bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease
Authors: Kalla R , Adams AT , Bergemalm D , Vatn S , Kennedy NA , Ricanek P , Lindstrom J , Ocklind A , Hjelm F , Ventham NT , Ho GT , Petren C ,   IBD-Character Consortium, Repsilber D , Söderholm J , Pierik M , D’Amato M , Gomollón F , Olbjorn C , Jahnsen J , Vatn MH , Halfvarson J , Satsangi J 
Published: September 2020

SummaryBackgroundSuccess in personalised medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay (PEA) to identify diagnostic and prognostic biomarkers in inflammatory bowel disease (IBD).MethodsWe conducted a prospective case-control study in an inception cohort of 552 patients (328 IBD, 224 non-IBD), profiling proteins recruited across 6 centres. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross validation was used to examine the performance of diagnostic and prognostic proteins.ResultsA total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls including Matrix Metalloproteinase-12 (Holm adjusted p=4.1×10−23) and Oncostatin-M (OSM, p=3.7×10−16). Nine of these proteins associate withcis- germline variation (59 independent SNPs). Fifteen proteins, all members of TNF independent pathways including interleukin-1 and OSM predicted escalation, over a median follow-up of 518 (IQR 224-756) days. Nested cross-validation of the entire data set allows characterisation of 5-protein-models (96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7, and IL8) which define a high-risk subgroup in IBD (HR 3.90, 95% CI: 2.43-6.26), or allows distinct 2, and 3 protein models for UC and CD respectively.ConclusionWe have characterised a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and predicts the evolution of disease over time. The technology could be suitable as a point of care testing in defining risk. Further prospective work is required to characterise the utility of the approach.
Antigen-specific competitive inhibition of CD4+T cell recruitment into the primary immune response
Authors: Spencer Alexandra J. , Smith Adrian L. , de St Groth Barbara Fazekas 
Published: September 2020

AbstractPrevious studies suggest that recruitment of naïve T cells into a program of cell division and differentiation is a highly synchronous process under tight regulation. However it is not known whether antigen availability is the major regulator of this process, or whether other factors such as ongoing responses to unrelated antigens can affect the size of the primary response. We have developed an adoptive transfer system to investigate the efficiency with which additional antigen specific cells are recruited into an ongoing primary immune response. Recruitment of additional cells is an inverse function of the size of the response and is progressively inhibited with time. Cells recruited late into the response proliferate less, and fewer secrete IL-2 and IFN-γ. Thus the size of the response changes very little as a result of late recruitment. The inhibition of recruitment, proliferation and differentiation affects only cells of the same specificity as the ongoing response, indicating that the size of an antigen specific response is independent of any shared factors such as access to APCs, costimulation or cytokines. Thus, during infection, the immune system retains the ability to respond as necessary to secondary infections or antigens not presented until later stages of the response.
The actin nucleator Spir-1 is a virus restriction factor that promotes IRF3 activation
Authors: Torres Alice Abreu , Macilwee Stephanie L. , Rashid Amir , Cox Sarah E. , Albarnaz Jonas D. , Bonjardim Claudio A. , Smith Geoffrey L. 
Published: September 2020

AbstractCellular proteins often have multiple and diverse functions. This is illustrated with protein Spir-1 that is an actin nucleator, but, as shown here, also functions to enhance IRF3 activation downstream of RNA sensing by RIG-I/MDA-5. In human and mouse cells lacking Spir-1, IRF3 activation is impaired, whereas Spir-1 overexpression enhanced IRF3 activation. Furthermore in Spir-1-/-cells, the infectious virus titres and sizes of plaques formed by two viruses that are sensed by RIG-I, vaccinia virus (VACV) and Zika virus, are increased. These observations demonstrate the biological importance of Spir-1 in the response to virus infection. Like cellular proteins, viral proteins also have multiple and diverse functions. Here, we also show that VACV virulence factor K7 binds directly to Spir-1 and that a diphenylalanine motif of Spir-1 is needed for this interaction and for Spir-1-mediated enhancement of IRF3 activation. Thus, Spir-1 is a new virus restriction factor and is targeted directly by an immunomodulatory viral protein that enhances virus virulence and diminishes IRF3 activation.Author SummaryInfection of cells by viruses is sensed by host molecules called pattern recognition receptors (PRRs) that activate signalling pathways leading to an anti-viral response. In turn, viruses express proteins that negate these host responses to mediate escape from the anti-viral response. Here, we report that protein K7 from a large DNA virus called vaccinia virus (VACV), binds to a host cell protein called Spir-1. Spir-1 is known to regulate the assembly of actin filaments inside cells, but here we show that Spir-1 also functions to activate the host response to virus infection and to limit the replication and spread of both RNA and DNA viruses. Thus, this study has uncovered new functions of cellular protein Spir-1 as an activator of innate immunity and as a restriction factor for diverse viruses. Further, it shows that Spir-1 is targeted by a virus protein during infection.
Functional insights from KpfR, a new transcriptional regulator of fimbrial expression that is crucial forKlebsiella pneumoniaepathogenicity
Authors: Gomes Ana E. I. , Pacheco Thaisy , Santos Cristiane S. , Pereira José A. , Ribeiro Marcelo L. , Darrieux Michelle , Ferraz Lúcio F. C. 
Published: September 2020

