purkayastha Soumik , Kleinsasser Michael , Beesley Lauren J. , Mukherjee Bhramar 
Published: September 2020

AbstractThe false negative rate of the diagnostic RT-PCR test for SARS-CoV-2 has been reported to be substantially high. Due to limited availability of testing, only a non-random subset of the population can get tested. Hence, the reported test counts are subject to a large degree of selection bias. We consider an extension of the Susceptible-Exposed-Infected-Removed (SEIR) model under both selection bias and misclassification. We derive closed form expression for the basic reproduction number under such data anomalies using the next generation matrix method. We conduct extensive simulation studies to quantify the effect of misclassification and selection on the resultant estimation and prediction of future case counts. Finally we apply the methods to reported case-death-recovery count data from India, a nation with more than 5 million cases reported over the last seven months. We show that correcting for misclassification and selection can lead to more accurate prediction of case-counts (and death counts) using the observed data as a beta tester. The model also provides an estimate of undetected infections and thus an undereporting factor. For India, the estimated underreporting factor for cases is around 21 and for deaths is around 6. We develop an R-packageSEIR-fansyfor broader dissemination of the methods.
Hitting the diagnostic sweet spot: Point-of-care SARS-CoV-2 salivary antigen testing with an off-the-shelf glucometer
Authors: Singh Naveen K. , Ray Partha , Carlin Aaron F. , Magallanes Celestine , Morgan Sydney , Laurent Louise C. , Aronoff-Spencer Eliah S. , A. Hall Drew 
Published: September 2020

AbstractSignificant barriers to the diagnosis of latent and acute SARS-CoV-2 infection continue to hamper population-based screening efforts required to contain the COVID-19 pandemic in the absence of effective antiviral therapeutics or vaccines. We report an aptamer-based SARS-CoV-2 salivary antigen assay employing only low-cost reagents ($3.20/test) and an off-the-shelf glucometer. The test was engineered around a glucometer as it is quantitative, easy to use, and the most prevalent piece of diagnostic equipment globally making the test highly scalable with an infrastructure that is already in place. Furthermore, many glucometers connect to smartphones providing an opportunity to integrate with contract tracing apps, medical providers, and electronic medical records. In clinical testing, the developed assay detected SARS-CoV-2 infection in patient saliva across a range of viral loads - as benchmarked by RT-qPCR - within one hour, with 100% sensitivity (positive percent agreement) and distinguished infected specimens from off-target antigens in uninfected controls with 100% specificity (negative percent agreement). We propose that this approach can provide an inexpensive, rapid, and accurate diagnostic for distributed screening of SARS-CoV-2 infection at scale.
When it is available, will we take it? Public perception of hypothetical COVID-19 vaccine in Nigeria
Authors: Adebisi Yusuff Adebayo , Alaran Aishat Jumoke , Bolarinwa Obasanjo Afolabi , Akande-Sholabi Wuraola , Lucero-Prisno Don Eliseo 
Published: September 2020

AbstractCOVID-19 pandemic is a global public health threat facing mankind. There is no specific antiviral treatment for COVID-19, and no vaccine is currently available. This study aims to understand the perception of the public towards hypothetical COVID-19 vaccine in Nigeria. We conducted a cross-sectional survey in August 2020 across the 36 states of Nigeria using an online questionnaire. The questionnaire includes sections on the demographic characteristics of the respondents and their perception regarding hypothetical COVID-19 vaccine. A total of 517 respondents completed and returned the informed consent along with the questionnaire electronically. Data were coded and abstracted into the Microsoft Excel spreadsheet and loaded into the STATA 14 software for final analysis. The results showed that more than half of the respondents were male 294 (56.87%). Most of the respondents (385, 74.47%) intend to take the COVID-19 vaccine when it becomes available. Among the 132 respondents that would not take the COVID-19 vaccine, the major reason for non-acceptance is unreliability of the clinical trials 49 (37.12%), followed by the belief that their immune system is sufficient to combat the virus 36 (27.27%). There are significant association with the respondents age and having reservations toward vaccination [χ2= 19.0389 P-value=0.00] and COVID-19 vaccine acceptance [χ2=24.3316 P-value=0.00]. Furthermore, geographical location and acceptance of the COVID-19 vaccine [χ2=13.7786 P-value=0.02] are significantly associated. Even though the majority of our respondents are willing to take the COVID-19 vaccine, our findings reiterate the need to reassure the public that any vaccine which becomes available is safe and effective.
Anti-SARS-CoV-2 IgM and IgG antibodies in health workers in Sergipe, Brazil
Authors: de Melo Mônica Santos , Borges Lysandro Pinto , de Souza Daniela Raguer Valadão , Martins Aline Fagundes , de Rezende Neto José Melquiades , Ribeiro Anderson Alves , Santos Aryanne Araujo , da Invenção Grazielly Bispo , Matos Igor Leonardo Santos , Santos Kezia Alves dos , Souza Nicolas Alessandro Alves , Borges Pâmela Chaves , de Oliveira Makson Gleydson Brito 
Published: September 2020

