bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ronapreve (REGN-CoV; casirivimab and imdevimab) reduces the viral burden and alters the pulmonary response to the SARS-CoV-2 Delta variant (B.1.617.2) in K18-hACE2 mice using an experimental design reflective of a treatment use case
Authors: Tatham Lee , Kipar Anja , Sharp Joanne , Kijak Edyta , Herriott Joanne , Neary Megan , Box Helen , Gallardo Toledo Eduardo , Valentijn Anthony , Cox Helen , Pertinez Henry , Curley Paul , Arshad Usman , Rajoli Rajith KR , Rannard Steve , Stewart James , Owen Andrew 
Published: January 2022

AbstractBackgroundRonapreve demonstrated clinical application in post-exposure prophylaxis, mild/moderate disease and in the treatment of seronegative patients with severe COVID19 prior to the emergence of the Omicron variant in late 2021. Numerous reports have described loss ofin vitroneutralisation activity of Ronapreve and other monoclonal antibodies for BA.1 Omicron and subsequent sub-lineages of the Omicron variant. With some exceptions, global policy makers have recommended against the use of existing monoclonal antibodies in COVID19. Gaps in knowledge regarding the mechanism of action of monoclonal antibodies are noted, and further preclinical study will help understand positioning of new monoclonal antibodies under development.ObjectivesThe purpose of this study was to investigate the impact of Ronapreve on compartmental viral replication as a paradigm for a monoclonal antibody combination. The study also sought to confirm absence ofin vivoactivity against BA.1 Omicron (B.1.1.529) relative to the Delta (B.1.617.2) variant.MethodsVirological efficacy of Ronapreve was assessed in K18-hACE2 mice inoculated with either the SARS-CoV-2 Delta or Omicron variants. Viral replication in tissues was quantified using qRT-PCR to measure sub-genomic viral RNA to the E gene (sgE) as a proxy. A histological examination in combination with staining for viral antigen served to determine viral spread and associated damage.ResultsRonapreve reduced sub-genomic viral RNA levels in lung and nasal turbinate, 4 and 6 days post infection, for the Delta variant but not the Omicron variant of SARS-CoV-2 at doses 2-fold higher than those shown to be active against previous variants of the virus. It also appeared to block brain infection which is seen with high frequency in K18-hACE2 mice after Delta variant infection. At day 6, the inflammatory response to lung infection with the Delta variant was altered to a mild multifocal granulomatous inflammation in which the virus appeared to be confined. A similar tendency was also observed in Omicron infected, Ronapreve-treated animals.ConclusionsThe current study provides evidence of an altered tissue response to the SARS-CoV-2 after treatment with a monoclonal antibody combination that retains neutralization activity. These data also demonstrate that experimental designs that reflect the treatment use case are achievable in animal models for monoclonal antibodies deployed against susceptible variants. Extreme caution should be taken when interpreting prophylactic experimental designs when assessing plausibility of monoclonal antibodies for treatment use cases.
Structural basis for the neurotropic AAV9 and the engineered AAVPHP.eB recognition with cellular receptors
Authors: Xu Guangxue , Zhang Ran , Li Huapeng , Yin Kaixin , Ma Xinyi , Lou Zhiyong 
Published: January 2022

AbstractClade F adeno-associated virus (AAV) 9 has been utilized as therapeutic gene delivery vector, and it is capable of crossing blood brain barrier (BBB). Recently, an AAV9 based engineering serotype with enhanced BBB crossing ability, AAVPHP.eB, further expand clade F AAVs’ usages in the central nervous system (CNS) gene delivery. In this study, we determined the cryo-electron microscopy (cryo-EM) structures of the AAVPHP.eB, and its parental serotype AAV9 alone or in complex with their essential receptor Adeno-associated virus receptor (AAVR). These structures reveal the molecular details of their AAVR recognition, where the polycystic kidney disease (PKD) repeat domain 2 (PKD2) of AAVR interact to the 3-fold protrusions and the raised capsid regions between the 2- and 5-fold axes termed the 2/5-fold wall of both AAV9 and AAVPHP.eB virions. The interacting patterns of AAVR to AAV9 and AAVPHP.eB are similar with what was observed in AAV1/AAV2-AAVR complexes. Moreover, we found that AAVPHP.eB variable region VIII (VR-VIII) may independently facilitate the new receptor recognition responsible for enhanced CNS transduction. Our study provides insights into different receptor recognition for engineered AAVPHP.eB and parental serotype AAV9, and further reveal the potential molecular basis underlying their different tropism.
Latent circuit inference from heterogeneous neural responses during cognitive tasks
Authors: Langdon Christopher , Engel Tatiana A. 
Published: January 2022