ABSTRACTAlthough originally known as an opportunistic pathogen,Klebsiella pneumoniaehas been considered a worldwide health threat nowadays due to the emergence of hypervirulent and antibiotic-resistant strains capable of causing severe infections not only on immunocompromised patients but also on healthy individuals. Fimbriae is an essential virulence factor forK. pneumoniae, especially in urinary tract infections, because it allows the pathogen to adhere and invade urothelial cells and to form biofilms on biotic and abiotic surfaces. The importance of fimbriae forK. pneumoniaepathogenicity is highlighted by the large number of fimbrial gene clusters on the bacterium genome, which requires a coordinated and finely adjusted system to control the synthesis of these structures. In this work, we describe KpfR as a new transcriptional repressor of fimbrial expression inK. pneumoniaeand discuss its role in the bacterium pathogenicity.K. pneumoniaelacking thekpfRgene exhibited a hyperfimbriated phenotype with enhanced biofilm formation and greater adhesion to and replication within epithelial host cells. However, the mutant strain was attenuated for colonization of the bladder in a murine model of urinary tract infection. These results indicate that KpfR is an important transcriptional repressor that, by negatively controlling the expression of fimbriae, preventsK. pneumoniaefrom having a hyperfimbriated phenotype and from being recognized and eliminated by the host immune system.IMPORTANCEFimbriae are crucial virulence factor for many pathogens because they allow the pathogen to adhere and invade host cells and to form biofilm on biotic and abiotic surfaces. However, the synthesis of fimbriae requires a precise and coordinated control to guarantees the production of these structures only when necessary, thus avoiding unnecessary energy expenditure and bacterial clearance by the host immune cells. Herein, we describe for the first time the role of the transcriptional repressor of fimbrial expression KpfR on the pathogenicity ofK. pneumoniae, a Gram-negative pathogen that has gained worldwide attention, notably for being the causative agent of severe and metastatic infections even on healthy individuals. By deleting thekpfRgene, we show that the mutant strain loses the control of fimbriae production, resulting in a hyperfimbriated phenotype that impairsK. pneumoniaeability to colonize a murine model of urinary tract infection.
Variation in the Gut Microbiota of Common Marmosets: Differences with Colony of Origin and Integration
Authors: Cooper Rachel E. , Mangus Lisa M. , Lynch Jessica , Schonvisky Kayla , Wright Justin R. , McLimans Christopher J. , Wong Hoi Tong , See Jeremy Chen , Lamendella Regina , Mankowski Joseph L. 
Published: September 2020

AbstractCharacterization of the gut microbiome may aid understanding and management of natural and experimental disease states in research animals, thereby promoting reproducibility. In this study, the rectal bacterial communities of three separate common marmoset (Callithrix jacchus) breeding colonies were defined using 16S rRNA sequencing of rectal swab samples. Study animals originated from two German colonies and a United States colony (JHU). The two German cohorts, previously fed the same diet, were imported into the JHU facility; they were then isolated, transitioned onto JHU diet, and then moved into rooms housing JHU animals. To dissect the contributions of diet and integration in shaping the rectal bacterial community, samples were collected from German origin marmosets upon JHU arrival (baseline), following diet transition (100 d), and following cohousing (390 d). Baseline and 390 d samples were collected from stably maintained JHU marmosets. Bacterial community composition was distinct between all three cohorts at baseline, suggesting that factors other than primary diet confer significant differences between captive populations. Beta-diversity of the animals from the two German colonies converged by 100 d but remained distinct from JHU sample beta-diversity throughout the 390-d study, indicating that diet had greater influence on bacterial community composition than did housing animals within the same room. Our results demonstrate substantial differences in gut bacteria between different captive marmoset colonies, with persistence of these differences following husbandry standardization and housing integration. Goals of rigor and reproducibility in research underscore the need to consider microbial differences between marmosets of diverse origin.ImportanceCharacterizing gut microbial populations is expected to promote health and enhance research reproducibility in animal studies. As use of common marmosets as animal models of human diseases expands, evaluating the marmoset gut bacterial community will be critical for interpreting research findings, especially as marmosets are prone to gastrointestinal inflammation. In this study, using 16S rRNA sequencing of rectal swab samples, we compared bacterial community among three captive colonies of marmosets at baseline and following importation of cohorts from two of the colonies into the third colony. Diet history had sustained influence on bacterial community composition, while housing the animals within the same room over a period of eight months did not appear to be a major factor. These persistent differences in marmoset gut bacterial community highlight the need for careful consideration of animal origin as a variable in marmoset research studies.
Mental healthcare and service user impact of the COVID-19 pandemic: results of a UK survey of staff working with people with intellectual disability and developmental disorders
Authors: Sheehan Rory , Dalton-Locke Christian , Ali Afia , Totsika Vasiliki , Vera San Juan Norha , Hassiotis Angela 
Published: September 2020

