bluuebunny/crossref_metadata_2025_split huggingface dataset:
A renewal equation model to assess roles and limitations of contact tracing for disease outbreak control
Authors: Scarabel Francesca , Pellis Lorenzo , Ogden Nicholas H. , Wu Jianhong 
Published: January 2021

AbstractWe propose a deterministic model capturing essential features of contact tracing as part of public health non-pharmaceutical interventions to mitigate an outbreak of an infectious disease. By incorporating a mechanistic formulation of the processes at the individual level, we obtain an integral equation (delayed in calendar time and advanced in time since infection) for the probability that an infected individual is detected and isolated at any point in time. This is then coupled with a renewal equation for the total incidence to form a closed system describing the transmission dynamics involving contact tracing. We define and calculate basic and effective reproduction numbers in terms of pathogen characteristics and contact tracing implementation constraints. When applied to the case of SARS-CoV-2, our results show that only combinations of diagnosis of symptomatic infections and contact tracing that are almost perfect in terms of speed and coverage can attain control, unless additional measures to reduce overall community transmission are in place. Under constraints on the testing or tracing capacity, a temporary interruption of contact tracing may, depending on the overall growth rate and prevalence of the infection, lead to an irreversible loss of control even when the epidemic was previously contained.
Sodium intake and high blood pressure among adults on caloric restriction: a multi-year cross-sectional analysis of the U.S. Population, 2007-2018
Authors: Delgado-Ron Jorge Andrés , López-Jaramillo Patricio , Karim Mohammad Ehsanul 
Published: January 2021

Abstract and KeywordsAimSmall studies have shown reduced sodium sensitivity of blood pressure in obese adolescents on caloric restriction. However, no study at the population level has studied such an effect. We aimed to explore the association between mean daily sodium intake and prevalent hypertension among a nationally representative sample of U.S. adults on caloric restriction who participated in the National Health Examination and Nutrition Survey over the last twelve years.Methods and ResultsWe used a design-based regression model to explore the association between sodium intake and prevalent hypertension. We also conducted sensitivity analyses using multiple imputation chained equations and propensity score matching. We also measured the effect of a binary exposure derived from two widely recommended thresholds of sodium intake: 2.3 and 5.0 grams per day. Among 5,756 individuals, we did not detect any significant association between increased sodium and the odds of hypertension (OR: 0.97; CI 95%: 0.90; 1.05). All our sensitivity analyses are consistent with our main findings.ConclusionOur findings suggest that people on caloric restriction—a component of healthy weight loss—would see no benefit in reducing sodium intake to lower blood pressure. These results highlight the need to explore new population-specific strategies for sodium intake reduction, including new dietary prescription approaches to improve dietary adherence and reduce the risk associated with sodium-deficient diets.
Determinants of in-hospital mortality in COVID-19; a prospective cohort study from Pakistan
Authors: Sarfaraz Samreen , Shaikh Quratulain , Saleem Syed Ghazanfar , Rahim Anum , Herekar Fivzia Farooq , Junejo Samina , Hussain Aneela 
Published: January 2021

SummaryA prospective cohort study was conducted at the Indus Hospital Karachi, Pakistan between March and June 2020 to describe the determinants of mortality among hospitalized COVID-19 patients. 186 adult patients were enrolled and all-cause mortality was found to be 36% (67/186). Those who died were older and more likely to be males (p<0.05). Temperature and respiratory rate were higher among non-survivors while Oxygen saturation was lower (p<0.05). Serum CRP, D-dimer and IL-6 were higher while SpO2 was lower on admission among non-survivors (p<0.05). Non-survivors had higher SOFA and CURB-65 scores while thrombocytopenia, lymphopenia and severe ARDS was more prevalent among them (p<0.05). Use of non-invasive ventilation in emergency room, ICU admission and invasive ventilation were associated with mortality in our cohort (p<0.05). Length of hospital stay and days of intubation were longer in non-survivors (p<0.05). Use of azithromycin, hydroxychloroquine, steroids, tocilizumab, antibiotics, IVIG or anticoagulation showed no mortality benefit (p>0.05). Multivariable logistic regression showed that age > 60 years, oxygen saturation <93% on admission, pro-calcitonin > 2 ng/ml, unit rise in temperature and SOFA score, ICU admission and sepsis during hospital stay were associated with higher odds of mortality. Larger prospective studies are needed to further strengthen these findings.Key FindingsAge greater than 60 years is associated with in-hospital mortality among COVID-19 patientsOxygen saturation less than 93% and ICU admission are associated with higher odds of mortalityInflammatory markers including CRP, Ferritin and IL-6 were significantly higher among non-survivorsSerum pro-calcitonin greater than 2 ng/ml and sepsis during hospital stay are associated with higher odds of mortality among COVID-19 patients
Identifying, Protecting and Managing Stopover Habitats for Wild Whooping Cranes on U.S. Army Corps of Engineers Lakes
Authors: McConnell Chester 
Published: January 2021