ABSTRACTHigher cortical areas carry a wide range of sensory, cognitive, and motor signals supporting complex goal-directed behavior. These signals are mixed in heterogeneous responses of single neurons tuned to multiple task variables. Dimensionality reduction methods used to analyze neural responses rely merely on correlations, leaving unknown how heterogeneous neural activity arises from connectivity to drive behavior. Here we present a framework for inferring a low-dimensional connectivity structure—the latent circuit—from high-dimensional neural response data. The latent circuit captures mechanistic interactions between task variables and their mixed representations in single neurons. We apply the latent circuit inference to recurrent neural networks trained to perform a context-dependent decision-making task and find a suppression mechanism in which contextual representations inhibit irrelevant sensory responses. We validate this mechanism by confirming the behavioral effects of patterned connectivity perturbations predicted by the latent circuit structure. Our approach can reveal interpretable and causally testable circuit mechanisms from heterogeneous neural responses during cognitive tasks.
Quantitative clonal analysis reveals vast heterogeneity among fallopian tube cells for ovarian cancer-initiation and progression
Authors: Zeng Jianhao , Alvarez-Yela Astrid Catalina , Casarez Eli , Jiang Ying , Wang Lixin , Kelly Brianna E. , Ke Eugene , Jenkins Taylor , Atkins Kristen A. , Janes Kevin A. , Slack-Davis Jill K. , Zong Hui 
Published: January 2022

SummaryDifferent cellular compartments within a tissue present distinct cancer-initiating capacities. Current approaches to delineate cancer-initiating heterogeneity require a well-understood lineage hierarchy and cell-specific genetic tools, which are lacking for many tissues. Here, we circumvented this hurdle and investigated the capacity of fallopian tube cells in initiating serous ovarian cancer, utilizing a mouse genetic system that generates scattered GFP-labeled mutant cells. Through quantitative tracing of clonal expansion of individual mutant cells, we revealed that only a rare primitive subset enriched in the distal fallopian tube is capable of clonal expansion whereas others stall immediately upon acquiring oncogenic mutations. Expanded clones from this subset then encountered further attrition: many stalled shortly after while others sustained small cluster of proliferative cells and biased differentiation toward primitive fate. Taken together, our study showcases quantitative clonal tracing as a powerful approach to investigate cancer-initiating heterogeneity and clonal trajectory in tissues with limited prior knowledge.
A qualitative study exploring the impact of the COVID-19 pandemic on People Who Inject Drugs (PWID) and drug service provision in the UK: PWID and service provider perspectives
Authors: May Tom , Dawes Jo , Fancourt Daisy , Burton Alexandra 
Published: January 2022