ABSTRACTBackgroundVery little is known about the impact of previous epidemics on the care of people with intellectual and developmental disabilities, particularly in terms of mental health services. The COVID-19 pandemic has the potential to exacerbate existing health inequalities as well as expose gaps in service provision for this vulnerable population group.MethodsWe investigated the responses of 648 staff working in mental healthcare with people with intellectual disabilities and/or developmental disabilities. Participants contributed to a UK-wide online survey undertaken by the National Institute for Health Research Mental Health Policy Research Unit between 22nd April and 12th May 2020. Recruitment was via professional networks, social media and third sector organisations. Quantitative data describing staff experience over three domains (challenges at work, service user and carer problems, sources of help at work) were summarised and differences between groups explored using Chi square tests. Content analysis was used to organise qualitative data focusing on service changes in response to the pandemic.ResultsThe majority of survey respondents worked in the NHS and in community mental health services. One third had managerial responsibility. Major concerns expressed by mental healthcare staff were: difficulties for service users due to lack of access to usual support networks and health and social care services during the pandemic; and difficulties maintaining adequate levels of support secondary to increased service user need. Staff reported having to quickly adopt new digital ways of working was challenging; nevertheless, free text responses identified remote working as the innovation that staff would most like to retain after the pandemic subsides.ConclusionsUnderstanding the experiences of staff working across different settings in mental healthcare for people with intellectual and developmental disabilities during the COVID-19 pandemic is essential in guiding contingency planning and fostering service developments to ensure the health of this vulnerable group is protected in any future disease outbreaks.
Covid-19 SEIDRD Modelling for Pakistan with implementation of seasonality, healthcare capacity and behavioral risk reduction
Authors: Saadat Shoab , Mansoor Salman 
Published: September 2020

AbstractINTRODUCTIONIntroductionDecember 2019 saw the origins of a new Pandemic which would soon spread to the farthest places of the planet. Several efforts of modelling of the geo-temporal transmissibility of the virus have been undertaken, but none describes the incorporation of effect of seasonality, contact density, primary care and ICU bed capacity and behavioral risk reduction measures such as lockdowns into the simulation modeling for Pakistan. We use above variables to create a close to real data curve function for the active cases of covid-19 in Pakistan.ObjectiveThe objective of this study was to create a new computational epidemiological model for Pakistan by implementing symptomatology, healthcare capacity and behavioral risk reduction mathematically to predict of Covid-19 case trends and effects of changes in community characteristics and policy measures.MethodsWe used a modified version of SEIR model called SEIDRD (Susceptible - Exposed Latent - Diagnosed as Mild or severe - Recovered - Deaths). This was developed using Vensim PLE software version 8.0. This model also incorporated the seasonal and capacity variables for Pakistan and was adjusted for behavioral risk reduction measures such as lockdowns.ResultsThe SEIDRD model was able to closely replicate the active covid-19 cases curve function for Pakistan until now. It was able to show that given current trends, though the number of active cases are dropping, if the smart lockdown measures were to end, the cases are expected to show a rise from 28th August 2020 onwards reaching a second peak around 28th September 2020. It was also seen that increasing the ICU bed capacity in Pakistan from 4000 to 40000 will not make a significant difference in active case number. Another simulation for a vaccination schedule of 100000 vaccines per day was created which showed a decrease in covid cases in a slow manner over a period of months rather than days.ConclusionThis study attempts to successfully model the active covid-19 cases curve function of Pakistan and mathematically models the effect of seasonality, contact density, ICU bed availability and Lockdown measures. We were able to show the effectiveness of smart lockdowns and were also to predict that in case of no smart lockdowns, Pakistan can see a rise in active case number starting from 28th of August 2020.
Trust and Transparency in times of Crisis: Results from an Online Survey During the First Wave (April 2020) of the COVID-19 Epidemic in the UK
Authors: Enria Luisa , Waterlow Naomi , Rogers Nina T , Brindle Hannah , Lal Sham , Eggo Rosalind M , Lees Shelley , Roberts Chrissy h 
Published: September 2020

