bluuebunny/crossref_metadata_2025 huggingface dataset:
Accumulation of copy-back viral genomes during respiratory syncytial virus infection is preceded by diversification of the copy-back viral genome population followed by selection
Authors: Felt Sébastien A. , Achouri Emna , Faber Sydney R. , López Carolina B.
Published: May 2022

RNA viruses generate non-standard viral genomes during their replication, including viral genomes of the copy-back (cbVG) type that cannot replicate in the absence of a standard virus. cbVGs play a crucial role in shaping virus infection outcomes due to their ability to interfere with virus replication and induce strong immune responses. However, despite their critical role during infection, the principles that drive the selection and evolution of cbVGs within a virus population are poorly understood. As cbVGs are dependent on the virus replication machinery to be generated and replicated, we hypothesized that host factors that affect virus replication exert selective pressure on cbVGs and drive their evolution within a virus population. To test this hypothesis, we used respiratory syncytial virus (RSV) as model and took an experimental evolution approach by serially passaging RSV in immune competent A549 control and immune deficient A549 STAT1 KO cells which allow higher levels of virus replication. As predicted, we observed that virus populations accumulated higher amounts of cbVGs in the more permissive A549 STAT1 KO cells over time but, unexpectedly, the predominant cbVG species after passages in the two conditions were different. While A549 STAT1 KO cells accumulated relatively short cbVGs, A549 control cells mainly contained cbVGs of much longer predicted size that have not been described previously. These long cbVGs were predominant at first in both cell linesin vitroand the predominant ones observed in samples from RSV infected patients. Although sustained high replication levels are associated with cbVG generation and accumulation, our data show that sustained high levels of virus replication are critical for cbVG population diversification, a process that preceded the generation of shorter cbVGs that selectively accumulated over time. Taken together, we show that selection and evolution of cbVGs within a virus population is shaped by how resistant or permissive a host is to RSV.
Using Extracellular Vesicles Released by GDNF-transfected Macrophages for Therapy of Parkinson’s Disease
Authors: Zhao Yuling , Haney Matthew J. , Fallon John K. , Rodriguez Myosotys , Swain Carson J. , Arzt Camryn J. , Smith Philip C. , Loop Matthew Shane , Harrison Emily B. , El-Hage Nazira , Batrakova Elena V.
Published: May 2022

Extracellular vesicles (EVs) are cell-derived nanoparticles that facilitate transport of proteins, lipids and genetic material playing important roles in intracellular communication. They have a remarkable potential as non-toxic and non-immunogenic nanocarriers for drug delivery to unreachable organs and tissues, in particular, the central nervous system (CNS). Herein, we developed a novel platform based on macrophage derived EVs to treat Parkinson’s disease (PD). Specifically, we evaluated the therapeutic potential of EVs secreted by autologous macrophages that were transfectedex vivoto express glial cell line-derived neurotrophic factor (GDNF). EV-GDNF were collected from conditioned media of GDNF-transfected macrophages and characterized for GDNF content, size, charge, and expression of EV-specific proteins. The data revealed that along with the encoded neurotrophic factor, EVs released by pre-transfected macrophages carry GDNF-encoding DNA. Four months-old transgenic Parkin Q311(X)A mice were treated with EV-GDNFviaintranasal administration, and the effect of this therapeutic intervention on locomotor functions was assessed over a year. Significant improvements in mobility, increase in neuronal survival, and decrease in neuroinflammation were found in PD mice treated with EV-GDNF. No offsite toxicity caused by EV-GDNF administrations was detected. Overall, EV-based approach can provide a versatile and potent therapeutic intervention for PD.
Non-invasive monitoring of microbiota and host metabolism using Secondary electrospray ionization-Mass spectrometry
Authors: Lan Jiayi , Greter Giorgia , Streckenbach Bettina , Arnoldini Markus , Zenobi Renato , Slack Emma
Published: May 2022

The metabolic “handshake” between the microbiota and its mammalian host is a complex, dynamic process with potentially major influences on health. Dissecting the interaction between microbial species/strains and metabolites found in host tissues has been a challenge due to the high diversity of a complete micro-biota and the requirement for invasive sampling, which precludes high-resolution longitudinal analysis. Here we demonstrate that secondary electrospray ionization mass spectrometry can be used to non-invasively monitor metabolic activity of the intestinal microbiome of a live, awake mouse. This was achieved via analysis of the headspace volatile and semi-volatile metabolome of individual gut microbiota bacterial species growing in pure culture, as well as from live gnotobiotic mice specifically colonized with these microbes (i.e. metabolites released to the atmosphere via breath, the skin and from the gut). The microbial origin of these compounds was confirmed by feeding of heavy-isotope labeled microbiota-accessible sugars. This reveals that the microbiota is a major contributor to the released metabolites of a whole live mouse, and that it is possible to capture the catabolism of sugars and cross-feeding within the gut microbiota of a living animal using volatile/semi-volatile metabolite monitoring.
A system for generating reversible knockout cell lines
Authors: DiTacchio Kacee A. , DiTacchio Luciano
Published: May 2022

