bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical body experiences questionnaire simplified for active aging (PBE-QAG): Validation with Rasch measurement theory
Authors: Deng Wei , Carpentier Sydney , Van de Winckel Ann
Published: June 2021

Purpose

To validate the Physical body experiences questionnaire simplified for active aging (PBE-QAG) with Rasch measurement theory. PBE-QAG measures body awareness during physical activity and includes dimensions of body-mind relationship, body acceptance, and awareness of physical skills and limits.

Methods

Adults without pain (n=269), with pain (n=61), with mental health conditions (n=200), and with stroke (n=36) were recruited at the Minnesota State Fair, Highland Fest, and in the Brain Body Mind Lab (University of Minnesota) and completed demographic and clinical questionnaires as well as the PBE-QAG. The PBE-QAG has 12 items, with scores ranging between 0 (totally true) to 4 (totally false). A low total score on the PBE-QAG reflects better body awareness. We evaluated item and person fit, targeting, unidimensionality, person separation reliability (PSR), local item dependence (LID), and differential item functioning (DIF) for demographic and clinical characteristics. We compared with Kruskal-Wallis ANOVA the person mean location in four groups: Adults with or without mental health conditions; and whether those groups did body awareness training.

Results

Unidimensionality and item fit were obtained after deleting 2 and rescoring 5 items. Seven participants did not fit the model (1.23%). There was minimal floor (5.72%), no ceiling effect (0.00%), and no LID. No DIF was greater than 0.50 logits for any of the variables. The Wright-corrected PSR was 0.96. The person mean location was -1.71±1.21 logits. Adults with mental health conditions who did not practice body awareness had a higher person mean location [Median (IQR)=0.83(0.89) logits, p<0.0001] versus the other three groups, reflecting lower body awareness.

Conclusions

PBE-QAG demonstrated good item and person fit, but the targeting is off. Therefore, the current version of PBE-QAG is not recommended for use in the general population. We encourage further validation of PBE-QAG in adults with mental health conditions who do not practice body awareness.
Prenatal smoking, alcohol and caffeine exposure and offspring externalising disorders: A systematic review and meta-analysis
Authors: Haan Elis , Westmoreland Kirsten E. , Schellhas Laura , Sallis Hannah M. , Taylor Gemma , Zuccolo Luisa , Munafò Marcus R.
Published: June 2021

Background and aims

Several studies have indicated that there is an association between maternal prenatal substance use and offspring externalising disorders. However, it is uncertain whether this relationship is causal. Therefore, we updated a previously conducted systematic review to determine if the literature supports 1) a causal role of maternal prenatal substance use on offspring externalising disorders and 2) whether these associations differ across externalising disorders.

Methods

We searched Web of Science, Embase, PsycINFO and Medline databases. We included studies that examined smoking, alcohol or caffeine use during pregnancy as an exposure, and diagnosis of attention-deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional-defiant disorder (ODD) in offspring as an outcome. Studies on non-English language, fetal alcohol syndrome and comorbid autism spectrum disorders were excluded. Risk of bias assessment was conducted using Newcastle Ottawa Scale (NOS) and where possible meta-analysis was conducted for studies classed as low risk of bias.

Results

We included 63 studies. All studies were narratively synthesised, and 7 studies were meta-analysed on smoking and ADHD. The majority of studies (46 studies) investigated the association between smoking and ADHD. Studies which accounted for genetic effects indicate that the association between smoking and ADHD is unlikely to be causal. Studies on alcohol exposure in all the outcomes reported inconsistent findings and no strong conclusions on causality can be made. Studies on caffeine exposure were mostly limited to ADHD and these studies do not support a causal effect.

Conclusions

There is no causal relationship between maternal smoking during pregnancy and attention-deficit hyperactivity (ADHD) in offspring. However, given that the majority of identified studies investigated the association between ADHD and smoking exposure, findings with alcohol and caffeine exposures and conduct disorder (CD) and oppositional-defiant disorder (ODD) need more research, especially using more genetically sensitive designs.
A Cluster-based Model of COVID-19 Transmission Dynamics
Authors: Shayak B , Sharma Mohit M
Published: June 2021

Many countries have manifested COVID-19 trajectories where extended periods of constant and low daily case rate suddenly transition to epidemic waves of considerable severity with no correspondingly drastic relaxation in preventive measures. Such solutions are outside the scope of classical epidemiological models. Here we construct a deterministic, discrete-time, discrete-population mathematical model which can explain these non-classical phenomena. Our key hypothesis is that with partial preventive measures in place, viral transmission occurs primarily within small, closed groups of family members and friends, which we call clusters. Inter-cluster transmission is infrequent compared to intra-cluster transmission but it is the key to determining the course of the epidemic. If inter-cluster transmission is low enough, we see stable plateau solutions. Above a cutoff level however, such transmission can destabilize a plateau into a huge wave even though its contribution to the population-averaged spreading rate still remains small. We call this the cryptogenic instability. We also find that stochastic effects when case counts are very low may result in a temporary and artificial suppression of an instability; we call this the critical mass effect. Both these phenomena are absent from conventional infectious disease models and militate against the successful management of the epidemic.
Immunochemotherapy as induction treatment in Stage III (N2, N3) Non-small cell lung cancer
Authors: Deng Hongsheng , Liang Hengrui , Wang Wei , Li Jianfu , Xiong Shan , Cheng Bo , Li Caichen , Ai Qing , Chen Zhuxing , Wang Haixuan , Liang Wenhua , He Jianxing
Published: June 2021

Background

To increase locoregional and systemic tumor control, a portion of patients with stage III (N2, N3) non-small cell lung cancer (NSCLC) received pulmonary resection after immunochemotherapy in our center. Herein, we assessed the real-world downstage (T, N stage) effectiveness of immunochemotherapy as induction treatment and explored the proper cycle number for stage III (N2, N3) NSCLC.

