bluuebunny/crossref_metadata_2025 huggingface dataset:
Facilitators and Barriers to Compliance with COVID-19 Guidelines: A Structural Topic Modelling Analysis of Free-Text Data from 17,500 UK Adults
Authors: Wright Liam , Paul Elise , Steptoe Andrew , Fancourt Daisy
Published: July 2021

Background

During the COVID-19 pandemic, the UK government has implemented a series of guidelines, rules, and restrictions to change citizens’ behaviour to tackle the spread of the virus, such as the promotion of face-masks and the imposition of lockdown stay-at-home orders. The success of these measures requires active co-operation on the part of citizens, but compliance has not been complete. Detailed data is required on the factors aiding or hindering compliance with these measures.

Methods

To understand the facilitators and barriers to compliance with COVID-19 guidelines, we used structural topic modelling, a text mining technique, to extract themes from over 26,000 free-text survey responses from 17,500 UK adults, collected between 17 November and 23 December 2020.

Results

The main factors facilitating compliance were desires to reduce risk to one’s self and one’s family and friends and to, a lesser extent, the general public. Also of importance were a desire to return to normality, the availability of activities and technological means to contact family and friends, and the ability to work from home. Identified barriers were difficulties maintaining social distancing in public (due to the actions of other people or environmental constraints), the need to provide or receive support from family and friends, social isolation, missing loved one, and mental health impacts, perceiving the risks as low, social pressure to not comply, and difficulties understanding and keep abreast of changing rules. Several of the barriers and facilitators raised were related to participant characteristics. Notably, women were more likely to discuss needing to provide or receive mental health support from friends and family.

Conclusion

The results demonstrate an array of factors contribute to compliance with guidelines. Of particular policy importance, the results suggest that government communications that emphasizes the potential risks of COVID-19 and provides simple, consistent guidance on how to reduce the spread of the virus would improve compliance with preventive behaviours.
Implications of COVID-19 vaccination and public health countermeasures on SARS-CoV-2 variants of concern in Canada: evidence from a spatial hierarchical cluster analysis
Authors: Adeyinka Daniel A , Camillo Cheryl A. , Marks Wendie , Muhajarine Nazeem
Published: July 2021

Background

The influence of coronavirus disease-2019 (COVID-19) containment measures on variants of concern (VOC) has been understudied in Canada. Our objective was to identify provinces with disproportionate prevalence of VOC relative to COVID-19 mitigation efforts in provinces and territories in Canada.

Methods

We analyzed publicly available provincial- and territorial-level data on the prevalence of VOCs in relation to mitigating factors (summarized in three measures: 1. strength of public health countermeasures: stringency index, 2. how much people moved about outside their homes: mobility index, and 3. vaccine intervention: proportion of Canadian population fully vaccinated). Using spatial agglomerative hierarchical cluster analysis (unsupervised machine learning), the provinces and territories were grouped into clusters by stringency index, mobility index and full vaccine coverage. Kruskal-Wallis test was used to determine the differences in the prevalence of VOC (Alpha, or B.1.1.7, Beta, or B.1.351, Gamma, or P.1, and Delta, or B.1.617.2 variants) between the clusters.

Results

Three clusters of vaccine uptake and countermeasures were identified. Cluster 1 consisted of the three Canadian territories, and characterized by higher degree of vaccine deployment and lesser degree of countermeasures. Cluster 2 (located in Central Canada and Atlantic region) was typified by lesser implementation of vaccine deployment and moderate countermeasures. The third cluster was formed by provinces in the Pacific region, Central Canada, and Prairie region, with moderate vaccine deployment but stronger countermeasures. The overall and variant-specific prevalence were significantly different across the clusters.

Interpretation

This study found that implementation of COVID-19 public health measures varied across the provinces and territories. Considering the high prevalence of VOCs in Canada, completing the second dose of COVID-19 vaccine in a timely manner is crucial.
Examining the Relationship between COVID-19 Vaccinations and Reported Incidence
Authors: Shacham Enbal , Scroggins Stephen , Garza Alexander
Published: July 2021

As COVID-19 has caused significant morbidity and mortality throughout the world, the development and distribution of an effective vaccine have been swift but not without challenges. Earlier demand and access barriers have seemingly been addressed with more free and accessible vaccines now available for a wide variety of ages. While rates of COVID-19 have decreased overall, some geographic areas continue to experience rapid outbreaks. The purpose of this study was to examine the relationship between vaccination uptake and weekly COVID-19 cases throughout locations in the state of Missouri.

Methods

Among all Missouri counties and two cities (n=117), weekly COVID-19 incidence and cumulative proportion of residents fully vaccinated were abstracted from the Missouri Department of Health and Senior Services during a 25-week period from January 4 to Jun 26, 2021. Additional ecological variables known to be associated with COVID-19 incidence and prevalence were collected from the U.S. Census Bureau and integrated into data: total population, proportion of nonwhite residents, annual median household income, proportion of residents working in public facing occupations. Descriptive and inferential statistics were completed which included the calculation of both linear and nonlinear models using repeated measure data to determine the quantitative association between vaccination uptake and reported COVID-19 cases in the presence of location characteristics.

