bluuebunny/crossref_metadata_2025 huggingface dataset:
Structures of LIG1 engaging with mutagenic mismatches inserted by polβ in base excision repair
Authors: Tang Qun , McKenna Robert , Çağlayan Melike
Published: January 2022

DNA ligase I (LIG1) catalyzes final ligation step following DNA polymerase (pol) β gap filling and an incorrect nucleotide insertion by polβ creates a nick repair intermediate with mismatched end at the downstream steps of base excision repair (BER) pathway. Yet, how LIG1 discriminates against the mutagenic 3′-mismatches at atomic resolution remains undefined. Here, we determined X-ray structures of LIG1/nick DNA complexes with G:T and A:C mismatches and uncovered the ligase strategies that favor or deter ligation of base substitution errors. Our structures revealed that LIG1 active site can accommodate G:T mismatch in a similar conformation with A:T base pairing, while it stays in the LIG1-adenylate intermediate during initial step of ligation reaction in the presence of A:C mismatch at 3′-strand. Moreover, we showed mutagenic ligation and aberrant nick sealing of the nick DNA substrates with 3′-preinserted dG:T and dA:C mismatches, respectively. Finally, we demonstrated that AP-Endonuclease 1 (APE1), as a compensatory proofreading enzyme, interacts and coordinates with LIG1 during mismatch removal and DNA ligation. Our overall findings and ligase/nick DNA structures provide the features of accurate versus mutagenic outcomes at the final BER steps where a multi-protein complex including polβ, LIG1, and APE1 can maintain accurate repair.
Identification and Age-dependent Increase of Platelet Biased Human Hematopoietic Stem Cells
Authors: Aksöz Merve , Gafencu Grigore-Aristide , Stoilova Bilyana , Buono Mario , Meng Yiran , Jakobsen Niels Asger , Metzner Marlen , Clark Sally-Ann , Beveridge Ryan , Thongjuea Supat , Vyas Paresh , Nerlov Claus
Published: January 2022

Hematopoietic stem cells (HSC) reconstitute multi-lineage human hematopoiesis after clinical bone marrow transplantation and are the cells-of-origin of hematological malignancies. Though HSC provide multi-lineage engraftment, individual murine HSCs are lineage-biased and contribute unequally to blood cell lineages. Now, by combining xenografting of molecularly barcoded adult human bone marrow (BM) HSCs and high-throughput single cell RNA sequencing we demonstrate that human individual BM HSCs are also functionally and transcriptionally lineage biased. Specifically, we identify platelet-biased and multi-lineage human HSCs. Quantitative comparison of transcriptomes from single HSCs from young, and aged, BM show that both the proportion of platelet-biased HSCs, and their level of transcriptional platelet priming, increases with age. Therefore, platelet-biased HSCs, as well as their increased prevalence and elevated transcriptional platelet priming during ageing, are conserved between human and murine hematopoiesis.

One-Sentence Summary

In vivo barcoding and single cell RNA sequencing identifies platelet-biased human bone marrow HSCs.
CtIP-dependent nascent RNA expression flanking DNA breaks guides the choice of DNA repair pathway
Authors: Gómez-Cabello Daniel , Pappas Giorgios , Aguilar-Morante Diana , Dinant Christoffel , Bartek Jiri
Published: January 2022

The RNA world is changing our views about sensing and resolution of DNA damage. Here, we developed single-molecule DNA/RNA analysis approaches to visualize how nascent RNA facilitates the repair of DNA double-strand breaks (DSBs). RNA polymerase II (RNAPII) is crucial for DSB resolution in human cells. DSB-flanking, RNAPII-generated nascent RNA forms RNA:DNA hybrids, guiding the upstream DNA repair steps towards favouring the error-free Homologous Recombination (HR) pathway over Non-Homologous End Joining. Specific RNAPII inhibitor, THZ1, impairs recruitment of essential HR proteins to DSBs, implicating nascent RNA in DNA end resection, initiation and execution of HR repair. We further propose that resection factor CtIP interacts with and re-activates RNAPII when paused by the RNA:DNA hybrids, collectively promoting faithful repair of chromosome breaks to maintain genomic integrity.
Non-target effects of ten essential oils on the egg parasitoidTrichogramma evanescens
Authors: van Oudenhove Louise , Cazier Aurélie , Fillaud Marine , Lavoir Anne-Violette , Fatnassi Hicham , Pérez Guy , Calcagno Vincent
Published: January 2022