A powerful use of gene editing technology is the generation of genetic-null (knockout) mutants of human immortalized cell lines. However, a problem that arises in the process of generating such edited lines is that to ensure edit homogeneity, clonal selection must often be performed and, given the genomic instability of immortalized cell lines and the high division number inherent to the clonal selection process, the resulting clone can exhibit genotypic and phenotypic differences from the parental line. Here, we present a system that allows for the generation of genetic null cell lines with an excisable cassette. This system allows for the generation of suitable controls without the need of further rounds of clonal selection.
A Versatile Nanoluciferase Reporter Reveals Structural Properties Associated With a Highly Efficient, N-Terminal Legionella pneumophila type IV Secretion Translocation Signal
Authors: Kang Yoon-Suk , Kirby James E.
Published: May 2022

Many gram-negative pathogens rely on type IV secretion systems (T4SS) for infection. One limitation in the field has been the lack of ideal reporters to identify T4SS translocated effectors and study T4SS function. Most existing reporter systems make use of fusions to reporter proteins, for example, β-lactamase, to detect translocated enzymatic activity inside the host cell. However, these systems require costly substrates, complex procedures to separate eukaryotic cytoplasm for analysis, and/or are insensitive. Here, we developed and characterized a novel reporter system using nanoluciferase (NLuc) fusions to address these limitations. Serendipitously, we discovered that Nluc itself is efficiently translocated by L. pneumophila T4SS in an IcmSW chaperone-dependent manner via an N-terminal translocation signal. Extensive directed and random mutagenesis in the NLuc N-terminus revealed a critical α-helical domain spanning D5 to V9, as mutations that are predicted to disrupt this α-helix were translocation defective. Notably, NLuc was capable of translocating several proteins examined when fused to the N or C-terminus, while maintaining robust luciferase activity. In particular, it delivered the split GFP11 fragment into J774 macrophages permanently transfected with GFPopt, thereby resulting in in vivo assembly of superfolder GFP. This provided a bifunctional assay in which translocation could be assayed in by fluorescence microplate, confocal microscopy, and/or luciferase assay. We further identified an optimal NLuc substrate, which allowed a robust, inexpensive, one-step, high throughput screening assay to identify T4SS translocation substrates and inhibitors. Taken, together NLuc provides both new insight into and tools for studying T4SS biology.

Importance

Type IV secretion systems (T4SS) are used by gram-negative pathogens to coopt host cell function. However, the translocation signals recognized by T4SS are not fully explained by primary amino acid sequence, suggesting yet to be defined contributions of secondary and tertiary structure. Here, we unexpectedly identify nanoluciferase (NLuc) as an efficient IcmSW-dependent translocated T4SS substrate and provide extensive mutagenesis data suggesting that the first N-terminal, alpha helix domain is a critical translocation recognition motif. Notably, most existing reporter systems for studying translocated proteins make use of fusions to reporters to permit detection of translocated enzymatic activity inside the host cell. However, existing systems require extremely costly substrates, complex technical procedures to isolate eukaryotic cytoplasm for analysis, and/or are insensitive. Importantly, we find that NLuc provides a powerful, cost-effective new tool to address these limitations and facilitate high throughput exploration of secretion system biology.
Women’s knowledge, attitudes and views of preconception health and intervention delivery methods: A cross-sectional survey
Authors: Daly Michael P , White James , Sanders Julia , Kipping Ruth R
Published: May 2022

Background

Several preconception exposures have been associated with adverse pregnancy, birth and postpartum outcomes. However, few studies have investigated women’s knowledge of and attitudes towards preconception health, and the acceptability of potential intervention methods.

Methods

Seven GP practices in the West of England posted questionnaires to 4,330 female patients aged 18 to 48 years. Without providing examples, we asked women to list maternal preconception exposures that might affect infant and maternal outcomes, and assessed their knowledge of nine literature-derived risk factors. Attitudes towards preconception health (interest, intentions, self-efficacy and perceived awareness and importance) and the acceptability of intervention delivery methods were also assessed. Multivariable multilevel regression examined participant characteristics associated with these outcomes.

Results

Of those who received questionnaires, 835 (19.3%) responded. Women were most aware of the preconception risk factors of diet (86.0%) and physical activity (79.2%). Few were aware of weight (40.1%), folic acid (32.9%), abuse (6.3%), advanced age (5.9%) and interpregnancy intervals (0.2%), and none mentioned interpregnancy weight change or excess iron intake. After adjusting for demographic and reproductive covariates, women aged 18-25-years (compared to 40-48-years) and nulligravid women were less aware of the benefit of preconception folic acid supplementation (adjusted odds ratios (aOR) for age: 4.30 [2.10-8.80], gravidity: aOR 2.48 [1.70-3.62]). Younger women were more interested in learning more about preconception health (aOR 0.37 [0.21-0.63]) but nulligravid women were less interested in this (aOR 1.79 [1.30-2.46]). Women with the lowest household incomes (versus the highest) were less aware of preconception weight as a risk factor (aOR: 3.11 [1.65-5.84]) and rated the importance of preconception health lower (aOR 3.38 [1.90-6.00]). The most acceptable information delivery channels were websites/apps (99.5%), printed healthcare materials (98.6%), family/partners (96.3%), schools (94.4%), television (91.9%), pregnancy tests (91.0%) and doctors, midwives and nurses (86.8-97.0%). Dentists (23.9%) and hairdressers/beauticians (18.1%) were the least acceptable.