Methods

Biopsy confirmed stage III (N2, N3) NSCLC patients who underwent immunochemotherapy between January 1st, 2018, to August 30th, 2019, were identified. Tumor radiologic regression, lymph node down-staging, and pathological response information were collected.

Results

In total, 16 patients with stage IIIA NSCLC, 30 with stage IIIB NSCLC, 9 with stage IIIC NSCLC (N2, N3 metastasis) were included. After immunochemotherapy, 25/55 (45.5%) patients achieved an objective response. Ultimately, 33/55 (60.0%) patients received lobectomy plus systemic lymphadenectomy, of whom 18/33 (54.5%) obtained major pathological response (MPR) of the primary lesion, and 24 (72.7%) had pathological-confirmed lymph node downstage (N2-3 to N0-1). Notably, four patients had MPR of the primary lesion but without lymph node downstage. At the time of data cutoff (December 30th, 2020), the median follow-up duration was 9.2 months (IQR 8.0-11.7), 24/33 (72.7%) of patients that had pulmonary resection were progression-free, with 30 of them alive. Binary logistics analysis showed that 3-4 induction cycles were favorably associated with MPR than 1-2 cycles (p = 0.017).

Conclusions

Immunochemotherapy as induction treatment showed encouraging MPR and lymph nodes down-staging rates in stage III (N2, N3) NSCLC in this study. Prolonged (3-4) cycles of immunochemotherapy were recommended for a better pathological response.
Breadth of neutralising antibody responses to SARS-CoV-2 variants of concern is augmented by vaccination following prior infection: studies in UK healthcare workers and immunodeficient patients
Authors: Nadesalingam Angalee , Cantoni Diego , Wells David A , Aguinam Ernest T , Ferrari Matteo , Smith Peter , Chan Andrew , Carnell George , Ohlendorf Luis , Einhauser Sebastian , Wagner Ralf , Temperton Nigel , Castillo-Olivares Javier , Baxendale Helen , Heeney Jonathan L ,   the HICC consortium
Published: June 2021

Approximately 75% of the UK population has received only one dose of a 2-dose COVID-19 vaccine regime in the face of circulating SARS-CoV-2 Variants of Concern (VOCs). We aimed to determine the levels of vaccine-induced neutralising antibodies to SARS-CoV-2 variants B.1.1.7, B.1.351 and P.1. To do so, we undertook a single-centre cross-sectional study of health care workers (HCWs) and outpatients with immunodeficiencies (IDP) based at the same critical care tertiary NHS Trust, following a single dose of either BNT162b2 or AZD1222 vaccines. Data revealed low neutralising antibodies (nAbs) in IDPs, with only 5% and 3% showing detectable neutralisation of B.1.1.7 and B.1.351, respectively. In contrast, healthy HCWs without a prior SARS-CoV-2 infection demonstrated a wide range of nAb titres post-vaccination with responses significantly lower than HCWs with prior SARS-CoV-2 infection. Neutralisation of VOCs with the E484K mutation (B.1.351 and P.1) were consistently lower in HCWs in the absence of evidence of prior SARS-CoV-2 infection (p<0.001). Notably, in vaccinated HCWs with prior SARS-CoV-2 infection, there was a significant increase of neutralising titres post-vaccination to all variants, compared to their pre-vaccination neutralisation titres. This underscores the importance of vaccination to boost neutralising antibody breadth to VOCs, and also provides support for the hypothesis that repeated immunisations will boost protective immunity in individuals without prior SARS-CoV-2 exposure.
Subtle anomaly detection in MRI brain scans: Application to biomarkers extraction in patients withde novoParkinson’s disease
Authors: Muñoz-Ramírez Verónica , Kmetzsch Virgilio , Forbes Florence , Meoni Sara , Moro Elena , Dojat Michel
Published: June 2021

With the advent of recent deep learning techniques, computerized methods for automatic lesion segmentation have reached performances comparable to those of medical practitioners. However, little attention has been paid to the detection of subtle physiological changes caused by evolutive pathologies such as neurodegenerative diseases. In this work, we investigated the ability of deep learning models to detect anomalies in magnetic resonance imaging (MRI) brain scans of recently diagnosed and untreated (de novo) patients with Parkinson’s disease (PD). We evaluated two families of auto-encoders, fully convolutional and variational auto-encoders. The models were trained with diffusion tensor imaging (DTI) parameter maps of healthy controls. Then, reconstruction errors computed by the models in different brain regions allowed to classify controls and patients with ROC AUC up to 0.81. Moreover, the white matter and the subcortical structures, particularly the substantia nigra, were identified as the regions the most impacted by the disease, in accordance with the physio-pathology of PD. Our results suggest that deep learning-based anomaly detection models, even trained on a moderate number of images, are promising tools for extracting robust neuroimaging biomarkers of PD. Interestingly, such models can be seamlessly extended with additional quantitative MRI parameters and could provide new knowledge about the physio-pathology of neuro-degenerative diseases.
Small Area Estimation of Food Insecurity in the Eastern Indo-Gangetic Plain
Authors: Chandra Hukum , Guha Saurav , Desai Meghana , Pyne Saumyadipta
Published: June 2021

Achieving food security for all citizens is an important policy issue in India. While the existing data based on socio-economic surveys provide accurate estimates of food insecurity indicators at state and national level, due to small sample sizes, the surveys cannot be used directly to produce reliable estimates at the district or lower administrative levels. The availability of reliable and representative disaggregated measures of food insecurity is necessary for effective policy planning and monitoring, as food insecurity is often distributed unevenly within relatively small areas.