AbstractBackgroundThe exponential growth of COVID-19 cases in Brazil is overloading health systems with overcrowding of hospitals and overflowing intensive care units. Increasing infection rates in health professionals can lead to the collapse of the health system and further worsen the pandemic. The aim of this study was to evaluate the seroprevalence of IgM and IgG for SARS-CoV-2 in health workers in Sergipe, Brazil.MethodsThe targeted tests involved health professionals working on the front line to combat COVID-19. The samples were collected in the month of June, in six hospital units in the state of Sergipe.Results471 health professionals were tested. Of these, 28 workers (5.95%) tested positive for IgM and 64 (13.59%) tested positive for IgG. 9 workers (1.91%) tested positive for IgM and were also positive for IgG.DiscussionHealth workers must be monitored constantly, because if they are infected, they can spread the virus to colleagues, hospitalized patients and even family members.ConclusionKnowing the prevalence of antibodies to the virus in health workers is an important measure of viral spread control.
Quantifying the impact of quarantine duration on COVID-19 transmission
Authors: Ashcroft Peter , Lehtinen Sonja , Bonhoeffer Sebastian 
Published: September 2020

AbstractThe numbers of confirmed cases of SARS-CoV-2 infection are increasing in many places. Consequently, the number of individuals placed into quarantine is increasing too. The large number of individuals in quarantine has high societal and economical costs, as well as infringing on the freedom of the individual. This has led to a vigorous debate about the duration of quarantine, particularly in light of the potentially low specificity of quarantine (i.e. low probability of quarantined individuals indeed being infected). We present a mathematical model that leverages empirically determined distributions of incubation period, infectivity, and generation time to quantify how the duration of quarantine affects transmission. With this model we address the impact of shortening the quarantine for returning travellers and traced contacts of confirmed cases, both in terms of prevented transmission and the ratio of prevented transmission to days spent in quarantine. We also consider the impact of i) test-and-release strategies; ii) additional hygiene measures imposed upon release after a negative test; iii) the development of symptoms during quarantine; iv) the relationship between quarantine duration and adherence; and v) the specificity of quarantine. When considering the benefit versus cost utility of quarantine, we find that the diminishing impact of longer quarantine on transmission prevention may support a quarantine duration below 10 days, particularly for returning travellers. A greater gain of utility can be achieved through a test-and-release strategy, and this can be even further strengthened by imposed hygiene measures post-release. We also find that unless a test-and-release strategy is considered, the specificity of quarantine does not affect the optimal duration of quarantine. Therefore, the argument that we should shorten quarantine because of lack of specificity is misguided.
A Generalized Evolutionary Classifier for Evolutionary Guided Precision Medicine
Authors: McCoy Matthew , Yeang Chen-Hsiang , Parashar Deepak , Beckman Robert A. 
Published: September 2020

ABSTRACTBackgroundCurrent precision medicine (CPM) matches patients to therapies, utilizing traditional biomarker classifiers. Dynamic precision medicine (DPM) is an evolutionary guided precision medicine (EGPM) approach that specifically accounts for intratumoral genetic heterogeneity and evolutionary dynamics. DPM adapts as frequently as every six weeks, plans proactively for future resistance development, and incorporates multiple therapeutic agents. Simulations indicate that DPM can double mean and median survival and significantly improve long-term survival in a cohort of 3 million virtual patients representing a pan-oncology spectrum. Given the cost and invasiveness of monitoring subclones frequently in the DPM paradigm, we sought to determine the value of a DPM window study of only two six-week adaptations (“moves”).Methods3 million virtual patients, differing in DPM input parameters of initial subclonal compositions, drug sensitivities, and growth and mutational kinetics, were simulated as previously described. Each virtual patient was treated with CPM, DPM, and DPM for two moves followed by CPM.ResultsThe first two DPM moves provide similar benefit to a five-year, 40-move sequence in the full virtual population. In simulations, if the first two moves are identical for DPM and CPM, patients will not benefit from DPM (89% negative predictive value). The patient subset (20%) in which two-move and 40-move DPM sequences are closely similar in outcome has extraordinary predicted benefit (HR-DPM/CPM 0.04).ConclusionsThe first two DPM moves provide most of the clinical benefit of DPM, reducing the duration of required subclonal monitoring. This leads to an evolutionary classifier (EC) that selects patients who will benefit, i.e. those in whom DPM and CPM recommendations differ early. This EC development paradigm may apply to other EGPM approaches despite different underlying assumptions.CONTEXT SUMMARYKey objective: Current precision medicine (CPM) performs static matching of biomarker classifiers to therapies. We asked, using computer simulation, whether dynamic precision medicine (DPM), a highly adaptive and proactive evolutionary guided precision medicine (EGPM) paradigm, could benefit patients with only two six-week adaptive treatment periods (“moves”), and still enhance long term survival by preventing late term relapses.Knowledge generated: Two moves of DPM were highly effective, nearly as effective as 40 moves in the full population. Patients for whom DPM and CPM recommend the same treatment sequence for the first two moves will likely not benefit from DPM.Relevance: A 2-move DPM paradigm is far more cost-effective and less invasive than a 40-move paradigm, and opens up the neoadjuvant period for studying DPM. The findings establish an evolutionary classifier (EC) for selecting patients who will benefit from DPM. This general approach to developing an EC may work for other EGPM.
Beam image-shift accelerated data acquisition for near-atomic resolution single-particle cryo-electron tomography
Authors: Bouvette Jonathan , Liu Hsuan-Fu , Du Xiaochen , Zhou Ye , Sikkema Andrew P. , Da Fonseca Rezende E Mello Juliana , Klemm Bradley P. , Huang Rick , Schaaper Roel M. , Borgnia Mario J. , Bartesaghi Alberto 
Published: September 2020