Conclusions

Our findings demonstrate a need to promote awareness of preconception risk factors and motivation for preconception health changes, particularly amongst younger and nulligravid women and women with lower incomes. Interventions to improve preconception health should focus on communication from healthcare professionals, schools, family members, and digital media.
pyTCR: a comprehensive and scalable platform for TCR-Seq data analysis to facilitate reproducibility and rigor of immunogenomics research
Authors: Peng Kerui , Moore Jaden , Brito Jaqueline , Kao Guoyun , Burkhardt Amanda M. , Alachkar Houda , Mangul Serghei
Published: May 2022

T cell receptor (TCR) studies have grown substantially with the advancement in the sequencing techniques of T cell receptor repertoire sequencing (TCR-Seq). The analysis of the TCR-Seq data requires computational skills to run the computational analysis of TCR repertoire tools. However biomedical researchers with limited computational backgrounds face numerous obstacles to properly and efficiently utilizing bioinformatics tools for analyzing TCR-Seq data. Here we report pyTCR, a computational notebook-based platform for comprehensive and scalable TCR-Seq data analysis. Computational notebooks, which combine code, calculations, and visualization, are able to provide users with a high level of flexibility and transparency for the analysis. Additionally, computational notebooks are demonstrated to be user-friendly and suitable for researchers with limited computational skills. Our platform has a rich set of functionalities including various TCR metrics, statistical analysis, and customizable visualizations. The application of pyTCR on large and diverse TCR-Seq datasets will enable the effective analysis of large-scale TCR-Seq data with flexibility, and eventually facilitate new discoveries.
Magneto-acoustic protein nanostructures for non-invasive imaging of tissue mechanics in vivo
Authors: Kim Whee-Soo , Min Sungjin , Kim Su Kyeom , Kang Sunghwi , Davis Hunter , Bar-Zion Avinoam , Malounda Dina , Kim Yu Heun , An Soohwan , Lee Jae-Hyun , Bae Soo Han , Lee Jin Gu , Kwak Minsuk , Cho Seung-Woo , Shapiro Mikhail G. , Cheon Jinwoo
Published: May 2022

Measuring cellular and tissue mechanics inside intact living organisms is essential for interrogating the roles of force in physiological and disease processes, and is a major goal in the field of mechanobiology. However, existing biosensors for 3D tissue mechanics, primarily based on fluorescent emissions and deformable materials, are limited for in vivo measurement due to the limited light penetration and poor material stability inside intact, living organisms. While magneto-motive ultrasound (MMUS), which uses superparamagnetic nanoparticles as imaging contrast agents, has emerged as a promising modality for real-time in vivo imaging of tissue mechanics, it has poor sensitivity and spatiotemporal resolution. To overcome these limitations, we introduce magneto-gas vesicles (MGVs), a unique class of protein nanostructures based on gas vesicles and magnetic nanoparticles that produces differential ultrasound signals in response to varying mechanical properties of surrounding tissues. These hybrid protein nanostructures significantly improve signal strength and detection sensitivity. Furthermore, MGVs enable non-invasive, long-term, and quantitative measurement of mechanical properties within 3D tissues and organs in vivo. We demonstrated the performance of MGV-based mechano-sensors in vitro, in fibrosis models of organoids, and in vivo in mouse liver fibrosis models.
The emergence of variants with increased fitness accelerates the slowdown of genome sequence heterogeneity in the SARS-CoV-2 coronavirus
Authors: Oliver José L. , Bernaola-Galván Pedro , Perfectti Francisco , Martín Cristina Gómez , Castiglione Silvia , Raia Pasquale , Verdú Miguel , Moya Andrés
Published: May 2022

Disclaimer text

The author has withdrawn this manuscript due to a duplicate posting of manuscript number BIORXIV/2021/467547. Therefore, the author does not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Low heritability of crossover rate in wild sticklebacks
Authors: Kivikoski Mikko , Fraimout Antoine , Rastas Pasi , Löytynoja Ari , Merilä Juha
Published: May 2022

Crossover rate is mostly studied with domesticated or lab-reared populations and little is known about its genetic variation in the wild. We studied the variation and genetic underpinnings of crossover rate in outbred wild nine- (Pungitius pungitius) and three-spined (Gasterosteus aculeatus) sticklebacks. In both species, the crossover rate of females exceeded that of males as did also its repeatability (RFemales=0.21–0.33,RMales=0.026–0.11), implying individual differences of crossover rate in females, but no or less so in males. However, in both species and sexes additive genetic variance and heritability of crossover rate were effectively zero. A review of the previously reported repeatability and heritability estimates revealed that the repeatabilities in stickleback females were moderately high, whereas those in males were very low. Genome-wide association analyses recovered a few candidate regions possibly involved with control of crossover rate. The low additive genetic variance of crossover rate in wild sticklebacks suggest limited evolvability of crossover rate.
Virological characteristics of the novel SARS-CoV-2 Omicron variants including BA.2.12.1, BA.4 and BA.5
Authors: Kimura Izumi , Yamasoba Daichi , Tamura Tomokazu , Nao Naganori , Oda Yoshitaka , Mitoma Shuya , Ito Jumpei , Nasser Hesham , Zahradnik Jiri , Uriu Keiya , Fujita Shigeru , Kosugi Yusuke , Wang Lei , Tsuda Masumi , Kishimoto Mai , Ito Hayato , Suzuki Rigel , Shimizu Ryo , Begum MST Monira , Yoshimatsu Kumiko , Sasaki Jiei , Sasaki-Tabata Kaori , Yamamoto Yuki , Nagamoto Tetsuharu , Kanamune Jun , Kobiyama Kouji , Asakura Hiroyuki , Nagashima Mami , Sadamasu Kenji , Yoshimura Kazuhisa , Kuramochi Jin , Schreiber Gideon , Ishii Ken J , Hashiguchi Takao ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ikeda Terumasa , Saito Akatsuki , Fukuhara Takasuke , Tanaka Shinya , Matsuno Keita , Sato Kei
Published: May 2022