Essential oils (EOs) are increasingly used as biopesticides due to their insecticidal potential. This study addresses their non-target effects on a biological control agent: the egg parasitoidTrichogramma evanescens. In particular, we tested whether EOs affected parasitoid fitness either directly, by decreasing pre-imaginal survival, or indirectly, by disrupting parasitoids’ orientation abilities. The effect of Anise, Fennel, Sweet orange, Basil, Coriander, Oregano, Peppermint, Mugwort, Rosemary and Thyme EOs were studied on five strains ofT. evanescens. Specific experimental setups were developed, and data obtained from image analysis were interpreted with phenomenological models fitted with Bayesian inference. Results highlight the fumigant toxicity of EOs on parasitoid development. Anise, Fennel, Basil, Coriander, Oregano, Peppermint and Thyme EOs are particularly toxic and drastically reduce the emergence rate ofT. evanescens. Most EOs also affect parasitoid behavior: (i) Basil, Coriander, Oregano, Peppermint, Mugwort and Thyme EOs are highly repellent for naive female parasitoids; (ii) Anise and Fennel EOs can have repellent or attractive effects depending on strains; and (iii) Sweet orange, Oregano and Rosemary EOs have no detectable impact on orientation behavior. This study shows that EOs fumigation have non-target effects on egg parasitoids. This highlights the need to cautiously precise the deployment framework of biopesticides in an agroecological perspective.
Utilizing citizen science to model the distribution ofAedes aegypti([Diptera]: [Culicidae]) in West Africa
Authors: Freeman Elizabeth A. , Carlton Elizabeth J. , Paull Sara , Dadzie Samuel , Buchwald Andrea
Published: January 2022

In a rapidly urbanizing region such as West Africa,Aedesmosquitoes pose an emerging threat of infectious disease that is compounded by limited vector surveillance. Citizen science has been proposed as a way to fill surveillance gaps by training local residents to collect and share information on disease vectors. Increasing citizen science efforts can begin to bridge the gaps in our current knowledge ofAedesdistribution while engaging locals with mosquito control and public health efforts. Understanding the distribution of disease vectors in West Africa can inform researchers and public health officials on where to conduct disease surveillance and focus public health interventions. We aimed to compare citizen science data to published literature observations ofAedesmosquitoes and to quantify how incorporating citizen science changes our understanding ofAedesmosquito distribution in West Africa. We utilized citizen science data collected through NASA’s GLOBE Observer mobile phone application and data from a previously published literature review onAedesmosquito distribution to examine the contribution of citizen science to understanding the distribution ofAe. aegyptiin West Africa using Maximum Entropy modeling. Combining citizen science and literature-derived observations improved the fit of the model compared to models created by each data source alone, but did not alleviate location bias within the models, likely due to lack of widespread observations. UnderstandingAe. aegyptidistribution will require greater investment inAedesmosquito surveillance in the region, and citizen science should be utilized as a tool in this mission to increase the reach of surveillance.
Deciphering the evolution of microbial interactions: in silico studies of two-member microbial communities
Authors: Sambamoorthy Gayathri , Raman Karthik
Published: January 2022

