bluuebunny/crossref_metadata_2025_split huggingface dataset:
A platform for post-translational spatiotemporal control of cellular proteins
Authors: Jayanthi Brianna , Bachhav Bhagyashree , Wan Zengyi , Martinez Legaspi Santiago , Segatori Laura 
Published: February 2021

Abstract
Mammalian cells process information through coordinated spatiotemporal regulation of proteins. Engineering cellular networks thus relies on efficient tools for regulating protein levels in specific subcellular compartments. To address the need to manipulate the extent and dynamics of protein localization, we developed a platform technology for the target-specific control of protein destination. This platform is based on bifunctional molecules comprising a target-specific nanobody and universal sequences determining target subcellular localization or degradation rate. We demonstrate that nanobody-mediated localization depends on the expression level of the target and the nanobody, and the extent of target subcellular localization can be regulated by combining multiple target-specific nanobodies with distinct localization or degradation sequences. We also show that this platform for nanobody-mediated target localization and degradation can be regulated transcriptionally and integrated within orthogonal genetic circuits to achieve the desired temporal control over spatial regulation of target proteins. The platform reported in this study provides an innovative tool to control protein subcellular localization, which will be useful to investigate protein function and regulate large synthetic gene circuits.
Joint universal modular plasmids (JUMP): a flexible vector platform for synthetic biology
Authors: Valenzuela-Ortega Marcos , French Christopher 
Published: February 2021

Abstract
Generation of new DNA constructs is an essential process in modern life science and biotechnology. Modular cloning systems based on Golden Gate cloning, using Type IIS restriction endonucleases, allow assembly of complex multipart constructs from reusable basic DNA parts in a rapid, reliable and automation-friendly way. Many such toolkits are available, with varying degrees of compatibility, most of which are aimed at specific host organisms. Here, we present a vector design which allows simple vector modification by using modular cloning to assemble and add new functions in secondary sites flanking the main insertion site (used for conventional modular cloning). Assembly in all sites is compatible with the PhytoBricks standard, and vectors are compatible with the Standard European Vector Architecture (SEVA) as well as BioBricks. We demonstrate that this facilitates the construction of vectors with tailored functions and simplifies the workflow for generating libraries of constructs with common elements. We have made available a collection of vectors with 10 different microbial replication origins, varying in copy number and host range, and allowing chromosomal integration, as well as a selection of commonly used basic parts. This design expands the range of hosts which can be easily modified by modular cloning and acts as a toolkit which can be used to facilitate the generation of new toolkits with specific functions required for targeting further hosts.
Torsadogenic Action of Cisapride, dl-Sotalol, Bepridil, and Verapamil Analyzed by the Chronic Atrioventricular Block Cynomolgus Monkeys: Comparison With That Reported in the CiPA In Silico Mechanistic Model
Authors: Goto Ai , Sakamoto Kengo , Kambayashi Ryuichi , Nunoi Yoshio , Izumi-Nakaseko Hiroko , Kawai Shinichi , Takei Yoshinori , Matsumoto Akio , Kanda Yasunari , Sugiyama Atsushi 
Published: February 2021

Abstract
In order to bridge the gap of information between the in silico model and human subjects, we evaluated torsadogenic risk of cisapride, dl-sotalol, bepridil and verapamil selected from 12 training compounds in the comprehensive in vitro proarrhythmia assay using the chronic atrioventricular block monkeys. Cisapride (0, 1, and 5 mg/kg, n = 5 for each dose), dl-sotalol (0, 1, 3, and 10 mg/kg, n = 5 for each dose), bepridil (0, 10, and 100 mg/kg, n = 4 for each dose), verapamil (0, 1.5, 15, and 75 mg/kg, n = 4 for each dose) were orally administered to the monkeys in conscious state. Five mg/kg of cisapride, 1, 3, and 10 mg/kg of dl-sotalol and 100 mg/kg of bepridil prolonged ΔΔQTcF, which was not observed by verapamil. Torsade de pointes was induced by 5 mg/kg of cisapride in 2 out of 5 animals, by 10 mg/kg of dl-sotalol in 5 out of 5 and by 100 mg/kg of bepridil in 2 out of 4, which was not induced by verapamil. These torsadogenic doses were normalized by their maximum clinical daily ones to estimate torsadogenic risk. The order of risk was dl-sotalol &gt;bepridil ≥cisapride &gt;verapamil in our study. Since the order was bepridil ≥dl-sotalol &gt;cisapride &gt;verapamil in comprehensive in vitro proarrhythmia assay (CiPA) in silico mechanistic model validation, sympathetic regulation on the heart may play a pivotal role in the onset of torsade de pointes in vivo.
DPP9 deficiency: an Inflammasomopathy which can be rescued by lowering NLRP1/IL-1 signaling
Authors: Harapas Cassandra R. , Robinson Kim S. , Lay Kenneth , Wong Jasmine , Moreno Traspas Ricardo , Nabavizadeh Nasrin , Raas-Rothschild Annick , Boisson Bertrand , Drutman Scott B. , Laohamonthonkul Pawat , Bonner Devon , Gorrell Mark , Davidson Sophia , Yu Chien-Hsiung , Kayserili Hulya , Hatipoglu Nevin , Casanova Jean-Laurent , Bernstein Jonathan A. , Zhong Franklin L. , Masters Seth L. , Reversade Bruno 
Published: February 2021

AbstractDipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it impacts inflammasome regulation in vivo is not yet established. Here, we report two families with immune-associated defects, skin pigmentation abnormalities and neurological deficits that segregate with biallelicDPP9rare variants. Using patient-derived primary cells and biochemical assays, these variants are shown to behave as hypomorphic or loss-of-function alleles that fail to repress NLRP1. Remarkably, the removal in mice, of a single copy of eitherNlrp1a/b/c, Asc, Gsdmd, Il-1r, but notIl-18, was sufficient to rescue the lethality ofDpp9mutant neonates. These experiments suggest that the deleterious consequences of DPP9 deficiency are mostly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1β signaling. Collectively, our results delineate a Mendelian disorder of DPP9 deficiency driven by increased NLRP1 activity as demonstrated in patient cells and in a mouse model of the disease.
Sarilumab treatment of hospitalised patients with severe or critical COVID-19: a multinational, randomised, adaptive, phase 3, double-blind, placebo-controlled trial
Authors: Lescure Francois-Xavier , Honda Hitoshi , Fowler Robert A. , Lazar Jennifer Sloane , Shi Genming , Wung Peter , Patel Naimish , Hagino Owen 
Published: February 2021

SummaryBackgroundElevated proinflammatory cytokines have been associated with 2019 coronavirus disease (COVID-19) severity. We assessed efficacy and safety of sarilumab, an interleukin-6 receptor inhibitor, in severe (requiring supplemental oxygen by nasal canula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19.MethodsThis was a 60-day, randomised, double-blind, placebo-controlled, multinational trial in patients hospitalised with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomised 2:2:1 to intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. The primary endpoint was time to ≥2-point clinical improvement (7-point scale; range: 1 [death] to 7 [not hospitalised]). The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This trial is registered withClinicalTrials.gov(NCT04327388).FindingsBetween March 28 and July 3, 2020, 420 patients were randomised; 416 received treatment (placebo, n=84; sarilumab 200 mg, n=159; sarilumab 400 mg, n=173). At day 29, there were no significant differences in median (95% CI) time to ≥2-point improvement between placebo (12·0 [9·0–15·0] days) and sarilumab groups (200 mg: 10·0 [9·0–12·0] days, p=0.96, log-rank test; 400 mg: 10·0 [9·0–13·0] days, p=0.34) or in proportions of patients alive (placebo, 91·7%; sarilumab 200 mg, 89·9%, p=0·63; sarilumab 400 mg, 91·9%, p=0·85). At day 29, there were numerical, nonsignificant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +9%, 95% CI −7·7 to 25·5, p=0·25) for critical patients. There were no unexpected safety signals.InterpretationThis trial did not demonstrate efficacy of sarilumab in patients hospitalised with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19.FundingSanofi and Regeneron Pharmaceuticals, Inc.
Diffusion kurtosis imaging of white matter in bipolar disorder
Authors: Goghari Vina M , Kusi Mavis , Shakeel Mohammed K , Beasley Clare , David Szabolcs , Leemans Alexander , De Luca Alberto , Emsell Louise 
Published: February 2021