After the global spread of SARS-CoV-2 Omicron BA.2 lineage, some BA.2-related variants that acquire mutations in the L452 residue of spike protein, such as BA.2.9.1 and BA.2.13 (L452M), BA.2.12.1 (L452Q), and BA.2.11, BA.4 and BA.5 (L452R), emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these L452R/M/Q-bearing BA.2-related Omicron variants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1 and BA.2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. Furthermore, infection experiments using hamsters indicated that BA.4/5 is more pathogenic than BA.2. Altogether, our multiscale investigations suggest that the risk of L452R/M/Q-bearing BA.2-related Omicron variants, particularly BA.4 and BA.5, to global health is potentially greater than that of original BA.2.

Highlights

Spike L452R/Q/M mutations increase the effective reproduction number of BA.2

BA.4/5 is resistant to the immunity induced by BA.1 and BA.2 infections

BA.2.12.1 and BA.4/5 more efficiently spread in human lung cells than BA.2

BA.4/5 is more pathogenic than BA.2 in hamsters
O-GlcNAc transferase plays a non-catalytic role in C. elegans male fertility
Authors: Konzman Daniel , Fukushige Tetsunari , Dagnachew Mesgana , Krause Michael , Hanover John A.
Published: May 2022

Animal behavior is influenced by the competing drives to maintain energy and to reproduce. The balance between these evolutionary pressures and how nutrient signaling pathways intersect with mating drive remains unclear. The nutrient sensor O-GlcNAc transferase, which post-translationally modifies intracellular proteins with a single monosaccharide, is responsive to cellular nutrient status and regulates diverse biological processes. Though essential in most metazoans, O-GlcNAc transferase (ogt-1) is dispensable in Caenorhabditis elegans, allowing genetic analysis of its physiological roles. Compared to control, ogt-1 males have a four-fold reduction in mean offspring, with nearly two thirds producing zero progeny. Interestingly, we found that isolated ogt-1 males are less likely to engage in mate-searching, and they initiate mating less often when exposed to mates. In addition, ogt-1 males which do initiate mating are less likely to continue with subsequent steps in the mating process, resulting in fewer successful sperm transfers. Lowering barriers to mating such as immobilizing mates or allowing more mating time significantly improves ogt-1 male mating. Surprisingly, we found high fertility levels for ogt-1 mutant males with hypodermal expression of wild-type ogt-1 and by ogt-1 harboring mutations that prevent the transfer of O-GlcNAc by OGT-1. This suggests OGT-1 serves a non-catalytic function in the hypodermis impacting the male mating drive. This study builds upon research on the nutrient sensor O- GlcNAc transferase and demonstrates a role it plays in the interplay between the evolutionary drives for reproduction and survival.

Author Summary

Animals must make decisions on whether to engage in reproduction or conserve energy. These decisions must take into account the energy available to the animal, therefore making the nutrient sensing enzyme OGT of particular interest. In response to nutrient levels in the cell, OGT transfers the GlcNAc sugar onto proteins to regulate their function. OGT is implicated in a number of human diseases including diabetes, cancer, and X-linked intellectual disability. By deleting the gene encoding OGT in the nematode C. elegans, we show OGT is required for male fertility. We assessed the behavior of these mutant male worms and found they have a reduced mating drive. Surprisingly, restoring OGT specifically in the hypodermis was able to raise male fertility and mating drive back to normal levels. In addition, missense mutations in the OGT catalytic domain which prevent the enzyme from transferring GlcNAc do not negatively impact fertility, suggesting a different function of OGT is important in this process. Our study demonstrates that OGT is important in critical behavioral decisions and that further investigation in C. elegans may help reveal new functions of the enzyme.
The inner nuclear membrane protein NEMP1 is required for nuclear envelope openings and enucleation of erythroblasts during erythropoiesis
Authors: Hodzic Didier , Wu Jun , Krchma Karen , Jurisicova Andrea , Tsatskis Yonit , Liu Yijie , Ji Peng , Choi Kyunghee , McNeill Helen
Published: May 2022

Nuclear Envelope Membrane Proteins (NEMP) are a conserved family of nuclear envelope proteins that reside within the inner nuclear membrane. Even though Nemp1 knockout (KO) mice are overtly normal, they display a pronounced splenomegaly. This phenotype and recent reports describing a requirement for nuclear envelope openings during erythroblasts terminal maturation led us to examine a potential role for Nemp1 in erythropoiesis. Here, we report that Nemp1 knockout (KO) mice show peripheral blood defects, anemia in neonates, ineffective erythropoiesis, splenomegaly and stress erythropoiesis. The erythroid lineage of Nemp1 KO mice is overrepresented until the pronounced apoptosis of polychromatophilic erythroblasts. We show that NEMP1 localizes to the nuclear envelope of erythroblasts and their progenitors. Mechanistically, we discovered that NEMP1 accumulates into aggregates that localize near or at the edge of nuclear envelope openings and Nemp1 deficiency leads to a marked decrease of both nuclear envelope openings and ensuing enucleation. Together, our results for the first time demonstrate that NEMP1 is essential for nuclear envelope openings and erythropoietic maturation in vivo and provide the first mouse model of defective erythropoiesis directly linked to the loss of an inner nuclear membrane protein.
Vertical and horizontal transmission of cell fusing agent virus in Aedes aegypti
Authors: Logan Rhiannon A. E. , Quek Shannon , Muthoni Joseph N. , von Eicken Anneliese , Brettell Laura E. , Anderson Enyia R. , Villena Marcus E.N. , Hegde Shivanand , Patterson Grace T. , Heinz Eva , Hughes Grant L. , Patterson Edward I.
Published: May 2022