This article explores a small area estimation (SAE) approach to derive reliable and representative estimates of food insecurity prevalence (FIP), gap (FIG), and severity (FIS) among people in different districts of the rural areas of the Eastern Indo-Gangetic Plain (EIGP) region by linking the latest round of available data from the Household Consumer Expenditure Survey collected by the National Sample Survey Office of India as well as the latest available Indian Population Census data. District-specific food insecurity indictors such as FIP, FIG, and FIS were estimated based on a recommended threshold of per capita caloric intake of 2400 kilocalories per day, as defined by the Ministry of Health and Family Welfare, Government of India. Spatial maps showing district level inequality in the distribution of the indicators of food insecurity among the population in EIGP region are also produced. Our disaggregated estimates can provide district-specific focused insights into food insecurity to policy-analysts and decision-makers, and could thereby prove to be useful and relevant to the U.N. Sustainable Development Goal Indicator 2.1.2.
ASSESSMENT OF PERFORMANCE AND IMPLEMENTATION CHARACTERISTICS OF RAPID POINT OF CARE SARS-CoV-2 ANTIGEN TESTING
Authors: Muthamia Eva , Mungai Samuel , Mungai Mary , Bandawe Gama , Qadri Firdausi , Kawser Zannat , Lockman Shahin , Ivers Louise C. , Walt David , Suliman Sara , Mwau Matilu , Gitaka Jesse
Published: June 2021

Background

The COVID-19 pandemic has resulted in a need for rapid identification of infectious cases. Testing barriers have prohibited adequate screening for SARS COV2, resulting in significant delays in treatment provision and commencement of outbreak control measures. This study aimed to generate evidence on the performance and implementation characteristics of the BD Veritor rapid antigen test as compared to the gold standard test for diagnosis of SARS COV2 in Kenya.

Methods

This was a field test performance evaluation in symptomatic and asymptomatic adults undergoing testing for SARS COV2. Recruited participants were classified as SARS-CoV2-positive based on the locally implemented gold standard reverse transcription polymerase chain reaction (RT-PCR) test performed on nasopharyngeal swabs. 272 antigen tests were performed with simultaneous gold standard testing, allowing us to estimate sensitivity, specificity, positive and negative predictive values for the BD Veritor rapid antigen test platform. Implementation characteristics were assessed using the Consolidated Framework for Implementation Research for feasibility, acceptability, turn-around time, and ease-of-use metrics.

Results and Discussion

We enrolled 97 PCR negative symptomatic and 128 PCR negative asymptomatic, and 28 PCR positive symptomatic and 19 PCR positive asymptomatic participants. Compared to the gold standard, the sensitivity of the BD Veritor antigen test was 94% (95% confidence interval [CI] 86.6 to 100.0) while the specificity was 98% (95% confidence interval [CI] 96 to 100). The sensitivity of BD Veritor antigen test was higher among symptomatic (100%) compared to asymptomatic (84%) participants, although this difference was not statistically significant. There was also a lack of association between cycle threshold value and sensitivity of BD Veritor test. The BD Veritor test had quick turnaround time and minimal resource requirements, and laboratory personnel conducting testing felt that it was easier to use than the gold standard RT-PCR.

Conclusion

The BD Veritor rapid antigen test exhibited excellent sensitivity and specificity when used to detect SARS-CoV-2 infection among both symptomatic and asymptomatic individuals in varied population settings in Kenya. It was feasible to implement and easy to use, with rapid turnaround time.
Interpretable machine learning identifies paediatric Systemic Lupus Erythematosus subtypes based on gene expression data
Authors: Yones Sara A. , Annett Alva , Stoll Patricia , Diamanti Klev , Holmfeldt Linda , Barrenäs Carl Fredrik , Meadows Jennifer R. S. , Komorowski Jan
Published: June 2021

Transcriptomic analyses are commonly used to identify differentially expressed genes between patients and controls, or within individuals across disease courses. These methods, whilst effective, cannot encompass the combinatorial effects of genes driving disease. We applied rule-based machine learning (RBML) models and rule networks (RN) to an existing paediatric Systemic Lupus Erythematosus (SLE) blood expression dataset, with the goal of developing gene networks to separate low and high disease activity (DA1 and DA3). The resultant model had an 81% accuracy to distinguish between DA1 and DA3, with unsupervised hierarchical clustering revealing additional subgroups indicative of the immune axis involved or state of disease flare. These subgroups correlated with clinical variables, suggesting that the gene sets identified may further the understanding of gene networks that act in concert to drive disease progression. This included roles for genes i) induced by interferons (IFI35 and OTOF), ii) key to SLE cell types (KLRB1 encoding CD161), or iii) with roles in autophagy and NF-κB pathway responses (CKAP4). As demonstrated here, RBML approaches have the potential to reveal novel gene patterns from within a heterogeneous disease, facilitating patient clinical and therapeutic stratification.
An Alanine Aminotransferase is Required for Polysaccharide Regulation and Resistance of Aspergillus fumigatus Biofilms to Echinocandin Treatment
Authors: Kerkaert Joshua D. , Le Mauff François , Wucher Benjamin R. , Beattie Sarah R. , Vesely Elisa M. , Sheppard Donald C , Nadell Carey D. , Cramer Robert A.
Published: June 2021