Results

Throughout the 25 weeks of observations, the average weekly number of COVID-19 cases reported was 66.1 (SD=260.8) while the average cumulative proportion vaccinated individuals at the end of the 25 weeks was 25.8% (SD=6.8%) among study locations. While graphing seemed to suggest a more nonlinear relationship between COVID-19 incidence and proportion vaccinated, comparison of crude linear and nonlinear models pointed to the relationship likely being linear during study period. The final adjusted linear model exhibited a significant relationship between COVID-19 cases and proportion vaccinated, specifically every percent increase in population vaccinated resulted in 3 less weekly COVID-19 cases being reported (β -3.74, p<0.001. Additionally, when controlling for other factors, the adjusted model revealed locations with higher proportions of nonwhite residents were likely to experience less weekly COVID-19 cases (β -1.48, p=0.037).

Discussion

Overall, this study determined that increasing the proportion of residents vaccinated decreases COIVD-19 cases by a substantial amount over time. These findings provide insights into possible messaging strategies that can be leveraged to develop more effective implementation and uptake. As the COVID-19 pandemic persists and vaccination numbers begin to plateau, diverse communication strategies become a critical necessity to reach a wider population.
Attempted Suicide and Criminal Justice System in a Sample of Forensic Psychiatric Patients in Malaysia
Authors: Khamis Johari , Panirselvam Ravivarma Rao , Badruddin Norhameza Ahmad , Ab Rahman Farynna Hana , Chan Lai Fong
Published: July 2021

Criminalization of suicide attempts is an archaic barrier to suicide prevention. Globally, clinical profiles of prosecuted suicide attempters are an under-researched area. This retrospective study aims to describe the clinical profiles of individuals who were charged for attempted suicide and subsequently sent for criminal responsibility and fitness to plead evaluation in a forensic psychiatric unit in Malaysia from January 1, 2008, to December 31, 2019. We identified 22 cases who were mostly adult males (90.9%). Seventy-three percent have a psychiatric disorder. Mood disorders were more prevalent (32%) followed by psychotic disorders and substance use disorders. For most of these individuals, this was the first contact with any form of mental health services and 41% defaulted their treatment before arrest. This sample illustrates a vulnerable group who has been disengaged with mental healthcare. Future research is warranted to further investigate mechanisms that are effective in addressing unmet needs of persons in suicidal crisis as opposed to utilizing the criminal justice pathway.
Treatment of sarcoidosis with cutaneous involvement with tofacitinib
Authors: Damsky William , Wang Alice , Young Bryan D. , Ayasun Ruveyda , Ryu Changwan , McGeary Meaghan K. , Fazzone-Chettiar Ramesh , Pucar Darko , Gulati Mridu , Miller Edward J. , Bosenberg Marcus , Flavell Richard A. , King Brett
Published: July 2021

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids and there are no approved steroid-sparing medications. There is emerging evidence that Janus kinase (JAK) inhibitors, which inhibit JAK-dependent cytokine activity, may hold promise in sarcoidosis. In this open-label trial, 10 patients with recalcitrant sarcoidosis with cutaneous involvement were treated with tofacitinib 5 mg twice daily. There was no washout period and patients were permitted to continue, taper, or discontinue other treatments. The primary outcome was the change in the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) activity score after 6 months. Change in internal organ disease activity was also assessed using total lesion glycolysis (TLG) determined by full-body positron emission tomography. A mean reduction in the CSAMI activity score of 82.7% was observed, with 6 patients showing a complete response. Internal organ response data was available in 8 patients; a decrease in TLG of ≥50% was noted in 5 patients, with complete or near complete resolution in 3 (>98% reduction in TLG). Patients were generally able to significantly taper or discontinue their baseline immunosuppressive regimen, which included prednisone in 5 patients. Single cell RNA-sequencing, bulk RNA-sequencing, and high-throughput proteomic analyses were performed on skin and blood as a function of treatment in order to delineate changes in immunologic signals with therapy. We identified CD4+ T cell derived IFN-γ as a central cytokine driver of sarcoidosis and inhibition of its activity was achieved with tofacitinib and correlated closely with clinical improvement. Tofacitinib appears to have impressive activity in treatment of sarcoidosis and likely acts by inhibiting IFN-γ, larger, controlled studies are warranted.
Online tests for sexually transmitted infections – Friend or Foe? An analysis of providers in the United Kingdom
Authors: Clarke Eleanor , Horner Paddy , Muir Peter , Turner Katy M. E. , Harding-Esch Emma M.
Published: July 2021

Objectives

Online testing for sexually transmitted infections (STIs) may contribute to overcoming barriers to traditional testing such as stigma and inconvenience. However, regulation of these tests is lacking, and the quality of services is variable, with potential short- and long-term personal, clinical and public health implications. This study aimed to evaluate online tests available in the UK against national standards.

Methods

Providers of online STI tests (self-sampling and self-testing) in the UK were identified by an internet search of Google and Amazon (June 2020). Website information on tests and care was collected, and further information requested from providers via an online survey, sent twice (July 2020, April 2021). The information obtained was compared to British Association for Sexual Health and HIV (BASHH) guidelines for diagnostics and standards of STI management.