Cell fusing agent virus (CFAV) is an insect specific flavivirus (ISF) found in field and laboratory populations of Aedes aegypti. ISFs have recently demonstrated the ability to block the transmission of arboviruses such as dengue, West Nile and Zika viruses. It is thought that vertical transmission is the main route for ISF infections. This has been observed with CFAV, but there is evidence of horizontal and venereal transmission in other ISFs. Understanding the route of transmission can inform strategies to spread ISFs to wild vector populations as a method of controlling pathogenic arboviruses. We crossed individually reared male and female mosquitoes from both a naturally occurring CFAV-positive Ae. aegypti colony and its negative counterpart to provide information on maternal, paternal, and horizontal transmission. RT-PCR was used to detect CFAV in individual female mosquito pupal exuviae and was 89% sensitive, but only 41% in male mosquito pupal exuviae. This is a possible way to screen individuals for infection without destroying the adults. Female-to-male horizontal transmission was not observed during this study, however there was a 31% transmission rate from mating pairs of CFAV-positive males to negative female mosquitoes. Maternal vertical transmission was observed with a filial infection rate of 93%. The rate of paternal transmission was 85% when the female remained negative, 61% when the female acquired CFAV horizontally, and 76% overall. Maternal and paternal transmission of CFAV could allow the introduction of this virus into wild Ae. aegypti populations through male or female mosquito releases, and thus provides a potential strategy for ISF-derived arbovirus control.
CMV seropositivity in older adults changes the T cell repertoire, but does not prevent antibody or cellular responses to SARS-CoV-2 vaccination
Authors: Breznik Jessica A. , Huynh Angela , Zhang Ali , Bilaver Lucas , Bhakta Hina , Stacey Hannah D. , Ang Jann C. , Bramson Jonathan L. , Nazy Ishac , Miller Matthew S. , Denburg Judah , Costa Andrew P. , Bowdish Dawn M. E. ,   other members of the COVID-in-LTC Investigator Group
Published: May 2022

Chronic infection with human cytomegalovirus (CMV) may contribute to poor vaccine efficacy in older adults. We assessed effects of CMV serostatus on antibody quantity and quality, as well as cellular memory recall responses, after 2 and 3 SARS-CoV-2 mRNA vaccine doses, in older adults in assisted living facilities. CMV serostatus did not affect anti-Spike and anti-RBD IgG antibody levels, nor neutralization capacity against wildtype or beta variants of SARS-CoV-2 several months after vaccination. CMV seropositivity altered T cell expression of senescence-associated markers and increased TEMRA cell numbers, as has been previously reported; however, this did not impact Spike-specific CD4+ T cell memory recall responses. CMV seropositive individuals did not have a higher incidence of COVID-19, though prior infection influenced humoral immunity. Therefore, CMV seropositivity may alter T cell composition but does not impede the durability of humoral protection or cellular memory responses after SARS-CoV-2 mRNA vaccination in older adults.

Key Points

CMV seropositive older adults have more EMRA and terminally differentiated T cells CMV seropositivity does not prevent antibody maintenance after SARS-CoV-2 vaccination CMV seropositivity does not impede SARS-CoV-2 vaccine T cell memory recall responses
How early can an upcoming critical transition be detected?
Authors: Southall Emma , Tildesley Michael J , Dyson Louise
Published: May 2022

Numerous studies have suggested the use of early warning signals (EWSs) of critical transitions to overcome challenges of identifying tipping points in complex natural systems. However, the real-time application of EWSs has often been overlooked; many studies show the presence of EWSs but do not detect when the trend becomes significant. Knowing if the signal can be detected early enough is of critical importance for the applicability of EWSs. Detection methods which present this analysis are sparse and are often developed anew for each individual study. Here, we provide a summary and validation of a range of currently available detection methods developed from EWSs. We include an additional constraint, which requires multiple time-series points to satisfy the algorithms’ conditions before a detection of an approaching critical transition can be flagged. We apply this procedure to a simulated study of an infectious disease system undergoing disease elimination. For each detection algorithm we select the hyper-parameter which minimises classification errors using receiver operating characteristic (ROC) analysis. We consider the effect of time-series length on these results, finding that all algorithms become less accurate as the amount of data decreases. We compare EWS detection methods with alternate algorithms found from the change-point analysis literature and assess the suitability of using change-point analysis to detect abrupt changes in a system’s steady state.
Comparing the predictive power of machine learning and semi-mechanistic models of endemic measles dynamics
Authors: Lau Max SY , Becker Alex , Waller Lance , Metcalf Jessica , Grenfell Bryan
Published: May 2022