AbstractThe Whooping Crane(Grus americana)is one of North America’s most endangered species. There is only one wild, self-sustaining migratory population of Whooping Cranes, the Aransas–Wood Buffalo population (AWBP). The birds of the AWBP migrate 4,000 km twice each year between their nesting grounds in northern Canada and their wintering grounds on the Texas Gulf Coast. During migration, AWBP Whooping Cranes must land at suitable ponds or wetlands to forage, rest or roost. The Whooping Crane Recovery Plan, developed by federal wildlife agencies in Canada and the USA, calls for the protection and management of Whooping Crane stopover locations within the migration corridor. Although major stopover areas have been protected, many other smaller sites remain to be identified. However, the Recovery Plan offers no specific entity to identify, protect and manage the latter. To address these deficiencies in information and activity, Friends of the Wild Whoopers partnered with the United States Army Corps of Engineers (USACE) within the AWBP migration corridor to share information about Whooping Cranes and their habitat needs and identify potential stopover locations on USACE properties that could be protected and managed for cranes. This partnership identified 624 potential stopover sites on 34 USACE lakes, principally in North and South Dakota, Nebraska, Kansas, Oklahoma and Texas, with commitments to manage the habitats as resources allow.
Knowledge graph analytics platform with LINCS and IDG for Parkinson’s disease target illumination
Authors: Yang Jeremy J , Gessner Christopher R , Duerksen Joel L , Biber Daniel , Binder Jessica L , Ozturk Murat , Foote Brian , McEntire Robin , Stirling Kyle , Ding Ying , Wild David J 
Published: January 2021

AbstractBackgroundLINCS, “Library of Integrated Network-based Cellular Signatures”, and IDG, “Illuminating the Druggable Genome”, are both NIH projects and consortia that have generated rich datasets for the study of the molecular basis of human health and disease. LINCS L1000 expression signatures provide unbiased systems/omics experimental evidence. IDG provides compiled and curated knowledge for illumination and prioritization of novel drug target hypotheses. Together, these resources can support a powerful new approach to identifying novel drug targets for complex diseases, such as Parkinson’s disease (PD), which continues to inflict severe harm on human health, and resist traditional research approaches.ResultsIntegrating LINCS and IDG, we built the Knowledge Graph Analytics Platform (KGAP) to support an important use case: identification and prioritization of drug target hypotheses for associated diseases. The KGAP approach includes strong semantics interpretable by domain scientists and a robust, high performance implementation of a graph database and related analytical methods. Illustrating the value of our approach, we investigated results from queries relevant to PD. Approved PD drug indications from IDG’s resource DrugCentral were used as starting points for evidence paths exploring chemogenomic space via LINCS expression signatures for associated genes, evaluated as target hypotheses by integration with IDG. The KG-analytic scoring function was validated against a gold standard dataset of genes associated with PD as elucidated, published mechanism-of-action drug targets, also from DrugCentral. IDG’s resource TIN-X was used to rank and filter KGAP results for novel PD targets, and one, SYNGR3 (Synaptogyrin-3), was manually investigated further as a case study and plausible new drug target for PD.ConclusionsThe synergy of LINCS and IDG, via KG methods, empowers graph analytics methods for the investigation of the molecular basis of complex diseases, and specifically for identification and prioritization of novel drug targets. The KGAP approach enables downstream applications via integration with resources similarly aligned with modern KG methodology. The generality of the approach indicates that KGAP is applicable to many disease areas, in addition to PD, the focus of this paper.
Orchestrated Excitatory and Inhibitory Learning Rules Lead to the Unsupervised Emergence of Self-sustained and Inhibition-stabilized Dynamics
Authors: Soldado-Magraner Saray , Laje Rodrigo , Buonomano Dean V. 
Published: January 2021