AbstractObjectivesWhite matter pathology is thought to contribute to the pathogenesis of bipolar disorder (BD). However, most studies of white matter in BD have used the simple diffusion tensor imaging (DTI) model, which has several limitations. DTI studies have reported heterogenous results, leading to a lack of consensus about the extent and location of white matter alterations. Here, we applied two advanced diffusion magnetic resonance imaging (MRI) techniques to investigate white matter microstructure in BD.MethodsTwenty-five patients with BD and 24 controls comparable for age and sex were included in the study. Whole-brain voxel-based analysis (VBA) and a network-based connectivity approach using constrained spherical deconvolution (CSD)-tractography were used to assess group differences in diffusion kurtosis imaging (DKI) and DTI metrics.ResultsVBA showed lower mean kurtosis in the corona radiata and posterior association fibers in BD following threshold-free cluster enhancement. Regional differences in connectivity were indicated by lower mean kurtosis and kurtosis anisotropy in streamlines traversing the temporal and occipital lobes, and lower mean axial kurtosis in the right cerebellar, thalamo-subcortical pathways in BD. Significant differences were not seen in the DTI metrics following FDR- correction.ConclusionsDifferences between BD and controls were observed in DKI metrics in multiple brain regions, indicating altered connectivity across cortical, subcortical and cerebellar areas. DKI was more sensitive than DTI at detecting these differences, suggesting that DKI is useful for investigating white matter in BD.
A Remote Household-Based Approach to Influenza Self-Testing and Antiviral Treatment
Authors: Heimonen Jessica , McCulloch Denise J. , O’Hanlon Jessica , Kim Ashley E. , Emanuels Anne , Wilcox Naomi , Brandstetter Elisabeth , Stewart Mark , McCune David , Fry Scott , Parsons Sean , Hughes James P. , Jackson Michael L. , Uyeki Timothy M. , Boeckh Michael , Starita Lea M. , Bedford Trevor , Englund Janet A. , Chu Helen Y. 
Published: February 2021

AbstractBackgroundHouseholds represent important settings for transmission of influenza and other respiratory viruses. Current influenza diagnosis and treatment relies upon patient visits to healthcare facilities, which may lead to under-diagnosis and treatment delays. This study aimed to assess the feasibility of an at-home approach to influenza diagnosis and treatment via home testing, telehealth care, and rapid antiviral home delivery.MethodsWe conducted a pilot interventional study of remote influenza diagnosis and treatment in Seattle-area households with children during the 2019-2020 influenza season using pre-positioned nasal swabs and home influenza tests. Home monitoring for respiratory symptoms occurred weekly; if symptoms were reported within 48 hours of onset, participants collected mid-nasal swabs and used a rapid home-based influenza immunoassay. An additional home-collected swab was returned to a laboratory for confirmatory influenza RT-PCR testing. Baloxavir antiviral treatment was prescribed and delivered to symptomatic and age-eligible participants, following a telehealth encounter.Results124 households comprising 481 individuals self-monitored for respiratory symptoms, with 58 home tests administered. 12 home tests were positive for influenza, of which 8 were true positives confirmed by RT-PCR. The sensitivity and specificity of the home influenza test was 72.7% and 96.2%, respectively. There were 8 home deliveries of baloxavir, with 7 (87.5%) occurring within 3 hours of prescription, and all within 48 hours of symptom onset.ConclusionsWe demonstrate the feasibility of self-testing combined with rapid home delivery of influenza antiviral treatment. This approach may be an important control strategy for influenza epidemics and pandemics.SummaryIn this pilot study, 481 individuals self-monitored for respiratory symptoms. Of 58 home tests, 12 were influenza-positive. There were 8 baloxavir home deliveries within 48 hours of illness onset. A home-based approach to influenza diagnosis and treatment could be feasible.
The color pattern inducing genewinglessis expressed in specific cell types of campaniform sensilla of a polka-dotted fruit fly,Drosophila guttifera
Authors: Koseki Masato , Tanaka Nobuaki K. , Koshikawa Shigeyuki 
Published: February 2021