Measles is one the best-documented and most-mechanistically-studied non-linear infectious disease dynamical systems. However, systematic investigation into the comparative performance of traditional mechanistic models and machine learning approaches in forecasting the transmission dynamics of this pathogen are still rare. Here, we compare one of the most widely used semi-mechanistic models for measles (TSIR) with a commonly used machine learning approach (LASSO), comparing performance and limits in predicting short to long term outbreak trajectories and seasonality for both regular and less regular measles outbreaks in England and Wales (E&W) and the United States. First, our results indicate that the proposed LASSO model can efficiently use data from multiple major cities and achieve similar short-to-medium term forecasting performance to semi-mechanistic models for E&W epidemics. Second, interestingly, the LASSO model also captures annual to biennial bifurcation of measles epidemics in E&W caused by susceptible response to the late 1940s baby boom. LASSO may also outperform TSIR for predicting less-regular dynamics such as those observed in major cities in US between 1932-45. Although both approaches capture short-term forecasts, accuracy suffers for both methods as we attempt longer-term predictions in highly irregular, post-vaccination outbreaks in E&W. Finally, we illustrate that the LASSO model can both qualitatively and quantitatively reconstruct mechanistic assumptions, notably susceptible dynamics, in the TSIR model. Our results characterize the limits of predictability of infectious disease dynamics for strongly immunizing pathogens with both mechanistic and machine learning models, and identify connections between these two approaches.
Association of vasopressors with mortality in critically ill patients with COVID-19: A systematic review and meta-analysis
Authors: Mermiri Maria , Mavrovounis Georgios , Laou Eleni , Papagiannakis Nikolaos , Pantazopoulos Ioannis , Chalkias Athanasios
Published: May 2022

Purpose

The effect of vasopressors on mortality of critically ill patients with COVID-19 has not been studied extensively.

Materials and Methods

A systematic search of PubMed, Scopus, and clinicaltrials.gov was conducted for relevant articles until January 2022. Eligibility criteria were randomized controlled and non-randomized trials. The primary outcome was mortality at latest follow-up. The quality of studies was assessed using the MINORS tool. Paired meta-analysis was used to estimate the pooled risk ratios along with their 95% Confidence Interval.

Results

Analyses of 21 studies (n=7900) revealed that vasopressor use is associated with mortality in patients who receive vasopressors compared to those who do not receive vasopressor therapy [RR (95%CI): 4.26 (3.15, 5.76); p<0.001]. In-hospital and 30-day mortality are significantly higher in patients who receive vasopressors [RR (95%CI): 4.60 (2.47, 8.55); p<0.001 and RR (95%CI): 2.97 (1.72, 5.14); p<0.001, respectively]. The highest mortality rate was observed with vasopressin or epinephrine, while the lowest mortality rate was observed with angiotensin-II. Also, analyses of data from 10 studies (n=3519) revealed that vasopressor use is associated with acute kidney injury [RR (95%CI): 3.17 (2.21, 4.54); p<0.001].

Conclusion

Vasopressor use was associated with an increase in in-hospital mortality, 30-day mortality, and acute kidney injury in critically ill patients with COVID-19.
The evolution of two transmissible cancers in Tasmanian devils
Authors: Stammnitz Maximilian R. , Gori Kevin , Kwon Young Mi , Harry Ed , Martin Fergal J. , Billis Konstantinos , Cheng Yuanyuan , Baez-Ortega Adrian , Chow William , Comte Sebastien , Eggertsson Hannes , Fox Samantha , Hamede Rodrigo , Jones Menna E. , Lazenby Billie , Peck Sarah , Pye Ruth , Quail Michael A. , Swift Kate , Wang Jinhong , Wood Jonathan , Howe Kerstin , Stratton Michael R. , Ning Zemin , Murchison Elizabeth P.
Published: May 2022

Tasmanian devils have spawned two transmissible cancer lineages, named devil facial tumour 1 (DFT1) and devil facial tumour 2 (DFT2). We investigated the genetic diversity and evolution of these clones by analysing 78 DFT1 and 41 DFT2 genomes relative to a newly assembled chromosome-level reference. Time-resolved phylogenetic trees reveal that DFT1 first emerged in 1986 (1982-1989), and DFT2 in 2011 (2009-2012). Subclone analysis documents transmission of heterogeneous cell populations. DFT2 has faster mutation rates than DFT1 across all variant classes, including substitutions, indels, rearrangements, transposable element insertions and copy number alterations, and we identify a hypermutated DFT1 lineage with defective DNA mismatch repair. Several loci show plausible evidence of positive selection in DFT1 or DFT2, including loss of chromosome Y and inactivation ofMGA, but none are common to both cancers. This study illuminates the parallel long-term evolution of two transmissible cancers inhabiting a common niche in Tasmanian devils.
Structural basis of a two-antibody cocktail exhibiting highly potent and broadly neutralizing activities against SARS-CoV-2 variants including diverse Omicron sublineages
Authors: Li Xiaoman , Pan Yongbing , Yin Qiangling , Wang Zejun , Shan Sisi , Zhang Laixing , Yu Jinfang , Qu Yuanyuan , Sun Lina , Gui Fang , Lu Jia , Jing Zhaofei , Wu Wei , Huang Tao , Shi Xuanling , Li Jiandong , Li Xinguo , Li Dexin , Wang Shiwen , Yang Maojun , Zhang Linqi , Duan Kai , Liang Mifang , Yang Xiaoming , Wang Xinquan
Published: May 2022