Microbes thrive in communities, embedded in a complex web of interactions. These interactions, particularly metabolic interactions, play a crucial role in maintaining the community structure and function. As the organisms thrive and evolve, a variety of evolutionary processes alter the interactions among the organisms in the community, although the community function remains intact. In this work, we simulate the evolution of two-member microbial communities in silico to study how evolutionary forces can shape the interactions between organisms. We employ genome-scale metabolic models of organisms from the human gut, which exhibit a range of interaction patterns, from mutualism to parasitism. We observe that the evolution of microbial interactions varies depending upon the starting interaction and also on the metabolic capabilities of the organisms in the community. We find that evolutionary constraints play a significant role in shaping the dependencies of organisms in the community. Evolution of microbial communities yields fitness benefits in only a small fraction of the communities, and is also dependent on the interaction type of the wild-type communities. The metabolites cross-fed in the wild-type communities appear in only less than 50% of the evolved communities. A wide range of new metabolites are cross-fed as the communities evolve. Further, the dynamics of microbial interactions are not specific to the interaction of the wild-type community but vary depending on the organisms present in the community. Our approach of evolving microbial communities in silico provides an exciting glimpse of the dynamics of microbial interactions and offers several avenues for future investigations.
Glucose-stimulated calcium dynamics in beta cells from C57BL/6J, C57BL/6N, and NMRI mice: A systematic comparison of activation, activity, and deactivation properties in tissue slices
Authors: Pohorec Viljem , Bombek Lidija Križančić , Klemen Maša Skelin , Dolenšek Jurij , Stožer Andraž
Published: January 2022

Although mice are a very instrumental model in islet beta cell research, possible phenotypic differences between strains and substrains are largely neglected in the scientific community. In this study, we show important phenotypic differences in beta cell responses to glucose between NMRI, C57BL/6J, and C57BL/6N mice, i.e., the three most commonly used strains. High-resolution multicellular confocal imaging of beta cells in acute pancreas tissue slices was used to measure and quantitatively compare the calcium dynamics in response to a wide range of glucose concentrations. Strain- and substrain-specific features were found in all three phases of beta cell responses to glucose: a shift in the dose-response curve characterizing the delay to activation and deactivation in response to stimulus onset and termination, respectively, and distinct concentration-encoding principles during the plateau phase in terms of frequency, duration, and active time changes with increasing glucose concentrations. Our results underline the significance of carefully choosing and reporting the strain to enable comparison and increase reproducibility, emphasize the importance of analyzing a number of different beta cell physiological parameters characterizing the response to glucose, and provide a valuable standard for future studies on beta cell calcium dynamics in health and disease.
DeepGOZero: Improving protein function prediction from sequence and zero-shot learning based on ontology axioms
Authors: Kulmanov Maxat , Hoehndorf Robert
Published: January 2022

Motivation

Protein functions are often described using the Gene Ontology (GO) which is an ontology consisting of over 50,000 classes and a large set of formal axioms. Predicting the functions of proteins is one of the key challenges in computational biology and a variety of machine learning methods have been developed for this purpose. However, these methods usually require significant amount of training data and cannot make predictions for GO classes which have only few or no experimental annotations.

Results

We developed DeepGOZero, a machine learning model which improves predictions for functions with no or only a small number of annotations. To achieve this goal, we rely on a model-theoretic approach for learning ontology embeddings and combine it with neural networks for protein function prediction. DeepGOZero can exploit formal axioms in the GO to make zero-shot predictions, i.e., predict protein functions even if not a single protein in the training phase was associated with that function. Furthermore, the zero-shot prediction method employed by DeepGOZero is generic and can be applied whenever associations with ontology classes need to be predicted.

Availability

http://github.com/bio-ontology-research-group/deepgozero

Contact

robert.hoehndorf@kaust.edu.sa
White Matter Brain Structure Predicts Language Performance and Learning Success
Authors: Sánchez Stella M. , Schmidt Helmut , Gallardo Guillermo , Anwander Alfred , Brauer Jens , Friederici Angela D. , Knösche Thomas R.
Published: January 2022