Results

31 providers were identified: 13 self-test, 18-self-sample, and two laboratories that serviced multiple providers. Seven responded to the online survey. Many conflicts with national guidelines were identified, including: lack of health promotion information, lack of sexual history taking, use of tests licensed for professional use only marketed for self-testing, inappropriate infections tested for, incorrect specimen type used, and lack of advice for post-diagnosis management.

Conclusions

Very few online providers met the BASHH national STI management guidelines standards that were assessed, and there is concern that this will also be the case in areas that were not covered by this study. For-profit providers were the least compliant, with concerning implications for patient care and public health. Regulatory change is urgently needed to ensure that online providers are compliant with national guidelines to ensure high-quality patient care, and providers are held to account if non-compliant.

Key message box

Online providers help overcome many barriers to STI testing and are increasingly popular, but quality of services is not assured

Many online testing services, particularly for-profit providers, did not comply with national guidelines

Substandard services can lead to serious personal, clinical and public health

implications, such as inappropriate testing, inappropriate antimicrobial prescribing, unnecessary emotional distress and missed diagnoses

Regulatory change is required to ensure online providers comply with national guidelines and are held to account when they do not
Effective Connectivity in Subcortical Visual Structures in De Novo Patients with Parkinson’s Disease
Authors: Bellot Emmanuelle , Kauffmann Louise , Coizet Véronique , Meoni Sara , Moro Elena , Dojat Michel
Published: July 2021

Background

PD is associated with non-motor symptoms appearing before the motor symptoms onset. Recent studies report dysfunctions of visual structures at early stages of PD.

Objective

This study addresses effective connectivity in the visual network of PD patients.

Methods

Using brain functional MRI and Dynamic Causal Modeling analysis, we investigated the connectivity between the superior colliculus, the lateral geniculate nucleus and the primary visual area V1 in 22 de novo untreated PD patients and six months after starting dopaminergic treatment compared to age-matched healthy controls.

Results

Our findings indicate that the superior colliculus drives cerebral activity for luminance contrast processing both in healthy controls and untreated PD patients. The same effective connectivity was observed with neuromodulatory differences in terms of neuronal dynamic interactions. The modulation induced by luminance contrast changes of the superior colliculus connectivity (self-connectivity and connectivity to the lateral geniculate nucleus) was inhibited in PD patients (effect of contrast: p = 0.79 and p = 0.77 respectively). The introduction of dopaminergic medication failed to restore the effective connectivity modulation observed in the healthy controls.

Interpretation

The deficits in luminance contrast processing in PD seem due to a deficiency in connectivity adjustment from the superior colliculus to the lateral geniculate nucleus and to V1. Administration of a dopaminergic treatment over six months was not able to normalize the observed alterations in inter-regional coupling. These findings highlight the presence of early dysfunctions in primary visual areas, which might be used as early markers of the disease.
Cerebral hypoperfusion is a late pathological event in the course of Alzheimer's disease
Authors: Ahmadi Khazar , Pereira Joana B. , Berron David , Vogel Jacob , Ingala Silvia , Strandberg Olof T. , Janelidze Shorena , Barkhof Frederik , Pfeuffer Josef , Knutsson Linda , van Westen Danielle , Mutsaerts Henk J.M.M. , Palmqvist Sebastian , Hansson Oskar
Published: July 2021

Although several studies have shown decreased cerebral blood flow (CBF) in Alzheimer's disease (AD), the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, positron emission tomography, and biomarkers of cerebrospinal fluid, we investigated the associations between CBF and the key mechanisms in AD including amyloid-β (Aβ) and tau pathology, synaptic dysfunction and axonal degeneration. Further, we applied a disease progression modeling to characterize the temporal sequence of different AD biomarkers. Lower perfusion was observed in the temporo-occipito-parietal regions in the Aβ-positive cognitively impaired compared to both the Aβ-positive and Aβ-negative cognitively unimpaired individuals. In participants along the AD spectrum (those with Aβ pathology regardless of their cognitive status), CBF was inversely associated with tau and synaptic dysfunction, but not Aβ in similar cortical regions. Moreover, the disease progression modeling revealed that CBF disruption followed the abnormality of biomarkers of Aβ, tau and brain atrophy. These findings indicate that tau tangles and synaptic degeneration are more closely connected with CBF changes rather than Aβ pathology. This supports the notion that hypoperfusion is not an early event associated with the build-up of Aβ during the preclinical phase of AD.
Hot and sour: parasite adaptations to honey bee body temperature and pH
Authors: Palmer-Young Evan C , Raffel Thomas R , Evans Jay D
Published: July 2021

Host temperature and gut chemistry can shape resistance to parasite infection. Heat and acidity can limit trypanosomatid infection in warm-blooded hosts, and could shape infection resistance in insects as well. The colony-level endothermy and acidic guts of social bees provide unique opportunities to study how temperature and acidity shape insect-parasite associations. We compared temperature and pH tolerance between three trypanosomatid parasites from social bees and a related trypanosomatid from poikilothermic mosquitoes, which have alkaline guts.