SARS-CoV-2 variants of concern (VOCs), especially the latest Omicron, have exhibited severe antibody evasion. Broadly neutralizing antibodies with high potency against Omicron are urgently needed for understanding working mechanisms and developing therapeutic agents. In this study, we characterized previously reported F61, which was isolated from convalescent patients infected with prototype SARS-CoV-2, as a broadly neutralizing antibody against all VOCs including Omicron BA.1, BA.1.1, BA.2, BA.3 and BA.4 sublineages by utilizing antigen binding and cell infection assays. We also identified and characterized another broadly neutralizing antibody D2 with epitope distinct from that of F61. More importantly, we showed that a combination of F61 with D2 exhibited synergy in neutralization and protecting mice from SARS-CoV-2 Delta and Omicron BA.1 variants. Cryo-EM structures of the spike-F61 and spike-D2 binary complexes revealed the distinct epitopes of F61 and D2 at atomic level and the structural basis for neutralization. Cryo-EM structure of the Omicron-spike-F61-D2 ternary complex provides further structural insights into the synergy between F61 and D2. These results collectively indicated F61 and F61-D2 cocktail as promising therapeutic antibodies for combating SARS-CoV-2 variants including diverse Omicron sublineages.
A network of CLAVATA receptors buffers auxin-dependent meristem maintenance
Authors: John Amala , Smith Elizabeth Sarkel , Jones Daniel S. , Soyars Cara L. , Nimchuk Zachary L.
Published: May 2022

Plant body plans are elaborated in response to both environmental and endogenous cues. How these inputs intersect to promote growth and development remains poorly understood. During reproductive development, central zone stem cell proliferation in inflorescence meristems is negatively regulated by the CLAVATA3 (CLV3) peptide signaling pathway. In contrast, floral primordia formation on meristem flanks requires the hormone auxin. Here we show that CLV3 signaling is also necessary for auxin-dependent floral primordia generation and that this function is partially masked by both inflorescence fasciation and heat-induced auxin biosynthesis. Stem cell regulation by CLAVATA signaling is separable from primordia formation but is also sensitized to temperature and auxin levels. Additionally, we uncover a novel role for the CLV3 receptor CLAVATA1 in auxin- dependent meristem maintenance in cooler environments. As such, CLV3 signaling buffers multiple auxin-dependent shoot processes across divergent thermal environments with opposing effects on cell proliferation in different meristem regions.
MAVS signaling is required for clearance of chikungunya heart infection and prevention of chronic inflammation in vascular tissue
Authors: Noval Maria G. , Spector Sophie N. , Bartnicki Eric , Izzo Franco , Narula Navneet , Yeung Stephen T. , Damani-Yokota Payal , Dewan M. Zahidunnabi , Mezzano Valeria , Rodriguez-Rodriguez Bruno A. , Loomis Cynthia , Khanna Kamal M. , Stapleford Kenneth A.
Published: May 2022

Chikungunya virus (CHIKV) infection has been associated with severe cardiac manifestations, yet, how CHIKV infection leads to heart disease remains unknown. Here, we leveraged both mouse models and human primary cells to define the mechanisms of CHIKV heart infection. We found that CHIKV actively replicates in cardiac fibroblasts and is cleared without significant tissue damage through the induction of a local type-I interferon response from both infected and non-infected cardiac cells. Importantly, signaling through the mitochondrial antiviral-signaling protein (MAVS) is required for viral clearance from the heart. In the absence of MAVS, persistent infection leads to focal myocarditis and major vessel vasculitis persisting for up to 60 days post-infection, suggesting CHIKV can lead to vascular inflammation and potential long-lasting cardiovascular complications. This study provides a model of CHIKV cardiac infection and mechanistic insight into CHIKV-induced heart disease, underscoring the importance of monitoring cardiac function in patients with CHIKV infections.
Benzo[a]pyrene biodegradation by multiple and individual mesophilic bacteria in axenic conditions and in soil samples
Authors: Nzila Alexis , Musa Musa M. , Afuecheta Emmanuel , Thukair Assad , Sankaran Saravanan , Xiang Lei , Li Qing X.
Published: May 2022

Thus far, only a handful of bacterial strains that can independently degrade and utilize benzo[a]pyrene (BaP) as the sole carbon source have been isolated and characterized. Here, three new bacterial strains, JBZ1A, JBZ2B, and JBZ5E, were isolated from contaminated soil and, using 16S rRNA sequencing, were identified as Bradyrhizobium japonicum, Micrococcus luteus, and Bacillus cereus, respectively. The growth ability of each individual strain and a consortium of all strains in the presence of BaP (4–400 µmol·l−1, pH 7, 37°C) was identified by the doubling time (dt). The results illustrated that dt decreased with increasing BaP concentrations for individual strain and the consortium. The optimum growth conditions of the consortium were 37°C, 0.5% NaCl (w/v), and pH 7. Under these conditions, the degradation rate was 1.06 µmol·l−1·day−1, whereas that of individual strains ranged 0.9–0.38 µmol·l−1·day−1. B. cereus had the strongest contribution to the consortium’s activity, with a degradation rate of 0.9 µmol·l−1·day−1. The consortium could also remove BaP spiked with soil, but at a lower rate (0.01 µmol.l−1.day−1). High-performance liquid chromatography–high-resolution tandem mass spectrometry permitted the detection of the metabolites of these strains, and a biodegradation pathway has been proposed.
Uniaxial polarization analysis of bulk ferromagnets: theory and first experimental results
Authors: Malyeyev Artem , Titov Ivan , Dewhurst Charles , Suzuki Kiyonori , Honecker Dirk , Michels Andreas
Published: May 2022