Individual differences in the ability to deal with language have long been discussed. The neural basis of these, however, is yet unknown. Here we investigated the relationship between long-range white matter connectivity of the brain, as revealed by diffusion tractography, and the ability to process syntactically complex sentences in the participants’ native language as well as the improvement thereof by multi-day training. We identified specific network motifs that indeed related white matter tractography to individual language processing performance. First, for two such motifs, one in the left and one in the right hemisphere, their individual prevalence significantly predicted the individual language performance suggesting a predisposition for the individual ability to process syntactically complex sentences, which manifests itself in the white matter brain structure. Both motifs comprise a number of cortical regions, but seem to be dominated by areas known for the involvement in working memory rather than the classical language network itself. Second, we identified another left hemispheric network motif, whose change of prevalence over the training period significantly correlated with the individual change in performance, thus reflecting training induced white matter plasticity. This motif comprises diverse cortical areas including regions known for their involvement in language processing, working memory and motor functions. The present findings suggest that individual differences in language processing and learning can be explained, in part, by individual differences in the brain’s white matter structure. Brain structure may be a crucial factor to be considered when discussing variations in human cognitive performance, more generally.
Significant organic carbon acquisition byProchlorococcusin the oceans
Authors: Wu Zhen , Aharonovich Dikla , Roth-Rosenberg Dalit , Weissberg Osnat , Luzzatto-Knaan Tal , Vogts Angela , Zoccarato Luca , Eigemann Falk , Grossart Hans-Peter , Voss Maren , Follows Michael J. , Sher Daniel
Published: January 2022

Marine phytoplankton are responsible for about half of the photosynthesis on Earth. Many are mixotrophs, combining photosynthesis with heterotrophic assimilation of organic carbon but the relative contribution of these two carbon sources is not well quantified. Here, single-cell measurements reveal thatProchlorococcusat the base of the photic zone in the Eastern Mediterranean Sea are obtaining only ~20% of carbon required for growth by photosynthesis. Consistently, laboratory-calibrated evaluations ofProchlorococcusphotosynthesis indicate that carbon fixation is systematically too low to support publishedin situgrowth rates in the deep photic layer of the Pacific Ocean. Furthermore, agent-based model simulations show that mixotrophic cells maintain realistic growth rates and populations 10s of meters deeper than obligate photo-autotrophs, deepening the nutricline and Deep Chlorophyll Maximum by ~20 m. Time-series ofProchlorococcusecotype-abundance from the subtropical North Atlantic and North Pacific suggest that up to 30% of theProchlorococcuscells live where light intensity is not enough to sustain obligate photo-autotrophic populations during warm, stratified periods. Together, these data and models suggest that mixotrophy underpins the ecological success of a large fraction of the globalProchlorococcuspopulation and its collective genetic diversity.
A semi-supervised Bayesian mixture modelling approach for joint batch correction and classification
Authors: Coleman Stephen , Nicholls Kath , Dopico Xaquin Castro , Karlsson Hedestam Gunilla B. , Kirk Paul D.W. , Wallace Chris
Published: January 2022

Abstract

Systematic differences between batches of samples present significant challenges when analysing biological data. Suchbatch effectsare well-studied and are liable to occur in any setting where multiple batches are assayed. Many existing methods for accounting for these have focused on high-dimensional data such as RNA-seq and have assumptions that reflect this. Here we focus on batch-correction in low-dimensional classification problems. We propose a semi-supervised Bayesian generative classifier based on mixture models that jointly predicts class labels and models batch effects. Our model allows observations to be probabilistically assigned to classes in a way that incorporates uncertainty arising from batch effects. By simultaneously inferring the classification and the batch-correction our method is more robust to dependence between batch and class than pre-processing steps such as ComBat. We explore two choices for the within-class densities: the multivariate normal and the multivariatet. A simulation study demonstrates that our method performs well compared to popular off-the-shelf machine learning methods and is also quick; performing 15,000 iterations on a dataset of 750 samples with 2 measurements each in 11.7 seconds for the MVN mixture model and 14.7 seconds for the MVT mixture model. We further validate our model on gene expression data where cell type (class) is known and simulate batch effects. We apply our model to two datasets generated using the enzyme-linked immunosorbent assay (ELISA), a spectrophotometric assay often used to screen for antibodies. The examples we consider were collected in 2020 and measure seropositivity for SARS-CoV-2. We use our model to estimate seroprevalence in the populations studied. We implement the models in C++ using a Metropolis-within-Gibbs algorithm, available in the R packagebatchmix. Scripts to recreate our analysis are athttps://github.com/stcolema/BatchClassifierPaper.
Using intracerebral microdialysis to probe the efficacy of repurposed drugs in Alzheimer’s disease pathology
Authors: Bjorkli Christiana , Hemler Mary , Julian Joshua B. , Sandvig Axel , Sandvig Ioanna
Published: January 2022