AbstractBackgroundPeople Who Inject Drugs (PWID) are subject to distinct socio-structural inequalities that can expose them to high risks of COVID-19 transmission and related health and social complications. In response to COVID-19 mitigation strategies, these vulnerabilities are being experienced in the context of adapted drug treatment service provision, including reduced in-person support and increased regulatory flexibility in opioid substitution therapy (OST) guidelines. This study aimed to explore the longer-term impact of the pandemic on the health and wellbeing of PWID in the UK, including provider and client experiences of treatment changes.MethodsInterviews were conducted with 19 PWID and 17 drug treatment providers between May – September 2021, recruited from third-sector drug services in the UK. Data were analysed using reflexive thematic analysis.ResultsMost participants expressed ongoing fears of COVID-19 transmission, although socio-structural inequalities limited the contexts in which physical distancing could be practised. In addition, virus mitigation strategies altered the risk environment for PWID, resulting in ongoing physical (e.g. changing drug use patterns, including transitions to crack cocaine, benzodiazepine and pregabalin use) and socio-economic harms (e.g. limited opportunities for sex work engagement and income generation). Finally, whilst clients reported some favourable experiences from service adaptations prompted by COVID-19, including increased regulatory flexibility in OST guidelines, there was continued scepticism and caution among providers toward sustaining any treatment changes beyond the pandemic period.ConclusionsWhilst our findings emphasize the importance of accessible harm reduction measures attending to changing indices of drug-related harm during this period, there is a need for additional structural supports to ensure pre-existing disparities and harms impacting PWID are not exacerbated further by the conditions of the pandemic. In addition, any sustained policy and service delivery adaptations prompted by COVID-19 will require further attention if they are to be acceptable to both service users and providers.
Prediction of Hospital Outpatient Attendance in UK Hospitals: A Retrospective Study Applying Machine Learning to Routinely Collected Data for Patients of All Ages
Authors: Holdship Jonathan , Dhanoa Harpreet , Hopper Adrian , Steves Claire J. , Butler Mark , Wolfe Ingrid , Tucker Katie , Cooper Carolyn , Yates Jeremy 
Published: January 2022

AbstractObjectivesPatient non-attendance at outpatient appointments is a major concern for healthcare providers. Non-attendances increase waiting lists, reduce access to care and may be detrimental not for the patient who did not attend. We aim to produce a model which can accurately predict which appointments will be attended.SettingA teaching hospital in London, UK combining secondary and tertiary care.ParticipantsA set of 9.6 million outpatient appointments between April 2015 and September 2019 including all ages and specialities.Primary and secondary outcome measuresArea under the receiver operating characteristic curve (AU-ROC) for prediction of outpatient appointment non-attendances.ResultsThe model uses 27 predictors to achieve an AUROC score of 0.768 (95% CI: 0.767-0.769) and accuracy of 89.2% (95% CI: 89.16%-89.24%) on test data. We find that the waiting period between booking and the appointment, the patient’s past attendance behaviour, and the levels of deprivation in their local area are important factors in predicting future attendance.ConclusionOur model successfully predicts patient attendance at outpatient appointments. Its performance on both patients who did not appear in the training data and appointments from a different time period which covers the Covid-19 pandemic indicate it generalized well across both face to face and virtual appointments and could be used to target resources and intervention towards those patients who are likely to miss an appointment. Moreover, it highlights the impact of deprivation on patient access to healthcareStrengths and Limitation of this StudyWe make use of a large dataset which enables us to use complex machine learning algorithms.We validate the model on two large, distinct datasets giving high confidence in our model performance.An unknown amount of patient data is missing due to a nearby hospital which shares patients with the study setting.
SARS-CoV-2 viremia precedes an IL6 response in severe COVID-19 patients: results of a longitudinal prospective cohort
Authors: Roy-Vallejo Emilia , Cardeñoso Laura , Triguero-Martínez Ana , Llano Marta Chicot , Zurita Nelly , Ávalos Elena , Barrios Ana , Hernando Julia , Ortiz Javier , Rodríguez-García Sebastián C. , Sañudo Marianela Ciudad , Marcos Celeste , Castillo Elena García , García-Rodrigo Leticia Fontán , González Begoña , Méndez Rosa , Iturrate Isabel , Sanz-García Ancor , Villa Almudena , Azofra Ana Sánchez , Quicios Begoña , Arribas David , Rodríguez Jesús Álvarez , Patiño Pablo , Trigueros Marina , Uriarte Miren , Martín-Ramírez Alexandra , Arévalo Román Cristina , Galván-Román José María , García-Vicuña Rosario , Ancochea Julio , Calleja Cecilia Muñoz , Fernández-Ruiz Elena , de la Cámara Rafael , Fernández Carmen Suárez , Álvaro Isidoro González , Rodríguez Serrano Diego A. 
Published: January 2022