ABSTRACTTomographic reconstruction of cryopreserved specimens imaged in an electron microscope followed by extraction and averaging of sub-volumes has been successfully used to derive atomic models of macromolecules in their biological environment. Eliminating biochemical isolation steps required by other techniques, this method opens up the cell to in-situ structural studies. However, the need to compensate for errors in targeting introduced during mechanical navigation of the specimen significantly slows down tomographic data collection thus limiting its practical value. Here, we introduce protocols for tilt-series acquisition and processing that accelerate data collection speed by an order of magnitude and significantly improve map resolution compared to existing approaches. We achieve this by using beam-image shift to multiply the number of areas imaged at each stage position, by integrating geometrical constraints during imaging to achieve high precision targeting, and by performing per-tilt astigmatic CTF estimation and data-driven exposure weighting to improve final map resolution. We validated our beam image-shift electron cryo-tomography (BISECT) approach by determining the structure of a low molecular weight target (~300kDa) at 3.6 Å resolution where density for individual side chains is clearly resolved.
IL-7R signalling activates widespread VHand DHgene usage to drive antibody diversity in bone marrow B cells
Authors: Baizan-Edge Amanda , Stubbs Bryony A. , Stubbington Michael J. T. , Bolland Daniel J. , Tabbada Kristina , Andrews Simon , Corcoran Anne E. 
Published: September 2020

AbstractGeneration of the primary antibody repertoire requires V(D)J recombination of hundreds of gene segments in the immunoglobulin heavy chain (Igh) locus. It has been proposed that interleukin-7 receptor (IL-7R) signalling is necessary for Igh recombination, but this has been challenging to partition from the receptor’s role in B cell survival and proliferation. By generating the first detailed description of the Igh repertoire of murine IL-7Rα-/-bone marrow B cells, we demonstrate that IL-7R signalling profoundly influences VHgene selection during VH-to-DJHrecombination. We find skewing towards usage of 3’ VHgenes duringde novoVH-to-DJHrecombination that is more severe than the fetal liver (FL) B cell repertoire, and we now show a role for IL-7R signalling in DH-to-JHrecombination. Transcriptome and accessibility analyses suggests reduced expression of B lineage-specific transcription factors (TFs) and their targets, and loss of DHand VHantisense transcription in IL-7Rα-/-B cells. These results refute models suggesting that IL-7R signalling is only required for survival and proliferation, and demonstrate a pivotal role in shaping the Igh repertoire by activating underpinning epigenetic mechanisms.
From genotype to phenotype: maintenance of a chemical polymorphism in the context of high geneflow
Authors: Ehlers Bodil K. , Gauthier Perrine , Villesen Palle , Santoni Sylvain , Thompson John D. , Bataillon Thomas 
Published: September 2020

AbstractA major question in evolution is how to maintain many adaptive phenotypes within a species. In Mediterranean wild thyme, a staggering number of discrete chemical phenotypes (chemotypes) coexist in close geographic proximity. Plant chemotypes are defined by the dominant monoterpene produced in their essential oil. We study the genetics of six distinct chemotypes nested within two well established ecotypes. Ecotypes, and chemotypes within ecotypes, are spatially segregated, and their distribution tracks local differences in the abiotic environment. The ecotypes have undergone a rapid shift in distribution associated with current climate change. Here, combining genomic, phenotypic, and environmental data, we show how the genetics of ecotype determination can allow for such rapid evolutionary response despite high gene flow among ecotypes. Variation in three terpene-synthase loci explains almost all variation in ecotype identity, with one single locus accounting for as much as 78% of it. Phenotypic selection on ecotypes combined with low segregating genotypic redundancy and tight genetic determination leaves a clear footprint at the genomic level: alleles associated with ecotype identity track environmental variation despite extensive gene flow. Different chemotypes, nested within each ecotype, also track environmental variation. However, in contrast to ecotypes, chemotype identity is determined by more loci and show a wider range of genotypic redundancy, which dilutes the impact of phenotypic selection on alleles associated with different chemotypes. Identifying the genetics behind this polymorphism in thyme is a crucial step towards understanding the maintenance of this widespread chemical polymorphism found in many aromaticLamiaceae.