All disease-targeting drug trials completed to date have fallen short of meeting the clinical endpoint of significantly slowing cognitive decline in Alzheimer’s disease patients. Even the recently approved drug Aducanumab, has proven effective in removing amyloid-β, but does not reduce cognitive decline. This emphasizes the urgent need for novel therapeutic approaches that could reduce several AD neuropathologies simultaneously, eventually leading to improved cognitive performance. To validate whether our mouse model replicates AD neuropathology as observed in patients, we characterized the 3xTg AD mouse model to avoid premature translation of successful results. In this study we have repurposed two FDA-approved drugs, Fasudil and Lonafarnib, targeting the Wnt signaling and endosomal-lysosomal pathway respectively, to test their potential to attenuate AD pathology. Using intracerebral microdialysis, we simultaneously infused these disease-targeting drugs between 1-2 weeks, separately and also in combination, while collecting cerebrospinal fluid. We found that Fasudil reduces intracellular amyloid-β in young, and amyloid plaques in old animals, and overall cerebrospinal fluid amyloid-β. Lonafarnib reduces tau neuropathology and cerebrospinal fluid tau biomarkers in young and old animals. Co-infusion of both drugs was more effective in reducing intracellular amyloid-β than either drug alone, and appeared to improve contextual memory performance. However, an unexpected finding was that Lonafarnib treatment increased amyloid plaque size, suggesting that activating the endosomal-lysosomal system may inadvertently increase amyloid-β pathology if administered too late in the AD continuum. Taken together, these findings lend support to the application of repurposed drugs to attenuate AD neuropathology at various therapeutic time windows.

One Sentence Summary

Here we circumvented the blood-brain barrier for drug delivery aimed at attenuating AD neuropathology.
Comparative analysis of cattle breeds as satellite cell donors for cultured beef
Authors: Melzener Lea , Ding Shijie , Hueber Rui , Messmer Tobias , Zhou Guanghong , Post Mark J , Flack Joshua E
Published: January 2022

Background

Cultured meat is a promising new field with the potential for considerable environmental and animal welfare benefits. One technological approach to cultured meat production utilises the proliferative and differentiative capacity of muscle-derived satellite cells (SCs) to produce large volumes of cultured muscle tissue from small biopsies of donor animals. Differing genotypes between cattle breeds lead to predictable phenotypic traits, resulting in breeds being favoured for their respective meat or milk production characteristics in the livestock industry. However, whilst these breeds show significant differences in muscle growth, it is unclear whether the physiological differences observed between them in vivo are reflected in differences in SC behaviour in vitro, particularly with respect to proliferation, differentiation and cellular longevity, and hence whether particular breeds might represent preferred SC donors for a cultured beef bioprocess.

Results

Comparing SCs isolated from five breeds (Belgian Blue, Holstein Friesian, Galloway, Limousin and Simmental), we found that the proliferation rates were largely unaffected by the donor breed. In contrast, potentially meaningful differences were observed in the kinetics and extent of myogenic differentiation. Furthermore, whilst differentiation dropped for all breeds with increasing population doublings (PDs), SCs from Belgian Blue and Limousin cattle showed significantly longer retention of differentiation capacity over long-term passaging.

Conclusion

SCs from all breeds were able to proliferate and differentiate, although Limousin and (particularly) Belgian Blue cattle, both breeds commonly used for traditional meat production, may represent preferred donors for cultured beef production.
Proteasome dysfunction disrupts adipogenesis and induces inflammation via ATF3
Authors: Willemsen Nienke , Arigoni Isabel , Studencka-Turski Maja , Krüger Elke , Bartelt Alexander
Published: January 2022

Objective

Regulation of proteasomal activity is an essential component of cellular proteostasis and function. This is evident in patients with mutations in proteasome subunits and regulators, who suffer from proteasome-associated autoinflammatory syndromes (PRAAS). These patients display lipodystrophy and fevers, which may be partly related to adipocyte malfunction and abnormal thermogenesis in adipose tissue. However, the cell-intrinsic pathways that could underlie these symptoms are unclear. Here, we investigate the impact of two proteasome subunits implicated in PRAAS, Psmb4 and Psmb8, on differentiation, function and proteostasis of brown adipocytes.