AbstractBackgroundInterleukin 6 (IL6) levels and SARS-CoV-2 viremia have been correlated with COVID-19 severity. The association over time between them has not been assessed in a prospective cohort. Our aim was to evaluate the relationship between SARS-CoV-2 viremia and time evolution of IL6 levels in a COVID-19 prospective cohort.MethodsSecondary analysis from a prospective cohort including COVID-19 hospitalized patients from Hospital Universitario La Princesa between November 2020 and January 2021. Serial plasma samples were collected from admission until discharge. Viral load was quantified by Real-Time Polymerase Chain Reaction and IL6 levels with an enzyme immunoassay. To represent the evolution over time of both variables we used the graphic command twoway of Stata.ResultsA total of 57 patients were recruited, with median age of 63 years (IQR [53-81]), 61.4% male and 68.4% caucasian. The peak of viremia appeared shortly after symptom onset in patients with persistent viremia (more than 1 sample with >1.3 log10 copies/ml) and also in those with at least one IL6>30 pg/ml, followed by a progressive increase in IL6 around 10 days later. Persistent viremia in the first week of hospitalization was associated with higher levels of IL6. Both IL6 and SARS-CoV-2 viral load were higher in males, with a quicker increase with age.ConclusionsIn those patients with worse outcomes, an early peak of SARS-CoV-2 viral load precedes an increase in IL6 levels. Monitoring SARS-CoV-2 viral load during the first week after symptom onset may be helpful to predict disease severity in COVID-19 patients.
The Choice of Response Alternatives in COVID-19 Social Science Surveys
Authors: Wright Daniel B. , Wolff Sarah M. , Jaspal Rusi , Barnett Julie , Breakwell Glynis M. 
Published: January 2022

AbstractSocial science research is key for understanding and for predicting compliance with COVID-19 guidelines, and much of this research relies on survey data. While much focus is on the survey question stems, less is on the response alternatives presented that both constrain responses and convey information about the assumed expectations of the survey designers. The focus here is on the choice of response alternatives for the types of behavioral frequency questions used in many COVID-19 and other health surveys. We examine issues with two types of response alternatives. The first are vague quantifiers, like “rarely” and ‘frequently.” Using data from 30 countries from the Imperial COVID data hub, we show that the interpretation of these vague quantifiers (and their translations) depends on the norms in that country. If the mean amount of hand washing in your country is high, it is likely “frequently” corresponds to a higher numeric value for hand washing than if the mean in your country is low. The second type are precise numeric response alternatives and they can also be problematic. Using a US survey, respondents were randomly allocated to receive either response alternatives where most of the scale corresponds to low frequencies or where most of the scale corresponds to high frequencies. Those given the low frequency set provided lower estimates of the health behaviors. The choice of response alternatives for behavioral frequency questions can affect the estimates of health behaviors. How the response alternatives mold the responses should be taken into account for epidemiological modeling. We conclude with some recommendations for response alternatives for health behavioral frequency questions in surveys.
Modelling preventive measures and their effect on generation times in emerging epidemics
Authors: Favero Martina , Tomba Gianpaolo Scalia , Britton Tom 
Published: January 2022

AbstractWe present a stochastic epidemic model to study the effect of various preventive measures, such as uniform reduction of contacts and transmission, vaccination, isolation, screening and contact tracing, on a disease outbreak in a homogeneously mixing community. The model is based on an infectivity process, which we define through stochastic contact and infectiousness processes, so that each individual has an independent infectivity profile. In particular, we monitor variations of the reproduction number and of the distribution of generation times. We show that some interventions, i.e. uniform reduction and vaccination, affect the former while leaving the latter unchanged, whereas other interventions, i.e. isolation, screening and contact tracing, affect both quantities. We provide a theoretical analysis of the variation of these quantities, and we show that, in practice, the variation of the generation time distribution can be significant and that it can cause biases in the estimation of basic reproduction numbers. The framework, because of its general nature, captures the properties of many infectious diseases, but particular emphasis is on COVID-19, for which numerical results are provided.
The Hyaloperanospora arabidopsidis effector HaRxL77 is hypermobile between cells and manipulates host defence
Authors: Liu Xiaokun , Bellandi Annalisa , Johnston Matthew G. , Faulkner Christine 
Published: January 2022