Relative to the mosquito parasites, all three bee parasites had higher heat tolerance that reflected levels of endothermy in hosts. Heat tolerance of the honey bee parasiteCrithidia mellificaewas exceptional for its genus, implicating honey bee endothermy as a filter of parasite establishment. The lesser heat tolerance of the emergingLotmaria passimsuggests possible spillover from a less endothermic host. Whereas both honey bee parasites tolerated the acidic pH’s found in bee intestines, mosquito parasites tolerated the alkaline conditions found in mosquito midguts, suggesting that both gut pH and temperature could structure host-parasite specificity. Elucidating how host temperature and gut pH affect infection—and corresponding parasite adaptations to these factors—could help explain trypanosomatids’ distribution among insects and invasion of mammals.
Combined tumor and immune signals from genomes or transcriptomes predict outcomes of checkpoint inhibition in melanoma
Authors: Freeman Samuel S. , Sade-Feldman Moshe , Kim Jaegil , Stewart Chip , Gonye Anna L. K. , Ravi Arvind , Arniella Monica B. , Gushterova Irena , LaSalle Thomas J. , Blaum Emily M. , Yizhak Keren , Frederick Dennie T. , Sharova Tatyana , Leshchiner Ignaty , Elagina Liudmila , Spiro Oliver G. , Livitz Dimitri , Rosebrock Daniel , Aguet François , Carrot-Zhang Jian , Ha Gavin , Lin Ziao , Chen Jonathan H. , Barzily-Rokni Michal , Hammond Marc R. , Vitzthum von Eckstaedt Hans C. , Blackmon Shauna M. , Jiao Yunxin J. , Gabriel Stacey , Lawrence Donald P. , Duncan Lyn M. , Stemmer-Rachamimov Anat O. , Wargo Jennifer A. , Flaherty Keith T. , Sullivan Ryan J. , Boland Genevieve M. , Meyerson Matthew , Getz Gad , Hacohen Nir
Published: July 2021

Cancer immunotherapy with checkpoint blockade (CPB) leads to improved outcomes in melanoma and other tumor types, but a majority of patients do not respond. High tumor mutation burden (TMB) and high levels of tumor-infiltrating T cells have been associated with response to immunotherapy, but integrative models to predict clinical benefit using DNA or RNA alone have not been comprehensively explored. We sequenced DNA and RNA from melanoma patients receiving CPB, and aggregated previously published data, yielding whole exome sequencing data for 189 patients and bulk RNA sequencing data for 178 patients. Using these datasets, we derived genomic and transcriptomic factors that predict overall survival (OS) and response to immunotherapy. Using whole-exome DNA data alone, we calculated T cell burden (TCB) and B cell burden (BCB) based on rearranged TCR/Ig DNA sequences and found that patients whose melanomas have high TMB together with either high TCB or high BCB survived longer and had higher response rates as compared to patients with either low TMB or TCB/BCB. Next, using bulk RNA-Seq data, differential expression analysis identified 83 genes associated with high or low OS. By combining pairs of immune-expressed genes with tumor-expressed genes, we identified three gene pairs associated with response and survival (Bonferroni P<0.05). All three gene pair models were validated in an independent cohort (n=180) (Bonferroni P<0.05). The best performing gene pair model included the lymphocyte-expressed MAP4K1 (Mitogen- Activated Protein Kinase Kinase Kinase Kinase 1) combined with the transcription factor TBX3 (T-Box Transcription Factor 3) which is overexpressed in poorly differentiated melanomas. We conclude that RNA-based (MAP4K1&TBX3) or DNA-based (TCB&TMB) models combining immune and tumor measures improve predictions of outcome after checkpoint blockade in melanoma.
eQTL mapping using allele-specific gene expression
Authors: Zhabotynsky Vasyl , Huang Licai , Little Paul , Hu Yi-Juan , de Villena Fernando Pardo-Manuel , Zou Fei , Sun Wei
Published: July 2021

Using information from allele-specific gene expression (ASE) can sub-stantially improve the power to map gene expression quantitative trait loci (eQTLs). However, such practice has been limited, partly due to high computational cost and the requirement to access raw data that can take a large amount of storage space. To address these computational challenges, we have developed a computational framework that uses a statistical method named TReCASE as its computational engine, and it is computationally feasible for large scale analysis. We applied it to map eQTLs in 28 human tissues using the data from the Genotype-Tissue Expression (GTEx) project. Compared with a popular linear regression method that does not use ASE data, TReCASE can double the number of eGenes (i.e., genes with at least one significant eQTL) when sample size is relatively small, e.g., n = 200. We also demonstrated how to use the ASE data that we have collected to study dynamic eQTLs whose effect sizes vary with respect to another variable, such as age. We find the majority of such dynamic eQTLs are due to some underlying latent factors, such as cell type proportions. We further compare TReCASE versus another method RASQUAL. TReCASE is ten times or more faster than RASQUAL and it provides more robust type I error control.
Multivalent, asymmetric IL-2-Fc fusions provide optimally enhanced regulatory T cell selectivity
Authors: Orcutt-Jahns Brian , Emmel Peter C. , Snyder Eli M. , Taylor Scott D. , Meyer Aaron S.
Published: July 2021