Alanine metabolism has been suggested as an adaptation strategy to oxygen limitation in organisms ranging from plants to mammals. Within the pulmonary infection microenvironment A. fumigatus forms biofilms with steep oxygen gradients defined by regions of oxygen limitation. A significant increase in alanine levels was observed in A. fumigatus cultured under oxygen limiting conditions. An alanine aminotransferase, AlaA, was observed to function in alanine catabolism and is required for several aspects of A. fumigatus biofilm physiology. Loss of alaA, or its catalytic activity, results in decreased adherence of biofilms through a defect in the maturation of the extracellular matrix polysaccharide galactosaminogalactan (GAG). Additionally, exposure of cell wall polysaccharides is also impacted by loss of alaA and loss of AlaA catalytic activity confers increased biofilm susceptibility to echinocandin treatment which is correlated with enhanced fungicidal activity. The increase in echinocandin susceptibility is specific to biofilms and chemical inhibition of alaA by the alanine aminotransferase inhibitor β-chloro-L-alanine is sufficient to sensitize A. fumigatus biofilms to echinocandin treatment. Finally, loss of alaA increases susceptibility of A. fumigatus to in vivo echinocandin treatment in a murine model of invasive pulmonary aspergillosis. Our results provide insight into the interplay of metabolism, biofilm formation, and antifungal drug resistance in A. fumigatus and describes a mechanism of increasing susceptibility of A. fumigatus biofilms to the echinocandin class of antifungal drugs.

eLife Digest

Aspergillus fumigatus is a ubiquitous filamentous fungus that causes an array of diseases depending on the immune status of an individual, collectively termed aspergillosis. Antifungal therapy for invasive pulmonary aspergillosis (IPA) or chronic pulmonary aspergillosis (CPA) is limited and too often ineffective. This is in part due to A. fumigatus biofilm formation within the infection environment and the resulting emergent properties, particularly increased antifungal resistance. Thus, insights into biofilm formation and mechanisms driving increased antifungal drug resistance are critical for improving existing therapeutic strategies and development of novel antifungals. In this work, we describe an unexpected observation where alanine metabolism, via the alanine aminotransferase AlaA, is required for several aspects of A. fumigatus biofilm physiology including resistance of A. fumigatus biofilms to the echinocandin class of antifungal drugs. Importantly, we observed that chemical inhibition of alanine aminotransferases is sufficient to increase echinocandin susceptibility and that loss of alaA increases susceptibility to echinocandin treatment in a murine model of IPA.
Methanosarcina acetivorans simultaneously produces molybdenum, vanadium, and iron-only nitrogenases in response to fixed nitrogen and molybdenum depletion
Authors: Chanderban Melissa , Hill Christopher A. , Dhamad Ahmed E. , Lessner Daniel J.
Published: June 2021

All nitrogen-fixing bacteria and archaea (diazotrophs) use molybdenum (Mo) nitrogenase to reduce dinitrogen (N2) to ammonia. Some diazotrophs also contain alternative nitrogenases that lack Mo: vanadium (V) and iron-only (Fe) nitrogenases. Among diazotrophs, the regulation and usage of the alternative nitrogenases in methanogens is largely unknown. Methanosarcina acetivorans contains nif, vnf, and anf gene clusters encoding putative Mo-, V-, and Fe-nitrogenases, respectively. This study investigated the effect of fixed nitrogen and Mo/V availability on nitrogenase expression and growth by M. acetivorans. The availability of Mo and V did not affect growth of M. acetivorans with fixed nitrogen but significantly affected growth with N2. M. acetivorans exhibited the fastest growth rate and highest cell yield during growth with N2 in medium containing Mo. Depletion of Mo (Fe-only condition) resulted in a significant decrease in growth rate and cell yield. The addition of V to Mo-depleted medium stimulated diazotrophic growth but was still less than growth in Mo-replete medium. qPCR analysis revealed transcription of the nif operon is only moderately affected by depletion of fixed nitrogen and Mo. However, vnf and anf transcription increased significantly when fixed nitrogen and Mo were depleted, with removal of Mo being the key factor. Immunoblot analysis revealed Mo-nitrogenase is produced when fixed nitrogen is depleted regardless of Mo availability, while V- and Fe-nitrogenases are produced only in the absence of fixed nitrogen and Mo. These results reveal that alternative nitrogenase production in M. acetivorans is tightly controlled and that all three nitrogenases can be simultaneously produced.

IMPORTANCE

Methanogens and closely related methanotrophs are the only archaea known or predicted to possess nitrogenase. As such, methanogens play critical roles in both the global biological nitrogen and carbon cycles. Moreover, methanogens are an ancient microbial lineage and nitrogenase likely originated in methanogens. An understanding of the usage and properties of nitrogenases in methanogens can provide new insight into the evolution of nitrogen fixation and aid in the development nitrogenase-based biotechnology. This study provides the first evidence that a methanogen can produce all three forms of nitrogenases, even simultaneously. Surprisingly, Mo-nitrogenase was produced in cells grown in the absence of Mo, indicating components of Mo-nitrogenase regulate or are needed to produce V- and Fe-nitrogenases in methanogens. The results provide a foundation to understanding the assembly, regulation, and activity of the alternative nitrogenases in methanogens.
Definitions matter: heterogeneity of COVID-19 disease severity criteria and incomplete reporting compromise meta-analysis
Authors: Guérin Philippe J. , McLean Alistair R.D. , Rashan Sumayyah , Lawal AbdulAzeez , Watson James A , Strub-Wourgaft Nathalie , White Nicholas J
Published: June 2021