AbstractBackgroundThe success of a government’s COVID-19 control strategy relies on public trust and broad acceptance of response measures. We investigated public perceptions of the UK government’s COVID-19 response, focusing on the relationship between trust and transparency, during the first wave (April 2020) of the COVID-19 pandemic in the United Kingdom.MethodsAnonymous survey data were collected (2020-04-06 to 2020-04-22) from 9,322 respondents, aged 20+ using an online questionnaire. We took a mixed methods approach to data analysis, combining statistical analyses, structural topic modelling (STM) and qualitative thematic coding of a sub-set of responses. Missing data were imputed via multiple imputation.ResultsMost respondents (95.1%) supported government enforcement of behaviour change. While 52.1% of respondents thought the government was making good decisions, differences were apparent across demographic groups, for example respondents from Scotland had lower odds of responding positively than respondents in London. Higher educational levels saw decreasing odds of having a positive opinion of the government response and decreasing household income associated with decreasing positive opinion. Of respondents who thought the government was not making good decisions 60% believed the economy was being prioritised over people and their health. Positive views on government decision-making were associated with positive views on government transparency about the COVID-19 response. Qualitative analysis about government transparency highlighted five key themes: (1) the justification of opacity due to the condition of crisis, (2) generalised mistrust of politics, (3) concerns about the role of scientific evidence, (4) quality of government communication and (5) questions about political decision-making processes.ConclusionWe recommend targeted community engagement tailored to different groups’ experiences and a focus on accountability and openness around how decisions are made in the response to the UK COVID-19 pandemic.
Enhanced synaptic transmission in the extended amygdala and altered excitability in an extended amygdala to brainstem circuit in a Dravet syndrome mouse model
Authors: Yan Wen Wei , Xia Maya , Levitt Alyssa , Hawkins Nicole , Kearney Jennifer , Swanson Geoffrey T. , Chetkovich Dane , Nobis William P. 
Published: September 2020

ABSTRACTObjectiveDravet syndrome (DS) is a severe, early-onset epilepsy with an increased incidence of sudden death. Evidence of interictal breathing deficits in DS suggest that alterations in subcortical projections to brainstem nuclei may exist, which might be driving comorbidities in DS. The aim of this study was to determine if a subcortical structure, the bed nucleus of the stria terminalis (BNST) in the extended amygdala, is activated by seizures, exhibits changes in excitability, and expresses any alterations in neurons projecting to a brainstem nucleus associated with respiration, stress response and homeostasis.MethodsExperiments were conducted using F1 mice generated by breeding 129.Scn1a+/-mice with wildtype C57BL/6J mice. Immunohistochemistry was performed to quantify neuronal c-fos activation in DS mice after observed spontaneous seizures. Whole cell patch clamp and current clamp electrophysiology recordings were conducted to evaluate changes in intrinsic and synaptic excitability in the BNST.ResultsSpontaneous seizures in DS mice significantly enhanced neuronal c-fos expression in the BNST. Further, the BNST had altered AMPA/NMDA postsynaptic receptor composition and showed changes in spontaneous neurotransmission, with greater excitation and decreased inhibition. BNST to parabrachial nucleus (PBN) projection neurons exhibited intrinsic excitability in wildtype mice, while these projection neurons were hypoexcitable in DS mice.SignificanceThe findings suggest that there is altered excitability in neurons of the BNST, including BNST to PBN projection neurons, in DS mice. These alterations could potentially be driving comorbid aspects of DS outside of seizures, including respiratory dysfunction and sudden death.SIGNIFICANCE STATEMENTDravet syndrome (DS) is an early-onset epilepsy with an increased risk of sudden death. We determined that there are alterations in a subcortical nucleus, the bed nucleus of the stria terminalis (BNST) of the extended amygdala, in a murine DS model. The BNST is involved in stress, anxiety, feeding, and respiratory function. We found enhanced activation in the BNST after seizures and alterations in basal synaptic neurotransmission–with enhanced spontaneous excitatory and decreased spontaneous inhibitory postsynaptic events. Evaluating those neurons that project to the parabrachial nucleus (PBN), a nucleus with multiple homeostatic roles, we found them to be hypoexcitable in DS. Alterations in BNST to brainstem projections could be implicated in comorbid aspects of DS, including respiratory dysfunction and sudden death.