The common γ-chain receptor cytokines coordinate the proliferation and function of immune cell populations. One of these cytokines, interleukin (IL)-2, has potential as a therapy in autoimmune disease but is limited in effectiveness by its modest specificity toward regulatory T cells (Tregs). Engineering Treg-selective IL-2 has primarily focused on retaining binding to the high-affinity receptor, expressed more highly on Tregs, while reducing binding to the lower affinity receptor with broader expression. However, other parameters, such as the orientation and valency of Fc fusion, have signaling effects that have never been systematically explored. Here, we systematically profiled the signaling responses to a panel of wild type and mutein IL-2-Fc fusions across time, cell types, and concentrations. Exploring these responses, we found that dimeric muteins have unique specificity for Tregs through binding avidity. A mechanistic model of receptor interactions could capture these effects and directed the design of tetravalent IL-2-Fc fusions with greater Tregspecificity than possible with current design strategies. Exploration of other surface targets on Tregs revealed that there are no other binding moieties that could be fused to IL-2 for greater selectivity. Instead, IL2Rα itself is a maximally unique surface target for Tregs, and so avidity is likely the only route to more selective Treginteraction. However, the binding model revealed that asymmetrical, multivalent IL-2 fusions can bias avidity effects toward IL2Rα for even further enhanced Tregselectivity. These findings present a comprehensive analysis of how ligand properties and their effects on surface receptor-ligand interactions translate to selective activation of immune cell populations, and consequently reveals two new routes toward therapeutic cytokines with superior Tregselectivity that can be exploited for designing selective therapies in many other contexts.

Significance Statement

Signaling in off-target immune cells has hindered the effectiveness of IL-2 as an immunotherapy. We show that IL-2-Fc fusions with higher valency can exhibit enhanced regulatory T cell selectivity. This altered selectivity is explained by the kinetics of surface receptor-ligand binding and can be quantitatively predicted using a multivalent binding model. Using these insights, we successfully develop two new strategies for IL-2 therapies with unprecedented selectivity.

Highlights

Current IL-2 therapies are limited by a selectivity/target potency tradeoff.

Multivalency enhances selectivity for Tregs through IL2Rα avidity.

Tregselectivity cannot be enhanced by targeting other surface protein markers.

Multivalency can decouple selectivity from signaling using asymmetric cytokine fusions.
Novel measures of Morris water maze performance that use vector field maps to assess accuracy, uncertainty, and intention of navigational searches
Authors: Meenakshi P. , Mehrotra D. , Nruthyathi N. , Almeida-Filho D. , Lee Y.-S. , Silva A.J. , Balaji J.
Published: July 2021

Most commonly used behavioural measures for testing learning and memory in the Morris water maze (MWM) involve comparisons of an animal’s residence time in different quadrants of the pool. Such measures are limited in their ability to test different aspects of the animal’s performance. Here, we describe novel measures of performance in the MWM that use vector fields to capture the motion of mice as well as their search pattern in the maze. Using these vector fields, we develop quantitative measures of performance that are intuitive and more sensitive than classical measures. First, we describe search patterns in terms of vector field properties and use these properties to define three metrics of spatial memory namely Spatial Accuracy, Uncertainty and, Intensity of Search. We demonstrate the usefulness of these measures using four different data sets including comparisons between different strains of mice, an analysis of two mouse models of Noonan syndrome (Ptpn11 D61G and Ptpn11 N308D/+), and a study of goal reversal training. Importantly, besides highlighting novel aspects of performance in this widely used spatial task, our measures were able to uncover previously undetected differences, including in an animal model of Noonan syndrome, which we rescued with the mitogen activated protein kinase kinase (MEK) inhibitor SL327. Thus, our results show that our approach breaks down performance in the Morris water maze into sensitive measurable independent components that highlight differences in spatial learning and memory in the MWM that were undetected by conventional measures.
Automated verification, assembly, and extension of GBM stem cell network model with knowledge from literature and data
Authors: Holtzapple Emilee , Cochran Brent , Miskov-Zivanov Natasa
Published: July 2021

Signaling network models are usually assembled from information in literature and expert knowledge or inferred from data. The goal of modeling is to gain mechanistic understanding of key signaling pathways and provide predictions on how perturbations affect large-scale processes such as disease progression. For glioblastoma multiforme (GBM), this task is critical, given the lack of effective treatments and pace of disease progression. Both manual and automated assembly of signaling networks from data or literature have drawbacks. Existing GBM networks, as well as networks assembled using state-of-the-art machine reading, fall short when judged by the quality and quantity of information, as well as certain attributes of the overall network structure. The contributions of this work are two-fold. First, we propose an automated methodology for verification of signaling networks. Next, we discuss automation of network assembly and extension that relies on methods and resources used for network verification, thus, implicitly including verification in these processes. In addition to these methods, we also present, and verify a comprehensive GBM network assembled with a hybrid of manual and automated methods. Finally, we demonstrate that, while an automated network assembly is fast, such networks still lack precision and realistic network topology.
Trycycler: consensus long-read assemblies for bacterial genomes
Authors: Wick Ryan R. , Judd Louise M. , Cerdeira Louise T. , Hawkey Jane , Méric Guillaume , Vezina Ben , Wyres Kelly L. , Holt Kathryn E.
Published: July 2021