ABSTRACTSelf-sustaining neural activity maintained through local recurrent connections is of fundamental importance to cortical function. We show that Up-states—an example of self-sustained, inhibition-stabilized network dynamics—emerge in cortical circuits across three weeks of ex vivo development, establishing the presence of unsupervised learning rules capable of generating self-sustained dynamics. Previous computational models have established that four sets of weights (WE←E, WE←I, WI←E, WI←I) must interact in an orchestrated manner to produce Up-states, but have not addressed how a family of learning rules can operate in parallel at all four weight classes to generate self-sustained inhibition-stabilized dynamics. Using numerical and analytical methods we show that, in part due to the paradoxical effect, standard homeostatic rules are only stable in a narrow parameter regime. In contrast, we show that a family of biologically plausible learning rules based on “cross-homeostatic” plasticity robustly lead to the emergence of self-sustained, inhibition-stabilized dynamics.
Precise genomic deletions using paired prime editing
Authors: Choi Junhong , Chen Wei , Suiter Chase C. , Lee Choli , Chardon Florence M. , Yang Wei , Leith Anh , Daza Riza M. , Martin Beth , Shendure Jay 
Published: January 2021

AbstractTechnologies that precisely delete genomic sequences in a programmed fashion can be used to study function as well as potentially for gene therapy. The leading contemporary method for programmed deletion uses CRISPR/Cas9 and pairs of guide RNAs (gRNAs) to generate two nearby double-strand breaks, which is often followed by deletion of the intervening sequence during DNA repair. However, this approach can be inefficient and imprecise, with errors including small indels at the two target sites as well as unintended large deletions and more complex rearrangements. Here we describe a prime editing-based method that we termPRIME-Del, which induces a deletion using a pair of prime editing gRNAs (pegRNAs) that target opposite DNA strands, effectively programming not only the sites that are nicked but also the outcome of the repair. We demonstrate thatPRIME-Delachieves markedly higher precision in programming deletions than CRISPR/Cas9 and gRNA pairs. We also show thatPRIME-Delcan be used to couple genomic deletions with short insertions, enabling deletions whose junctions do not fall at protospacer-adjacent motif (PAM) sites. Finally, we demonstrate that lengthening the time window of expression of prime editing components can substantially enhance efficiency without compromising precision. We anticipate thatPRIME-Delwill be broadly useful in enabling precise, flexible programming of genomic deletions, including in-frame deletions, as well as for epitope tagging and potentially for programming rearrangements.
Stabilized Supralinear Network: Model of Layer 2/3 of the Primary Visual Cortex
Authors: Obeid Dina , Miller Kenneth D. 
Published: January 2021

AbstractElectrophysiological recording in the primary visual cortex (V1) of mammals have revealed a number of complex interactions between the center and surround. Understanding the underlying circuit mechanisms is crucial to understanding fundamental brain computations. In this paper we address the following phenomena that have been observed in V1 of animals with orientation maps: 1) surround suppression that is accompanied by a decrease in the excitatory and inhibitory currents that the cell receives as the stimulus size increases beyond the cell’s summation field; 2) surround tuning to the center orientation, in which the strongest suppression arises when the surround orientation matches that of the center stimulus; and 3) feature-specific suppression, in which a surround stimulus of a given orientation specifically suppresses that orientation’s component of the response to a center plaid stimulus. We show that a stabilized supralinear network that has biologically plausible connectivity and synaptic efficacies that depend on cortical distance and orientation difference between neurons can consistently reproduce all the above phenomena. We explain the mechanism behind each result, and argue that feature-specific suppression and surround tuning to the center orientation are independent phenomena. Specifically, if we remove some aspects of the connectivity from the model it will still produce feature-specific suppression but not surround tuning to the center orientation. We also show that in the model the activity decay time constant is similar to the cortical activity decay time constant reported in mouse V1. Our model indicates that if the surround activates neurons that fall within the reach of the horizontal projections in V1, the above mentioned phenomena can be generated by V1 alone without the need of cortico-cortical feedback. Finally, we show that these results hold both in networks with rate-based units and with conductance-based spiking units. This demonstrates that the stabilized supra-linear network mechanism can be achieved in the more biological context of spiking networks.
Unbuttoning the impact of N501Y mutant RBD on viral entry mechanism: A computational insight
Authors: Sharma Tanuj , Baig Mohammad Hassan , Rahim Moniba , Dong Jae June , Cho Jae-Yong 
Published: January 2021