Therapeutic efficacy in COVID-19 is dependent upon disease stage and severity (treatment effect heterogeneity). Unfortunately, definitions of severity vary widely. This compromises the meta-analysis of randomised controlled trials (RCTs) and the therapeutic guidelines derived from them. The World Health Organisation ‘living’ guidelines for the treatment of COVID-19 are based on a network meta-analysis (NMA) of published RCTs. We reviewed the 81 studies included in the WHO COVID-19 living NMA and compared their severity classifications with the severity classifications employed by the international COVID-NMA initiative. The two were concordant in only 35% (24/68) of trials. Of the RCTs evaluated 69% (55/77) were considered by the WHO group to include patients with a range of severities (12 mild-moderate; 3 mild-severe; 18 mild-critical; 5 moderate-severe; 8 moderate-critical; 10 severe-critical), but the distribution of disease severities within these groups usually could not be determined, and data on the duration of illness and/or oxygen saturation values were often missing. Where severity classifications were clear there was substantial overlap in mortality across trials in different severity strata. This imprecision in severity assessment compromises the validity of some therapeutic recommendations; notably extrapolation of “lack of therapeutic benefit” shown in hospitalised severely ill patients on respiratory support to ambulant mildly ill patients is not warranted. Both harmonised unambiguous definitions of severity and individual patient data meta-analyses are needed to guide and improve therapeutic recommendations in COVID-19.
Clinical performance of two EUA-approved anti-COVID-19 IgG/IgM rapid lateral flow immunoassays using whole blood finger-sticks
Authors: Tagwerker Christian , Baig Irfan , Brunson Eric J. , Mundo Kristine , Dutra-Smith Davan , Carias-Marines Mary Jane , de Zoysa Ranulu Samanthi , Smith David J.
Published: June 2021

Serological, or antibody, tests detect immunoglobulins produced by the hosts plasma B cells following exposure to foreign antigens. Venipuncture blood draws to collect human venous whole blood, plasma from anticoagulated blood (Li+ heparin, K2EDTA and sodium citrate), or serum are commonly utilized and require refrigerated temperatures during transport to the testing facility. Subsequent laboratory testing by enzyme-linked immunosorbent assays (ELISA) or chemiluminescence immunoassays (CLIA) can take an additional 2-5 hours. In the context of the COVID-19 pandemic, rapid diagnostic tests (RDT) to be used in point-of-care (POC) and remote settings have become essential during mandatory quarantine and isolation periods. RDTs allowed for more cost-effective testing using less collection materials with an immediate (5-10 minutes) test result. However, the majority of emerging RDTs receiving Emergency Use Authorization (EUA) approval by the Food and Drug Administration (FDA) for qualitative detection and differentiation of IgM and IgG antibodies to SARS-CoV-2 were only approved for use in human venous whole blood, plasma or serum. In this study we summarize performance characteristics of one RDT (COVID-19 IgG/IgM lateral flow immunoassay rapid cassette) to another by simultaneous application of whole blood finger-stick specimens (n = 32). The study was performed over 5 different days, with daily quality controls consisting of serum previously verified to be positive or negative by COVID-19 IgG/IgM ELISA testing.
Serial intervals observed in SARS-CoV-2 B.1.617.2 variant cases
Authors: Pung Rachael , Mak Tze Minn ,   CMMID COVID-19 working group, Kucharski Adam J , Lee Vernon J.
Published: June 2021

Rapid growth of the SARS-CoV-2 variant B.1.617.2 has been observed in many countries. The factors driving the recent rapid growth of COVID-19 cases could be attributed to shorten generation intervals or higher transmissibility (effective reproduction number, R), or both. Establishing the reasons for the observed rapid growth is key for outbreak control. In this study, we analysed the serial interval of household transmission pairs infected with SARS-CoV-2 B.1.617.2 variant and compared with those who were infected prior to the occurrence of the major global SARS-CoV-2 variants. After controlling for confounding factors, our findings suggest no significant changes in the serial intervals for SARS-CoV-2 cases infected with the B.1.617.2 variant. This, in turn, lends support for the hypothesis of a higher R in B.1.617.2 cases.
Surveillance of airborne plant disease dissemination at continental scale using air mass trajectory analysis and network theory
Authors: Radici Andrea , Martinetti Davide , Bevacqua Daniele
Published: June 2021

Sustainable management of plant disease outbreaks in agriculture is one of the main challenges of the next years to restore economic and environmental viability of farming practices. Improving early-detection capabilities and disease surveillance is increasingly seen as an obligate step to design appropriate and effective prophylactic measures. In this context, plant diseases caused by wind-dispersed pathogens represent an interesting case of study, since they are particularly complex and hard to observe directly, especially if compared to other dissemination means, and demand for a multidisciplinary approach to be dealt with. Wind dispersal could imply a geographic differentiation in pathogens spreading potential, due to the emerging of local meteorological features. In this work we analyze the spatio-temporal patterns of wind connectivity in Europe and the Mediterranean basin in order to identify possible pathways of Puccinia graminis spores, the causal agent of stem rust of wheat. By running backwards Lagrangian simulations merging a biological layer coupled with a pathogen viability model, we investigate possible long-distance connections between regions in the study area across different seasons. We characterized these regions in terms of network centrality indicators to identify possible spreaders of stem rust of wheat, founding that Central and Western European regions appears to provide highest connectivity for the spread of P. graminis.
C. elegansTFIIH subunit GTF-2H5/TTDA is a non-essential transcription factor indispensable for DNA repair
Authors: Thijssen Karen L. , van der Woude Melanie , Davó-Martínez Carlota , Sabatella Mariangela , Vermeulen Wim , Lans Hannes
Published: June 2021