Assembly of bacterial genomes from long-read data (generated by Oxford Nanopore or Pacific Biosciences platforms) can often be complete: a single contig for each chromosome or plasmid in the genome. However, even complete bacterial genome assemblies constructed solely from long reads still contain a variety of errors, and different assemblies of the same genome often contain different errors. Here, we present Trycycler, a tool which produces a consensus assembly from multiple input assemblies of the same genome. Benchmarking using both simulated and real sequencing reads showed that Trycycler consensus assemblies contained fewer errors than any of those constructed with a single long-read assembler. Post-assembly polishing with Medaka and Pilon further reduced errors and yielded the most accurate genome assemblies in our study. As Trycycler can require human judgement and manual intervention, its output is not deterministic, and different users can produce different Trycycler assemblies from the same input data. However, we demonstrated that multiple users with minimal training converge on similar assemblies that are consistently more accurate than those produced by automated assembly tools. We therefore recommend Trycycler+Medaka+Pilon as an ideal approach for generating high-quality bacterial reference genomes.

Data availability

Supplementary figures, tables and code can be found at: github.com/rrwick/Trycycler-paper

Reads, assemblies and reference sequences can be found at: bridges.monash.edu/articles/dataset/Trycycler_paper_dataset/14890734
Pseudocritical and Precritical States in Brain Dynamics
Authors: Gu Lei , Wu Ruqian
Published: July 2021

Scale-free brain dynamics under external stimuli raises an apparent paradox since the critical point of the brain dynamics locates at the limit of zero external drive. Here, we demonstrate that relaxation of the membrane potential removes the critical point but facilitates scale-free dynamics in the presence of strong external stimuli. These findings feature biological neural networks as systems that have no real critical point but bear critical-like behaviors. Attainment of such pseudocritical states relies on processing neurons into a precritical state where they are made readily activatable. We discuss supportive signatures in existing experimental observations and advise new ones for these intriguing properties. These newly revealed repertoires of neural states call for reexamination of brain’s working states and open fresh avenues for the investigation of critical behaviors in complex dynamical systems.
Pro-inflammatory Cytokine GM-CSF Improves Learning/Memory and Brain Pathology in Dp16 Down Syndrome Mice and Improves Learning/Memory in Wild-Type Mice
Authors: Ahmed Md. Mahiuddin , Wang Athena Ching-Jung , Elos Mihret , Chial Heidi J. , Sillau Stefan , Solano D. Adriana , Coughlan Christina , Aghili Leila , Anton Paige , Markham Neil , Adame Vanesa , Gardiner Katheleen J. , Boyd Timothy D. , Potter Huntington
Published: July 2021

Down syndrome (DS) is characterized by chronic neuroinflammation, peripheral inflammation, astrogliosis, imbalanced excitatory/inhibitory neuronal function, and cognitive deficits in both humans and mouse models. Suppression of inflammation has been proposed as a therapeutic approach to treating DS co-morbidities, including intellectual disability (DS/ID). Conversely, we discovered previously that treatment with the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) improved cognition and reduced biomarkers of brain pathology in humans with Alzheimer’s disease (AD), another inflammatory disorder, and in a mouse model of AD. To investigate the effects of GM-CSF treatment on DS/ID, we assessed behavior and brain pathology in 12-14 month-old DS mice (Dp[16]1Yey) and their wild-type (WT) littermates, neither of which develop amyloid, and found that GM-CSF treatment improved performance in the radial arm water maze in both Dp16 and WT mice compared to placebo. Dp16 mice also showed abnormal astrocyte morphology and aggregation and fewer calretinin-positive interneurons, both of which were improved by GM-CSF treatment. These findings suggest that stimulating and/or modulating inflammation and the innate immune system with GM-CSF treatment may enhance cognition in both people with DS/ID and in the typical aging population.
Soft drinks can be misused to give false “false positive” SARS-CoV-2 lateral flow device results
Authors: Oni L , Hawcutt DB , Buchan IE , Semple MG
Published: July 2021

Background

The COVID-19 pandemic created the need for very large scale, rapid testing to prevent and contain transmission of the SARS-CoV-2 virus. Lateral flow device (LFD) immunoassays meet this need by indicating the presence of SARS-CoV-2 antigen from nose/throat swab washings in 30 minutes without laboratory processing, and can be manufactured quickly at low cost. Since March 2021, UK schools have asked pupils without symptoms to test twice weekly. Pupils have posted on social media about using soft drinks to create positive results. The aim of this study was to systematically test a variety soft drinks to determine whether they can cause false “false positive” LFD results.

Methods

This study used 14 soft drinks and 4 artificial sweeteners to determine the outcome of misusing them as analyte for the Innova SARS-CoV-2 antigen rapid qualitative LFD. The pH value, sugar content and ingredients of each sample are described. The LFD results were double read and a subset was repeated using the same devices and fake analytes but differently sourced.

Findings

One sample (1/14; 7%), spring water, produced a negative result. Ten drinks (10/14; 71%) produced a positive or weakly positive result. Three samples (3/14; 21%) produced void results, mostly the fruit concentrate drinks. There was no apparent correlation between the pH value (pH 5.0 in 13/14, 93%; pH 6.5 in 1/14; 7%) or the sugar content (range 0-10.7 grams per 100mls) of the drinks and their LFD result. The 4 artificial sweeteners all produced negative results. A subset of the results was fully replicated with differently sourced materials.