Methods

In immortalized mouse brown pre-adipocytes, levels of Psmb4, Psmb8, and downstream effectors genes were downregulated through reverse transfection with siRNA. Adipocytes were differentiated and analyzed with various assays of adipogenesis, lipogenesis, lipolysis, inflammation, and respiration.

Results

Loss of Psmb4, but not Psmb8, disrupted proteostasis and adipogenesis. Proteasome function was reduced upon Psmb4 loss, but partly recovered by the activation of Nuclear factor, erythroid-2, like-1 (Nfe2l1). In addition, cells displayed higher levels of surrogate inflammation and stress markers, including Activating transcription factor-3 (Atf3). Simultaneous silencing of Psmb4 and Atf3 lowered inflammation and restored adipogenesis.

Conclusions

Our study shows that Psmb4 is required for adipocyte development and function in cultured adipocytes. These results imply that in humans with PSMB4 mutations, PRAAS-associated lipodystrophy is partly caused by disturbed adipogenesis. While we uncover a role for Nfe2l1 in the maintenance of proteostasis under these conditions, Atf3 is a key effector of inflammation and blocking adipogenesis. In conclusion, our work highlights how proteasome dysfunction is sensed and mitigated by the integrated stress response in adipocytes with potential relevance for PRAAS patients and beyond.

Highlights

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PRAAS-associated PSMB4 is required for brown adipocyte differentiation

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Loss of PSMB4 activates NFE2L1 to counteract proteasome dysfunction

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The ATF3 pathway regulates adipocyte dysfunction and inflammation

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Loss of ATF3 restores adipogenesis in cells with loss of PSMB4

Graphical abstract
Phenology effects on productivity and hatching-asynchrony of American kestrels (Falco sparverius) across a continent
Authors: Callery Kathleen R. , Schulwitz Sarah E. , Hunt Anjolene R. , Winiarski Jason M. , McClure Christopher J. W. , Fischer Richard A. , Heath Julie A.
Published: January 2022

Climate-driven advances in spring can result in phenological mismatch between brood rearing and prey availability and consequently cause decreased productivity in birds. How consequences of mismatch vary across species’ ranges, and how individual behavior can mitigate mismatch effects is less studied. We quantified the relationship between phenological mismatch, productivity, and behavioral adaptations of American kestrels (Falco sparverius) across their breeding range in the United States and southern Canada. We obtained phenology and productivity data using nest observations from long term nest box monitoring, remote trail cameras, and community-scientist based programs. We collected data on parental incubation behavior and hatch asynchrony using trail cameras in nest boxes. Kestrels that laid eggs after the start of spring had higher rates of nest failure and fewer nestlings than earlier nesters, and effects of mismatch on productivity were most severe in the Northeast. In contrast, kestrels in the Southwest experienced a more gradual decline in productivity with seasonal mismatch. We attribute the effect of location to the growing season and temporal nesting windows (duration of nesting season). Specifically, resource availability in the Northeast is narrow and highly peaked during the breeding season, potentially resulting in shorter nesting windows. Conversely, resource curves may be more prolonged and dampened in the Southwest, and growing seasons are becoming longer with climate change, potentially resulting in longer nesting windows. We found that the onset of male incubation was negatively associated with lay date. Males from breeding pairs that laid eggs after the start of spring began incubation sooner than males from breeding pairs that laid before the start of spring. Early-onset male incubation was positively associated with hatching asynchrony, creating increased age variation in developing young. In sum, we demonstrate that American kestrels are vulnerable to phenological mismatch, and that this vulnerability varies across space. Northeastern populations could be more vulnerable to mismatch consequences, which may be one factor contributing to declines of kestrels in this region. Also, we demonstrate early onset of incubation as a potential adaptive behavior to advance average hatch date and spread out offspring demands, but it is unknown how impactful this will be in mitigating the fitness consequences of phenology mismatch.

Highlights

Climate-driven phenological mismatch is a growing conservation concern.

We studied phenology and productivity of an avian predator across North America.

American kestrels nesting after the start of spring had lower productivity.