The 10-subunit TFIIH complex is vital to both transcription initiation and nucleotide excision repair. Hereditary mutations in its smallest subunit, TTDA/GTF2H5, cause a photosensitive form of the rare developmental brittle hair disorder trichothiodystrophy (TTD). Some TTD features are thought to be caused by subtle transcription or gene expression defects. Strikingly, TTDA/GTF2H5 knockout mice are not viable, which makes it difficult to investigate how TTDA/GTF2H5 promotes transcriptionin vivo. Here, we show that deficiency of theC. elegansTTDA ortholog GTF-2H5 is, however, compatible with viability and growth, in contrast to depletion of other TFIIH subunits. We also show that GTF-2H5 promotes the stability of TFIIH in multiple tissues and is indispensable for nucleotide excision repair, in which it facilitates recruitment of the TFIIH complex to DNA damage. Strikingly, when transcription is challenged,gtf-2H5embryos die due to the intrinsic TFIIH fragility in the absence of GTF-2H5. These results support the idea that TTDA/GTF2H5 mutations cause transcription impairment underlying trichothiodystrophy and establishC. elegansas potential model for studying the pathogenesis of this disease.
Detection of an unstable minor QTL linked to fire blight resistance on linkage group 16 of Malus fusca
Authors: Emeriewen Ofere Francis , Richter Klaus , Wensing Annette , Malnoy Mickael , Peil Andreas
Published: June 2021

Objective

Erwinia amylovora causes fire blight disease in Malus. A strong resistance QTL (Mfu10) was previously detected on linkage group 10 of Malus fusca accession MAL0045, using several strains of the bacterium. As no strain capable of breaking the resistance of MAL0045 has been found, it was hypothesized that a second resistance factor contributes to the fire blight resistance of MAL0045. However, to date, no minor locus has been detected with previously published strains of the bacterium. We detected a minor QTL only on a subset of a population following inoculation with strain Ea1038, which heterologously expresses an effector in a derivative of isolate Ea3049. Two genetic maps of MAL0045, one scarce, the other dense with markers, were used for QTL analyses.

Results

Mfu10 was detected on LG10 with Ea1038, as was previously with Ea3049. Although no other QTLs of significant LOD was previously detected in other linkage groups with Ea3049, a QTL of significant LOD was detected on LG16 (Mfu16) after inoculation of a subset of 76 individuals with Ea1038, but only using the dense genetic map. Mfu16 improved the effect of Mfu10. However, when the number of individuals inoculated with Ea1038 was increased to 121, Mfu16 was no longer detected in the dense genetic map. We hypothesize some factors, which might be responsible for the instability of this QTL.
Desiccation-driven senescence and its repression in Xerophyta schlechteri are regulated at extremely low water contents
Authors: Radermacher Astrid L. , Williams Brett , Iranzadeh Arash , Dace Halford , Mundree Sagadevan , Hilhorst Henk W.M. , Farrant Jill M.
Published: June 2021

Vegetative desiccation tolerance, the ability to survive loss of over 90% of cellular water, is an extremely rare trait in Angiosperms. Xerophyta schlechteri survives such extreme water deficit by entering prolonged quiescence and suppressing drought-induced senescence in most of the leaf area, except the apical tip. Information on the molecular regulation of senescence in such plants is scarce and this is the first study to investigate such regulation in senescing and non-senescing tissues of the same leaf.

Genome-wide RNA sequencing enabled comparison of senescent and non-senescent tissues during desiccation and early rehydration, establishment of the water content range in which senescence is initiated and identification of molecular mechanisms employed to bring about cellular death.

Senescence-associated genes (XsSAG) specific to this species were identified and two potential regulatory sites were enriched in regions upstream to these XsSAGs, allowing us to create a model of senescence regulation in X. schlechteri based on homology with known Arabidopsis senescence regulators.

We hypothesise that desiccation-driven senescence occurs as a result of a convergence of signals around MAPK6 to trigger WRKY-mediated ethylene synthesis and XsSAG expression, not unlike aging and stress-related senescence in Arabidopsis, but at remarkably lower water contents (<35% RWC).
Topological and Structural Plasticity of the single Ig fold and the double Ig fold present in CD19
Authors: Youkharibache Philippe
Published: June 2021

The Ig-fold has had a remarkable success in vertebrate evolution, with a presence in over 2% of human genes. The Ig-fold is not just the elementary structural domain of antibodies and TCRs, it is also at the heart of a staggering 30% of immunologic cell surface receptors, making it a major orchestrator of cell-cell-interactions. While BCRs, TCRs, and numerous Ig-based cell surface receptors form homo or heterodimers on the same cell surface (in cis), many of them interface as ligand-receptors (checkpoints) on interacting cells (in trans) through their Ig domains. New Ig-Ig interfaces are still being discovered between Ig-based cell surface receptors, even in well known families such as B7. What is largely ignored however is that the Ig-fold itself is pseudo-symmetric, a property that makes the Ig-domain a versatile self-associative 3D structure and may in part explain its success in evolution, especially through its ability to bind in cis or in trans in the context of cell surface receptor-ligand interactions. In this paper we review the Ig domains tertiary and quaternary pseudo symmetries, with a particular attention to the newly identified double Ig fold in the solved CD19 molecular structure to highlight the underlying fundamental folding elements of Ig domains, i.e. Ig protodomains. This pseudosymmetric property of Ig domains gives us a decoding frame of reference to understand the fold, relate all Ig-domain forms, single or double, and suggest new protein engineering avenues.
Peptide-based inhibitors of Tau aggregation as a potential therapeutic for Alzheimer’s disease and other Tauopathies
Authors: Aggidis Anthony , Chatterjee Shreyasi , Townsend David , Fullwood Nigel J. , Ortega Eva Ruiz , Tarutani Airi , Hasegawa Masato , Lucas Hannah , Mudher Amritpal , Allsop David
Published: June 2021