AbstractA polka-dotted fruit fly,Drosophila guttifera,has a unique pigmentation pattern on its wings and is used as a model for evo-devo studies exploring the mechanism of evolutionary gain of novel traits. In this species, a morphogen-encoding gene,wingless, is expressed in species-specific positions and induces a unique pigmentation pattern. To produce some of the pigmentation spots on wing veins,winglessis thought to be expressed in developing campaniform sensilla cells, but it was unknown which of the four cell types there express(es)wingless. Here we show that two of the cell types, dome cells and socket cells, expresswingless, as indicated byin situhybridization together with immunohistochemistry. This is a unique case in which non-neuronal SOP (sensory organ precursor) progeny cells produce Wingless as an inducer of pigmentation pattern formation. Our finding opens a path to clarifying the mechanism of evolutionary gain of a uniquewinglessexpression pattern by analyzing gene regulation in dome cells and socket cells.
Short report: Ethnicity and COVID-19 death in the early part of the COVID-19 second wave in England: an analysis of OpenSAFELY data from 1st September to 9th November 2020
Authors: Bhaskaran Krishnan , Mathur Rohini , Rentsch Christopher T , Morton Caroline E , Hulme William J , Schultze Anna , MacKenna Brian , Eggo Rosalind M , Wong Angel YS , Williamson Elizabeth J , Forbes Harriet , Wing Kevin , McDonald Helen I , Bates Chris , Bacon Seb , Walker Alex J , Evans David , Inglesby Peter , Mehrkar Amir , Curtis Helen J , DeVito Nicholas J , Croker Richard , Drysdale Henry , Cockburn Jonathan , Parry John , Hester Frank , Harper Sam , Douglas Ian J , Tomlinson Laurie , Evans Stephen JW , Grieve Richard , Smeeth Liam , Goldacre Ben 
Published: February 2021

SummaryBlack and minority ethnic groups were at raised risk of dying from COVID-19 during the first few months of the COVID-19 epidemic in England. We aimed to investigate whether ethnic inequalities in COVID-19 deaths were similar in the more recent “second wave” of the epidemic. Working on behalf of NHS England, we used primary care and linked ONS mortality data within the OpenSAFELY platform. All adults in the database at 1st September 2020 and with at least 1 year of prior follow-up and a record of ethnicity were included. The outcome was COVID-19-related death (death with COVID-19 listed as a cause of death on the death certificate). Follow-up was to 9th November 2020. Hazard ratios for ethnicity were calculated using Cox regression models adjusted for age and sex, and then further adjusted for deprivation. 13,223,154 people were included. During the study period, people of South Asian ethnicity were at higher risk of death due to COVID-19 than white people after adjusting for age and sex (HR = 3.47, 95% CI 2.99-4.03); the association attenuated somewhat on further adjustment for index of multiple deprivation (HR = 2.86, 2.46-3.33, Table 2). In contrast with the first wave of the epidemic, we found little evidence of a raised risk in black or other ethnic groups compared to white (HR for black vs white = 1.28, 0.87-1.88 adjusted for age and sex; and 1.01, 0.69-1.49 further adjusted for deprivation). Our findings suggest that ethnic inequalities in the risk of dying COVID-19-related death have changed between the first and early second wave of the epidemic in England.
Effect of co-infection with parasites on severity of COVID-19
Authors: Gebrecherkos Teklay , Gessesse Zekarias , Kebede Yazezew , Gebreegzabher Atsbeha , Tasew Geremew , Abdulkader Mahmud , Ebuy Hiluf , Desta Abraham , Hailu Atakilti , Harris Vanessa , de Wit Tobias Rinke , Wolday Dawit 
Published: February 2021

SummaryBackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in a spectrum of clinical presentations. The effect of co-infection with parasites on the clinical features of COVID-19 is unknown.MethodsWe prospectively enrolled consecutive COVID-19 patients and screened them for intestinal parasitic infections. Patients were followed during hospitalization for clinical outcomes. Patients with parasitic co-infection were compared to those without parasitic co-infection. The primary outcome was the proportion of COVID-19 patients who developed severe disease. Factors associated with the development of severe disease were determined by logistic regression.ResultsA total of 515 patients with PCR-confirmed SARS-CoV-2 infection were screened for intestinal parasites, of whom 267 (51.8%) were co-infected with one or more parasites. Parasitic co-infection correlated inversely with COVID-19 severity. Severe COVID-19 was significantly higher in patients without parasites [47/248 (19.0%, CI: 14.52-24.35)] than in those with parasites [21/267 (7.9%, CI: 5.17-11.79)]; p<0.0001. There was a significantly higher proportion of patients who developed severe COVID-19 in the non-protozoa group [56/369 (15.2%, CI: 11.85-19.23)] as compared to the protozoa group [12/146 (8.2%, CI: 4.70-14.00)]; p=0.036. Significant higher proportion of the patients presented at baseline with severe COVID-19 in the helminth negative group [57/341 (16.7%, CI: 13.10 – 21.08)] than in the group with pre-existing helminth infection [11/174 (6.3%, CI: 3.51 – 11.11)]; p=0.001. In addition, after adjustment for age and presence of comorbidities, COVID-19 patients with any parasite co-infection [aOR 0.41 (95% CI: 0.22–0.77); p=0.006], or with protozoa co-infection [aOR 0.45 (95% CI: 0.21–0.98); p=0.044] as well as those with helminth co-infection [aOR 0.37 (95% CI: 0.17–0.80); p=0.011] had lower probability of developing severe COVID-19 compared with those without parasite, protozoa or helminth co-infection.ConclusionOur results suggest that co-infection with parasitic co-infection appears to be associated with reduced COVID-19 severity. The results suggest that parasite-driven immunomodulatory responses may mute hyperinflammation associated with severe COVID-19.
Periodontal inflammation mediates the link between homocysteine and high blood pressure
Authors: Botelho João , Machado Vanessa , Leira Yago , Proença Luís , Mendes José João 
Published: February 2021