AbstractMulticellular organisms require dynamic communication between cells, tissues and organs to integrate responses to external and internal signals. In plants, cell-to-cell communication relies in part on plasmodesmata, which connect adjacent cells and allow the exchange of signals and resources. Upon infection by pathogens, plants act to isolate infected cells from non-infected cells by closing plasmodesmata but pathogens can suppress this defence and maintain plasmodesmata in an open state. To address the question of what a pathogen might gain from keeping plasmodesmata open, we screened effectors from the biotrophic Arabidopsis pathogen Hyaloperonospora arabidopsidis (Hpa) for the ability to move cell-to-cell via plasmodesmata in plant tissues. We quantified the mobility of cytoplasmic effectors and identified six that were hypermobile, i.e., can move further than expected for a protein of that size. Of these, HaRxL77 indirectly modifies plasmodesmatal permeability to facilitate hypermobility and suppresses the flg22-induced ROS burst, suggesting that cell-to-cell mobility of effectors allows defence manipulation ahead of the infection front. Thus, this study provides novel insights into how Hpa exploits plasmodesmata-mediated intercellular connectivity to promote infection, characterising a poorly explored element of plant-pathogen interaction.Author SummaryDuring infection, pathogens secrete effectors into host cells to manipulate them for their benefit. Plant cells are connected via plasmodesmata, and pathogen effectors can use these connections to reach uninfected cells. We asked what a pathogen might gain by having effectors that can travel between cells and thus screened Arabidopsis downy mildew effectors for this capability. We found downy mildew produces many cell-to-cell mobile effectors, and that some of these can move further than we might expect. One ‘hypermobile’ effector, HaRxL77, can open plasmodesmata to allow this increased mobility, although how it does this is not clear. HaRxL77 interferes with several host defence mechanisms, suggesting that cell- to-cell mobility allows effectors to perturb host defence ahead of the infection front.
Post-embryonic maturation of the C. elegans motor circuit
Authors: Mulcahy Ben , Witvliet Daniel , Mitchell James , Schalek Richard , Berger Daniel , Wu Yuelong , Holmyard Doug , Lu Yangning , Ahamed Tosif , Samuel Aravinthan , Chisholm Andrew D , Lichtman Jeff , Zhen Mei 
Published: January 2022

SummaryDuring development, animals can maintain behavioral output even as the underlying circuits structurally remodel. After hatching, C. elegans undergoes substantial motor neuron expansion and synapse re-wiring while the animal continuously moves with an undulatory pattern. To understand how the circuit transitions from its juvenile to mature configuration without disrupting functional output, we reconstructed the C. elegans motor circuit by electron microscopy across larval development. We observed: 1) Embryonic motor neurons transiently interact with the developing post-embryonic motor neurons prior to remodeling of their juvenile wiring; 2) Post-embryonic neurons initiate synapse development with their future partners as their neurites navigate through the juvenile nerve cords; 3) Embryonic and post-embryonic neurons sequentially build structural machinery needed for the adult circuit before the embryonic neurons relinquish their roles to post-embryonic neurons; 4) This transition is repeated region by region along the body in an anterior to posterior sequence, following the birth order of post-embryonic neurons. Through this orchestrated, programmed and gradual rewiring, the motor circuit transforms from asymmetric to symmetric wiring. These maturation strategies support the continuous maintenance of motor patterns as the juvenile circuit develops into the adult configuration.HighlightsPost-embryonic motor circuit maturation was reconstructed by synapse-resolution serial EM.Motor patterns are maintained as the circuit matures from asymmetric to symmetric configuration.Programmed rewiring gradually and sequentially transforms the circuit structure.Preparatory and communicative wiring-rewiring allows maturation without functional disruption.