Interpretation

Several soft drinks can be misused to give false positive SARS-CoV-2 LFD results. Daily LFD testing should be performed first thing in the morning, prior to the consumption of any food or drinks, and supervised where feasible.

Funding

This work was self-funded by author LO and the LFD were gifted for use in this study.

Research in context

Evidence before this study

Lateral flow devices (LFD) for SARS-CoV-2 antigen testing have been used extensively in the UK and internationally in COVID-19 pandemic responses, providing rapid testing at low cost

Recent reports from young people on social media suggested soft drinks might be misused as LFD analyte and produce a seemingly positive result

Added value of this study

Various common soft drinks used as fake analyte can produce false positive SARS-CoV-2 LFD results

Artificial sweeteners alone in fake analyte solution did not produce false positive results

Implications of all the available evidence

Soft drinks misused as analyte can produce false “false positive” SARS-CoV-2 LFD results

Daily testing is best done first thing in the morning, prior to any food or drink, and under supervision where possible
The BLMP-1 transcription factor promotes oscillatory gene expression to achieve timely molting
Authors: Hauser Yannick P. , Meeuse Milou W.M. , Gaidatzis Dimos , Großhans Helge
Published: July 2021

Gene expression oscillators can coordinate developmental events in space and time. In C. elegans, a gene expression oscillator directs rhythmic accumulation of ∼25% of the transcriptome, and thus thousands of transcripts, presumably to control molting, a process of rhythmic skin regeneration. Recently, a reverse genetic screen identified several transcription factors important for molting. Here, we characterize one of these, BLMP-1, orthologous to the mammalian transcription repressor PRDM1. We find it to be important for timely molting, and oscillatory gene expression. We propose a dual function for BLMP-1 in shaping oscillatory gene expression and coupling it to a set of direct targets, which ensures cuticular integrity. With mammalian PRDM1/BLIMP1 promoting regular cycles of postnatal hair follicle regeneration, our findings point to the possible existence of a fundamentally conserved clock mechanism in control of rhythmic skin regeneration.
CXCL17 is an endogenous inhibitor of CXCR4 via a novel mechanism of action
Authors: White Carl W. , Kilpatrick Laura E. , Dale Natasha , Abhayawardana Rekhati S. , Dekkers Sebastian , Stocks Michael J , Pfleger Kevin D. G. , Hill Stephen J.
Published: July 2021

CXCL17 is the most recently described chemokine. It is principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages and has antimicrobial properties. CXCL17 is also implicated in the pathology of inflammatory disorders and progression of several cancers, as well as being highly upregulated during viral infections of the lung. However, the exact role of CXCL17 in health and disease is largely unknown, mainly due to a lack of known molecular targets mediating CXCL17 functional responses. Using a range of bioluminescence resonance energy transfer (BRET) based assays, here we demonstrate that CXCL17 inhibits CXCR4-mediated signalling and ligand binding. Moreover, CXCL17 interacts with neuropillin-1, a VEGFR2 co-receptor. Additionally, we find CXCL17 only inhibits CXCR4 ligand binding in intact cells and demonstrate that this effect is mimicked by known glycosaminoglycan binders, surfen and protamine sulfate. This indicates that CXCL17 inhibits CXCR4 by a unique mechanism of action that potentially requires the presence of a glycosaminoglycan containing accessory protein. Altogether, our results reveal that CXCL17 is an endogenous inhibitor of CXCR4 and represents an important discovery in our understanding of the (patho) physiological functions of CXCL17 and regulation of CXCR4 signalling.
Meta-analysis of exhausted CD8+ T cells from Homo sapiens and Mus musculus provides robust targets for immunotherapy
Authors: Zhang Lin , Guo Yicheng , Nishi Hafumi
Published: July 2021

T cell exhaustion is a state of T cell dysfunction during chronic infection and cancer. Antibody-targeting immune checkpoint inhibitors to reverse T cell exhaustion is a promising approach for cancer immunotherapy. However, the therapeutic efficacy of known immune checkpoint inhibitors remains low. To expand the potential effective targets to reverse T cell exhaustion, a meta-analysis was performed to integrate seven exhaustion datasets caused by multiple diseases in both humans and mice. In this study, an overlap of 21 upregulated and 37 downregulated genes was identified in human and mouse exhausted CD8+ T cells. These genes were significantly enriched in exhaustion response-related pathways, such as signal transduction, immune system processes, and regulation of cytokine production. Gene expression network analysis revealed that the well-documented exhaustion genes were defined as hub genes in upregulated genes, such as programmed cell death protein 1 and cytotoxic T-lymphocyte associated protein 4. In addition, a weighted gene co-expression analysis identified 175 overlapping genes that were significantly correlated with the exhaustion trait in both humans and mice. This study found that nine genes, including thymocyte selection associated high mobility group box and CD200 receptor 1, were significantly upregulated and highly related to T cell exhaustion. These genes should be additional robust targets for immunotherapy and T-cell dysfunction studies.
Sand dropseed (Sporobolus cryptandrus) – A new pest in Eurasian sand areas?
Authors: Török P. , Schmidt D. , Bátori Z. , Aradi E. , Kelemen A. , Hábenczyus A. A. , Diaz C. P. , Tölgyesi C. , Pál R.W. , Balogh N. , Tóth E. , Matus G. , Táborská J. , Sramkó G. , Laczkó L. , Jordán S. , Sonkoly J.
Published: July 2021