AbstractThe ongoing coronavirus disease 2019 (COVID-19) pandemic has become a serious global threat. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus responsible for this pandemic has imposed a severe burden on the medical settings. The spike (S) protein of SARS-CoV-2 is an important structural protein playing a key role in the viral entry. This protein is responsible for the receptor recognition and cell membrane fusion process. The recent reports of the appearance and spread of new SARS-CoV-2 strain has raised alarms. It was reported that this new variant containing the prominent active site mutation in the RBD (N501Y) was rapidly spreading within the population. The reported N501Y mutation within the spike’s essential part, known as the ‘receptor-binding domain’ has raised several questions. Here in this study we have tried to explore the effect of N501Y mutation within the spike protein using several in silico approaches
Major orchestration of shikimate, early phenylpropanoid and stilbenoid pathways by Subgroup 2 R2R3-MYBs in grapevine
Authors: Orduña Luis , Li Miaomiao , Navarro-Payá David , Zhang Chen , Santiago Antonio , Romero Pablo , Ramšak Živa , Magon Gabriele , Höll Janine , Merz Patrik , Gruden Kristina , Vannozzi Alessandro , Cantu Dario , Bogs Jochen , Wong Darren C. J. , Huang Shao-shan Carol , Matus José Tomás 
Published: January 2021

AbstractThe stilbenoid pathway is responsible for the production of resveratrol and its derivatives in grapevine. A few transcription factors (TFs) have been previously identified as regulators of this pathway but the extent of this control is yet to be fully understood. Here we demonstrate how DNA affinity purification sequencing (DAP-Seq) allows for genome-wide TF binding site interrogation in a non-model species. We obtained 5,190 and 4,443 binding events assigned to 4,041 and 3,626 genes for MYB14 and MYB15, respectively (around 40% of peaks being located within -10kb of transcription start sites). DAP-Seq of MYB14 and MYB15 was combined with aggregate gene centred co-expression networks built from more than 1,400 transcriptomic datasets from leaves, fruits and flowers to narrow down bound genes to a set of high confidence targets. The analysis of MYB14, MYB15 and MYB13, a third uncharacterised member of Subgroup 2 (S2), showed that in addition to the few previously known stilbene synthase (STS) targets, these three regulators bind to 30 out of 47STSfamily genes. Moreover all three MYBs bind to severalPAL,C4Hand4CLgenes, in addition to shikimate pathway genes, the WRKY03 stilbenoid co-regulator and novel resveratrol-modifying gene candidates amongst whichROMT2-3were validated enzymatically. A high proportion of DAP-Seq bound genes was induced in the activated transcriptomes of transientMYB15-overexpressing stilbenoid-producing grapevine leaves, validating our methodological approach for identifying gene regulatory networks of specialised metabolism. Overall, MYB genes from Subgroup 2 appear to play a key role in binding and directly regulating several primary and secondary metabolic steps leading to an increased flux towards stilbenoid production.
Genomic insights of high-risk clones of ESBL-producingEscherichia coliisolated from community infections and commercial meat in Southern Brazil
Authors: Soncini João Gabriel Material , Cerdeira Louise , Koga Vanessa Lumi , Tizura Ariane Tiemy , Nakazato Gerson , Kobayashi Renata Katsuko Takayama , Aires Caio Augusto Martins , Lincopan Nilton , Vespero Eliana Carolina 
Published: January 2021