ABSTRACTBackgroundHere, we assess the association between Hcy serum levels and periodontal status in a large representative sample of the National Health and Nutrition Examination Survey (NHANES).MethodsWe included 4,021 participants with a periodontal examination, medical self-reported data, BP and blood samples to determine complete blood count, C-reactive protein (CRP) and Hcy levels. We then calculated the periodontal inflamed surface area (PISA) and the periodontal epithelial surface area (PESA). Multivariable regression analysis explored the association between Hcy, periodontal measures and blood pressure. Mediation analysis was performed to understand the effect of age on the association of periodontitis with BP. Mediation analysis assessed the effect of PISA and PESA in the link between Hcy and BP.Results4,021 participants fulfilled the inclusion criteria. Hcy levels showed significant correlations with systolic BP, diastolic BP, PISA, PESA and age. PESA showed to be significantly associated with Hcy both for the crude and adjusted models (p<0.01), but not PISA (p>0.05). In the association of Hcy with systolic BP, PISA significantly mediated 17.4% and PESA 0.9%. In the association of Hcy with diastolic BP, PISA significantly mediated 16.3% and PESA 47.2%.ConclusionsThis report shows that Hcy and periodontitis are associated. Also, both PISA and PESA significantly mediated the association of Hcy with systolic BP and diastolic BP. Future studies shall deepen the mechanisms by which homocysteine levels increase in a clinical situation of periodontitis.One-sentence summary describing the key finding(s) from the studyHomocysteine and periodontitis are associated. The periodontal inflamed and epithelial surface areas significantly mediate the association of homocysteine with systolic and diastolic blood pressures.
Home Food Procurement Impacts Food Security and Diet Quality during COVID-19
Authors: Niles Meredith T. , Wirkkala Kristen Brassard , Belarmino Emily H. , Bertmann Farryl 
Published: February 2021

AbstractBackgroundHome food procurement (HFP) (i.e. gardening, fishing, foraging, hunting, backyard livestock and canning) have historically been important ways that people obtain food. Recently, some HFP activities have grown (e.g. gardening), while other activities (e.g. hunting) have become less common in the United States. Anecdotally, COVID-19 has sparked an increase in HFP evidenced by increased hunting licenses and shortages in seeds and canning supplies. HFP may have positive benefits for food security and diet quality, though research beyond gardening is especially limited in high-income countries.MethodsWe examine HFP activities before and since the COVID-19 pandemic, and their relationship to food security and dietary quality using multivariable logit models and matching analysis with a statewide representative survey (n=600) of residents of Vermont, United States.ResultsWe find 29% of respondent households classified as food insecure since COVID-19, and more prevalence among those experiencing a negative job change since COVID-19, households earning less than $50,000 annually, Hispanic and multi-race respondents. Forty-two percent of respondents engaged in HFP activities; the majority of those gardened, and more than half pursued HFP activities more intensely than before the pandemic. HFP was more common among food insecure households, who were more likely to fish, forage, hunt and have backyard livestock. Respondents who were food insecure, Black, Indigenous, People of Color and/or Hispanic, those with a negative job disruption, and larger households all had greater odds of increased intensity of HFP since COVID-19. HFP were significantly associated with eating greater amounts of fruits and vegetables, especially if gardening and canning, while respondents hunting or having backyard livestock were significantly more likely to have higher red meat intake.ConclusionOverall, these results suggest that HFP activities have increased since the start of the COVID-19 pandemic, and may be an important safety net for food insecure households, and provide diet quality impacts. Long-term, HFP activities may have important food security and diet quality impacts, as well as conservation implications, which should be more thoroughly explored. Regardless, the increased interest and intensity of HFP demonstrates multiple opportunities for educational and outreach efforts.