There are currently no disease altering drugs available for Tauopathies such as Alzheimer’s disease, which alone is predicted to affect ~88 million people worldwide by 2050. As Tau aggregation underpins its toxicity, aggregation inhibitors are likely to have disease-modifying potential. Guided by in-silico mutagenesis studies, we developed a potent retro-inverso peptide inhibitor of Tau aggregation, RI-AG03 [Ac-rrrrrrrrGpkyk(ac)iqvGr-NH2], based on the306VQIVYK311hotspot. Aggregation of recombinant Tau was reduced by >90% with equimolar RI-AG03 and no fibrils were observed by EM. When added during the growth phase, RI-AG03 blocked seeded aggregation. Fluorescein-tagged RI-AG03 efficiently penetrated HEK-293 cells over 24 hours and was non-toxic at doses up to 30 μM. In transgenicDrosophila, RI-AG03 significantly improves neurodegenerative and behavioural phenotypes caused by expression of human Tau. Collectively this shows that RI-AG03 can effectively reduce Tau aggregationin vitroand block aggregation-dependent phenotypesin vivo, raising possibilities for exploring its translational potential.
Targeted anti-BCR-ABL+ ALL therapy may benefit the heart
Authors: Kirchhoff Hanna , Ricke-Hoch Melanie , Wohlan Katharina , Pietzsch Stefan , Karsli Ümran , Erschow Sergej , Zweigerdt Robert , Ganser Arnold , Eder Matthias , Scherr Michaela , Hilfiker-Kleiner Denise
Published: June 2021

Targeted therapies are currently considered the best cost-benefit anti-cancer treatment. In hematological malignancies, however, relapse rates and non-hematopoietic side effects including cardiotoxicity remain high. We here describe significant heart damage due to advanced acute lymphoblastic leukemia with t(9;22) encoding the bcr-abl oncogene (BCR-ABL+ ALL) in murine xenotransplantation models. Echocardiography reveals severe cardiac dysfunction with impaired left ventricular function and reduced heart and cardiomyocyte dimensions associated with increased apoptosis. This cardiac damage is fully reversible, but cardiac recovery depends on the therapy used to induce ALL remission. Chemotherapy-free therapy with dasatinib and venetoclax (targeting the BCR-ABL oncoprotein and mitochondrial Bcl2, respectively), as well as dexamethasone can fully revert cardiac defects whereas depletion of otherwise identical ALL in a genetic model using HSV-TK cannot. Mechanistically, dexamethasone induces pro-apoptotic BIM expression and apoptosis in ALL cells but enhances pro-survival BCLXL expression in cardiomyocytes and clinical recovery with reversion of cardiac atrophy. These data demonstrate that therapies designed to optimize apoptosis induction in ALL may circumvent cardiac on-target side effects and may even activate cardiac recovery. In the future, combining careful clinical monitoring of cardiotoxicity in leukemic patients with further characterization of organ-specific side effects and signaling pathways activated by malignancy and/or anti-tumor therapies seems reasonable.
CRISPR-Cas systems are widespread accessory elements across bacterial and archaeal plasmids
Authors: Pinilla-Redondo Rafael , Russel Jakob , Mayo-Muñoz David , Shah Shiraz A. , Garrett Roger A. , Nesme Joseph , Madsen Jonas S. , Fineran Peter C. , Sørensen Søren J.
Published: June 2021

Many prokaryotes encode CRISPR-Cas systems as immune protection against mobile genetic elements (MGEs), yet, a number of MGEs also harbor CRISPR-Cas components. With a few exceptions, CRISPR-Cas loci encoded on MGEs are uncharted and a comprehensive analysis of their distribution, prevalence, diversity, and function is lacking. Here, we systematically investigated CRISPR-Cas loci across the largest curated collection of natural bacterial and archaeal plasmids. CRISPR-Cas loci are widely but heterogeneously distributed across plasmids and, in comparison to host chromosomes, their mean prevalence per Mbp is higher and their distribution is markedly distinct. Furthermore, the spacer content of plasmid CRISPRs exhibits a strong targeting bias towards other plasmids, while chromosomal arrays are enriched with virus-targeting spacers. These contrasting targeting preferences dominate across the diversity of CRISPR-Cas subtypes and host taxa, highlighting the genetic independence of plasmids and suggesting a major role of CRISPR-Cas for mediating plasmid-plasmid conflicts. Altogether, CRISPR-Cas are frequent accessory components of many plasmids, which is an overlooked phenomenon that possibly facilitates their dissemination across microbiomes.
A novel Fiji/ImageJ plugin for the rapid analysis of blebbing cells
Authors: Vosatka Karl W. , Lavenus Sandrine B. , Logue Jeremy S.
Published: June 2021

When confined, cells have recently been shown to undergo a phenotypic switch to what has been termed, fast amoeboid (leader bleb-based) migration. However, as this is a nascent area of research, few tools are available for the rapid analysis of cell behavior. Here, we demonstrate that a novel Fiji/ImageJ-based plugin, Analyze_Blebs, can be used to quickly obtain cell migration parameters and morphometrics from time lapse images. As validation, we show that Analyze_Blebs can detect significant differences in cell migration and morphometrics, such as the largest bleb size, upon introducing different live markers of F-actin, including F-tractin and LifeAct tagged with green and red fluorescent proteins. We also demonstrate, using flow cytometry, that live markers increase total levels of F-actin. Furthermore, that F-tractin increases cell stiffness, which was found to correlate with a decrease in migration, thus reaffirming the importance of cell mechanics as a determinant of Leader Bleb-Based Migration (LBBM).