ABSTRACTDuring a microbiological and genomic surveillance study to investigate the molecular epidemiology of extended-spectrum beta-lactamase (ESBL)-producingEscherichia colifrom community-acquired urinary tract infections (UTI) and commercial meat samples, in a Brazilian city with a high occurrence of infections by ESBL-producing bacteria, we have identified the presence of CTX-M (−55, −27, −24, −15, −14 and −2)-producingE. colibelonging to the international clones ST354, ST131, ST117, and ST38. The ST131 was more prevalent in human samples, and worryingly the high-risk ST131-C1-M27 was identified in human infections for the first time. We also detected CTX-M-55-producingE. coliST117 isolates from meat samples (i.e., chicken and pork) and human infections. Moreover, we have identified the important clone CTX-M-24-positiveE. coliST354 from human samples in Brazil for the first time. In brief, our results suggest a potential of commercialized meat as a reservoir of high-priorityE. colilineages in the community. In contrast, the identification ofE. coliST131-C1-M27 indicates that novel pandemic clones have emerged in Brazil, constituting a public health issue.
Novel antibiotic mode of action by repression of promoter isomerisation
Authors: Kerr Leena , Browning Douglas F. , Lemonidis Kimon , Salih Talal , Hunter Iain S. , Suckling Colin J. , Tucker Nicholas P. 
Published: January 2021

AbstractRising levels of antibiotic resistance dictate that new antibiotics with novel modes of action must be found. Here, we investigated the mode of action of a novel antibiotic that is a member of a family of synthetic DNA minor groove binding (MGB) molecules. MGB-BP-3 has successfully completed a Phase II clinical trial in humans as an orally administered drug for the treatment of chronicClostridioides(Clostridium) difficileinfections, where it outperformed the existing benchmark (vancomycin). MGB-BP-3 is active against a variety of Gram-positive pathogens includingStaphylococcus aureus,which was used as the model for this study. The transcriptomic response ofS. aureusto MGB-BP-3 identified downregulated promoters. DNase I and permanganate footprinting demonstrated binding to essential SigA promoters and the inhibition of promoter isomerisation by RNA polymerase holoenzyme. Promoters controlling DNA replication and peptidoglycan biosynthesis are amongst those affected by MGB-BP-3. Thus, MGB-BP-3 binds to and inhibits multiple essential promoters on theS. aureuschromosome, suggesting that evolution of resistance by drug target mutation should be unlikely. In confirmation, laboratory-directed evolution against sub-inhibitory concentrations of MGB-BP-3 resulted in no resistance whereas resistance to the single target RNA-polymerase inhibitor rifampicin arose rapidly.
Insights into Genome Recoding from the Mechanism of a Classic +1-Frameshifting tRNA
Authors: Gamper Howard , Li Haixing , Masuda Isao , Robkis D. Miklos , Christian Thomas , Conn Adam B. , Blaha Gregor , Petersson E. James , Gonzalez Ruben L. , Hou Ya-Ming 
Published: January 2021

ABSTRACTWhile genome recoding using quadruplet codons to incorporate non-proteinogenic amino acids is attractive for biotechnology and bioengineering purposes, the mechanism through which such codons are translated is poorly understood. Here we investigate translation of quadruplet codons by a +1-frameshifting tRNA,SufB2, that contains an extra nucleotide in its anticodon loop. Natural post-transcriptional modification ofSufB2in cells prevents it from frameshifting using a quadruplet-pairing mechanism such that it preferentially employs a triplet-slippage mechanism. We show thatSufB2uses triplet anticodon-codon pairing in the 0-frame to initially decode the quadruplet codon, but subsequently shifts to the +1-frame during tRNA-mRNA translocation.SufB2frameshifting involves perturbation of an essential ribosome conformational change that facilitates tRNA-mRNA movements at a late stage of the translocation reaction. Our results provide a molecular mechanism forSufB2-induced +1 frameshifting and suggest that engineering of a specific ribosome conformational change can improve the efficiency of genome recoding.