For the effective control of an invasive species, gathering as much information as possible on its ecology, establishment and persistence in the subjected communities is of utmost importance. We aimed to review the current distribution and characteristics of Sporobolus cryptandrus (sand dropseed), an invasive C4 grass species of North American origin recently discovered in Hungary. We aimed to provide information on (i) its current distribution paying special attention to its invasion in Eurasia; (ii) the characteristics of the invaded habitats in Central Europe; (iii) seed bank formation and germination characteristics, crucial factors in early establishment; and (iv) the effects of its increasing cover on vegetation composition. Finally, we aimed to (v) point out further research directions that could enable us to understand the invasion success of this potential invasive species. Field surveys uncovered large stands of the species in Central and Eastern Hungary with most of the locations in the former, especially the Kiskunság region. The species invaded disturbed stands of dry and open sand grasslands, closed dune slack grasslands and it also penetrates into natural open sand grasslands from neighbouring disturbed habitats. Increasing cover of Sporobolus cryptandrus caused a decline in species richness and abundance of subordinate species both in the vegetation and seed banks, but a low density of Sporobolus cryptandrus can even have a weak positive effect on these characteristics. Viable seeds of Sporobolus were detected from all soil layers (2.5 cm layers measured from the surface to 10 cm in depth), which indicates that the species is able to form a persistent seed bank (1,114 to 3,077 seeds/m2 with increasing scores towards higher abundance of the species in vegetation). Germination of Sporobolus cryptandrus was negatively affected by both litter cover and 1 cm deep soil burial. To sum up, Sporobolus cryptandrus can be considered as a transformer invasive species, whose spread forms a high risk for dry sand and steppe grasslands in Eurasia. We can conclude that for the effective suppression of the species it is necessary: (i) to clarify the origin of the detected populations; (ii) to assess its competitive ability including its potential allelopathic effects; (iii) to assess its seed bank formation potential in habitats with different abiotic conditions; and (iv) to assess the possibility of its suppression by natural enemies and management techniques such as mowing or livestock grazing.
Direct neuronal reprogramming by temporal identity factors
Authors: Boudreau-Pinsonneault Camille , Javed Awais , Fries Michel , Mattar Pierre , Cayouette Michel
Published: July 2021

Temporal identity factors are sufficient to reprogram developmental competence of neural progenitors, but whether they could also reprogram the identity of fully differentiated cells is unknown. To address this question, we designed a conditional gene expression system combined with genetic lineage tracing that allows rapid screening of potential reprogramming factors in the mouse retina. Using this assay, we report that co-expression of the early temporal identity transcription factor Ikzf1, together with Ikzf4, another Ikaros family member, is sufficient to directly convert adult Müller glial cells into neuron-like cells in vivo, without inducing a proliferative progenitor state. scRNA-seq analysis shows that the reprogrammed cells share some transcriptional signatures with both cone photoreceptors and bipolar cells. Furthermore, we show that co-expression of Ikzf1 and Ikzf4 can reprogram mouse embryonic fibroblasts to induced neurons by remodeling chromatin and promoting a neuronal gene expression program. This work uncovers general neuronal reprogramming properties for temporal identity factors in differentiated cells, opening new opportunities for cell therapy development.
Reassessing face topography in primary somatosensory cortex and remapping following hand loss
Authors: Root Victoria , Muret Dollyane , Arribas Maite , Amoruso Elena , Thornton John , Tarall-Jozwiak Aurelie , Tracey Irene , Makin Tamar R.
Published: July 2021

Cortical remapping after hand loss in the primary somatosensory cortex (S1) is thought to be predominantly dictated by cortical proximity, with adjacent body parts remapping into the deprived area. Traditionally, this remapping has been characterised by changes in the lip representation, which is assumed to be the immediate neighbour of the hand based on electrophysiological research in non-human primates. However, the orientation of facial somatotopy in humans is debated, with contrasting work reporting both an inverted and upright topography. We aimed to fill this gap in the S1 homunculus by investigating the topographic organisation of the face. Using both univariate and multivariate approaches we examined the extent of face-to-hand remapping in individuals with a congenital and acquired missing hand (hereafter one-handers and amputees, respectively), relative to two-handed controls. Participants were asked to move different facial parts (forehead, nose, lips, tongue) during fMRI scanning. We first report evidence for an upright facial organisation in all three groups, with the upper face and not the lips bordering the hand area. We further found little evidence for remapping of all tested facial parts in amputees, with no significant relationship to the chronicity of their PLP. In contrast, we found converging evidence for a complex pattern of face remapping in congenital one-handers across all facial parts, where the location of the cortical neighbour – the forehead – is shown to shift away from the deprived hand area, which is subsequently activated by the lips and the tongue. Together, our findings demonstrate that the face representation in humans is highly plastic, but that this plasticity is restricted by the developmental stage of input deprivation, rather than cortical proximity.