Highlight summary

A new plugin, Analyze_Blebs, enables the rapid analysis of cell migration and morphometrics of fast amoeboid cells. Morphometrics combined with cell stiffness are found to be predictive of confined, fast amoeboid (leader bleb-based), migration.
A hybridin silicoapproach reveals novel inhibitors of multiple SARS-CoV-2 variants
Authors: Jain Sankalp , Talley Daniel C. , Baljinnyam Bolormaa , Choe Jun , Hanson Quinlin , Zhu Wei , Xu Miao , Chen Catherine Z. , Zheng Wei , Hu Xin , Shen Min , Rai Ganesha , Hall Matthew D. , Simeonov Anton , Zakharov Alexey V.
Published: June 2021

The National Center for Advancing Translational Sciences (NCATS) has been actively generating SARS-CoV-2 high-throughput screening data and disseminates it through the OpenData Portal (https://opendata.ncats.nih.gov/covid19/). Here, we provide a hybrid approach that utilizes NCATS screening data from the SARS-CoV-2 cytophatic effect reduction assay to build predictive models, using both machine learning and pharmacophore-based modeling. Optimized models were used to perform two iterative rounds of virtual screening to predict small molecules active against SARS-CoV-2. Experimental testing with live virus provided 100 (~16% of predicted hits) active compounds (Efficacy > 30%, IC50≤ 15 μM). Systematic clustering analysis of active compounds revealed three promising chemotypes which have not been previously identified as inhibitors of SARS-CoV-2 infection. Further analysis identified allosteric binders to host receptor angiotensin-converting enzyme 2, which were able to inhibit the entry of pseudoparticles bearing spike protein of wild type SARS-CoV-2 as well as South African B.1.351 and UK B.1.1.7 variants.
Maize Brittle Stalk2-Like3, encoding a COBRA protein, functions in cell wall formation and carbohydrate partitioning
Authors: Julius Benjamin T. , McCubbin Tyler J. , Mertz Rachel A. , Baert Nick , Knoblauch Jan , Grant DeAna G. , Conner Kyle , Bihmidine Saadia , Chomet Paul , Wagner Ruth , Woessner Jeff , Grote Karen , Peevers Jeanette , Slewinski Thomas L. , McCann Maureen C. , Carpita Nicholas C. , Knoblauch Michael , Braun David M.
Published: June 2021

Carbohydrate partitioning from leaves to sink tissues is essential for plant growth and development. The maize (Zea mays) recessive carbohydrate partitioning defective28 (cpd28) and cpd47 mutants exhibit leaf chlorosis and accumulation of starch and soluble sugars. Transport studies with 14C-sucrose (Suc) found drastically decreased export from mature leaves in cpd28 and cpd47 mutants relative to wild-type siblings. Consistent with decreased Suc export, cpd28 mutants exhibited decreased phloem pressure in mature leaves, and altered phloem cell wall ultrastructure in immature and mature leaves. We identified the causative mutations in the Brittle Stalk2-Like3 (BK2L3) gene, a member of the COBRA family, which is involved in cell wall development across angiosperms. None of the previously characterized COBRA genes are reported to affect carbohydrate export. Consistent with other characterized COBRA members, the BK2L3 protein localized to the plasma membrane, and the mutants condition a dwarf phenotype in dark-grown shoots and primary roots, as well as the loss of anisotropic cell elongation in the root elongation zone. Likewise, both mutants exhibit a significant cellulose deficiency in mature leaves. Therefore, BK2L3 functions in tissue growth and cell wall development, and this work elucidates a unique connection between cellulose deposition in the phloem and whole-plant carbohydrate partitioning.

Funding Information

The research was supported by US National Science Foundation Plant Genome Research Program grants (IOS-1025976 and IOS-1444448) to DMB.
Targeting DNA topoisomerases or checkpoint kinases results in an overload of chaperone systems, triggering aggregation of a metastable subproteome
Authors: Huiting Wouter , Dekker Suzanne L. , van der Lienden Joris C. J. , Mergener Rafaella , Furtado Gabriel V. , Gerrits Emma , Musskopf Maiara K. , Oghbaie Mehrnoosh , Di Stefano Luciano H. , van Waarde-Verhagen Maria A.W.H. , Couzijn Suzanne , Barazzuol Lara , LaCava John , Kampinga Harm H. , Bergink Steven
Published: June 2021

A loss of the checkpoint kinase ATM leads to impairments in the DNA damage response, and in humans causes cerebellar neurodegeneration, and a high risk to cancer. A loss of ATM is also associated with increased protein aggregation. The relevance and characteristics of this aggregation are still incompletely understood. Moreover, it is unclear to what extent other genotoxic conditions can trigger protein aggregation as well. Here, we show that targeting ATM, but also ATR or DNA topoisomerases result in a similar, widespread aggregation of a metastable, disease-associated subfraction of the proteome. Aggregation-prone model substrates, including Huntingtin exon1 containing an expanded polyglutamine repeat, aggregate faster under these conditions. This increased aggregation results from an overload of chaperone systems, which lowers the cell-intrinsic threshold for proteins to aggregate. In line with this, we find that inhibition of the HSP70 chaperone system further exacerbates the increased protein aggregation. Moreover, we identify the molecular chaperone HSPB5 as a potent suppressor of it. Our findings reveal that various genotoxic conditions trigger widespread protein aggregation in a manner that is highly reminiscent of the aggregation occurring in situations of proteotoxic stress and in proteinopathies.