On the basis of Brown's static equations of micromagnetics, the uniaxial polarization of the scattered neutron beam of a bulk magnetic material is computed. The approach considers a Hamiltonian that takes into account the isotropic exchange interaction, the antisymmetric Dzyaloshinskii–Moriya interaction, magnetic anisotropy, the dipole–dipole interaction and the effect of an applied magnetic field. In the high-field limit, the solutions for the magnetization Fourier components are used to obtain closed-form results for the spin-polarized small-angle neutron scattering (SANS) cross sections and the ensuing polarization. The theoretical expressions are compared with experimental data on a soft magnetic nanocrystalline alloy. The micromagnetic SANS theory provides a general framework for polarized real-space neutron methods, and it may open up a new avenue for magnetic neutron data analysis on magnetic microstructures.
High-resolution X-ray Bragg diffraction in Al thermomigrated Si channels
Authors: Lomov Andrey A. , Punegov Vasily I. , Belov Alexander Yu. , Seredin Boris M.
Published: May 2022

Si(111) wafers patterned with an array of vertical 120 µm-wide Al-doped (1 × 1019 cm−3) p-channels extending through the whole wafer were studied with the X-ray double- and triple-crystal diffraction technique in Bragg geometry with copper radiation. Reciprocal space maps (RSMs) of diffraction intensity far from the channels and near them were measured, and their non-trivial shape was observed. The obtained experimental RSMs demonstrate high sensitivity to the structural distortions of the crystal in the subsurface layer owing to the influence of the surface on the elastic strain field in the channel. These features result from the small difference of the ionic radii of Si and Al, leading to the absence of misfit dislocations on the borders of the channel. Simulations of RSMs using the Takagi–Taupin dynamical diffraction theory taking into account the influence of the surface on the elastic strain field in the channel and the effect of the instrumental function were carried out. Finally, numerical RSM calculations showed that the proposed model of the surface effect on the elastic strain field in a semi-infinite crystal with a vertical Si(Al) channel can be used to retrieve the information on the concentration of aluminium in the thermomigrated Si(Al) channel from the diffraction data obtained in the Bragg geometry.
Multiple crack growth simulation for lap-joints based on three-dimensional finite element analysis
Authors: Zou Jun , Yuechao Zhang , Feng Zhenyu
Published: May 2022

Purpose

The fuselage riveted lap-joints are susceptible to multiple site damage (MSD) and should be considered in damage tolerance analysis. This paper aims to investigate the stress intensity factor (SIF) and crack growth simulation for lap-joints based on three-dimensional (3D) finite element analysis.

Design/methodology/approach

The 3D finite element model of lap-joints is established by detailed representation of rivets and considering the rivet clamping force and friction. Numerical study is conducted to investigate the SIF distribution along the thickness direction and the effect of clamping force. A predictive method for the cracks propagation of MSD is then developed, in which an integral mean is adopted to quantify the SIF at crack tips, and the crack closure effect is considered. For comparison, a fatigue test of a lap-joint with MSD cracks is conducted to determine the cracks growth live and measure the cracks growth.

Findings

The numerical study shows that the through-thickness crack at riveted hole in lap-joints can be treated as mode I crack. The distribution of SIF along the thickness direction is inconstant and nonmonotonic. Besides, the increase in clamping force will lead to more frictional load transfer at the faying surfaces. The multiple crack growth simulation results agreed well with the experimental data.

Originality/value

The novelty of this work is that the SIF distribution along the thickness direction and the MSD cracks growth simulation for lap-joints are investigated by 3D finite element analysis, which can reflect the secondary bending, rivet clamping, contact and friction in lap-joints.
Enhanced X-ray pulsar navigation based on ranging information of a satellite
Authors: Zhang Li , Fang Haiyan , Bao Weimin , Sun Haifeng , Shen Lirong , Su Jianyu , Zhao Liang
Published: May 2022

Purpose

X-ray pulsar navigation (XPNAV) is an autonomous celestial navigation technology for deep space missions. The error in the pulse time of arrival used in pulsar navigation is large for various practical reasons and thus greatly reduces the navigation accuracy of spacecraft near the Earth and in deep space. This paper aims to propose a novel method based on ranging information that improves the performance of XPNAV.

Design/methodology/approach

This method replaces one pulsar observation with a satellite observation. The ranging information is the difference between the absolute distance of the satellite relative to the spacecraft and the estimated distance of the satellite relative to the spacecraft. The proposed method improves the accuracy of XPNAV by combining the ranging information with the observation data of two pulsars.

Findings

The simulation results show that the proposed method greatly improves the XPNAV accuracy by 70% compared with the conventional navigation method that combines the observations of three pulsars. This research also shows that a larger angle between the orbital plane of the satellite and that of the spacecraft provides higher navigation accuracy. In addition, a greater orbital altitude difference implies higher navigation accuracy. The position error and ranging error of the satellite have approximately linear relationships with the navigation accuracy.

Originality/value

The novelty of this study is that the satellite ranging information is integrated into the pulsar navigation by using mathematical geometry.