Later nesting kestrels altered incubation to create hatching asynchrony.

Mismatch effects were strongest in the Northeast and may contribute to population declines.
Integrative analysis of relative abundance data and presence-absence data of the microbiome using the LDM
Authors: Zhu Zhengyi , Satten Glen A. , Hu Yi-Juan
Published: January 2022

We previously developed LDM for testing hypotheses about the microbiome that performs the test at both the community level and the individual taxon level. LDM can be applied to relative abundance data and presence-absence data separately, which work well when associated taxa are abundant and rare, respectively. Here we propose an omnibus test based on LDM that allows simultaneous consideration of data at different scales, thus offering optimal power across scenarios with different association mechanisms. The omnibus test is available for the wide range of data types and analyses that are supported by LDM.

Availability and Implementation

The omnibus test has been added to the R package LDM, which is available on GitHub at https://github.com/yijuanhu/LDM.

Contact

yijuan.hu@emory.edu

Supplementary information

Supplementary data are available at Bioinformatics online.
Cross-species permissivity: structure of a goat adeno-associated virus and its complex with the human receptor, AAVR
Authors: Large Edward E. , Silveria Mark A. , White Tommi A. , Chapman Michael S.
Published: January 2022

Adeno-associated virus (AAV) is a small ssDNA satellite virus of high interest (in recombinant form) as a safe and effective gene therapy vector. AAV’s human cell entry receptor (AAVR) contains Polycystic Kidney Disease (PKD) domains bound by AAV. Seeking understanding of the spectrum of interactions, goat AAVGo.1 is investigated, because its host is the species most distant from human with reciprocal cross-species cell susceptibility. The structure of AAVGo.1, solved by cryo-EM to 2.9 Å resolution, is most similar to AAV5. Through ELISA studies, it is shown that AAVGo.1 binds to human AAVR (huAAVR) more strongly than do AAV2 or AAV5, and that it joins AAV5 in a class that binds exclusively to PKD domain 1 (PKD1), in contrast to other AAVs that interact primarily with PKD2. The AAVGo.1 cryo-EM structure of a complex with a PKD12 fragment of huAAVR at 2.4 Å resolution shows PKD1 bound with minimal change in virus structure, except for disordering of a neighboring surface loop. Only 4 of the 42 capsid protein sequence differences between AAVGo.1 and AAV5 occur at the PKD1 binding interface. These result in only minor conformational changes in AAVR, including a near rigid domain rotation with maximal displacement of the receptor by ~1 Å. A picture emerges of two classes of AAV with completely different modes of binding to the same AAVR receptor, but within each class atomic interactions are mostly conserved.

IMPORTANCE

Adeno-Associated Virus (AAV) is a small ssDNA satellite parvovirus. As a recombinant vector with a protein shell encapsidating a transgene, recombinant AAV (rAAV) is a leading delivery vehicle for gene therapy with two FDA-approved treatments and 150 clinical trials for 30 diseases. The human entry receptor huAAVR has five PKD domains. To date, all serotypes, except AAV5, have interacted primarily with the second PKD domain, PKD2. Goat is the AAV host most distant from human with cross-species cell infectivity. AAVGo.1 is similar in structure to AAV5, the two forming a class with a distinct mode of receptor-binding. Within the two classes, binding interactions are mostly conserved, giving an indication of the latitude available in modulating delivery vectors.
Phosphatidylserine within the Viral Membrane Enhances Chikungunya Virus Infectivity in a Cell-type Dependent Manner
Authors: Miazgowicz Kerri L. , Reyes Ballista Judith Mary , Acciani Marissa D. , Jimenez Ariana R. , Belloli Ryan S. , Duncan Avery M. , Havranek Katherine E. , Brindley Melinda A.
Published: January 2022

Chikungunya virus (CHIKV), an alphavirus of the Togaviridae family, is the causative agent of the human disease chikungunya fever (CHIKF), which is characterized by debilitating acute and chronic arthralgia. No licensed vaccines or antivirals exist for CHIKV. Preventing the attachment of viral particles to host cells is an attractive intervention strategy. Viral entry of enveloped viruses from diverse families including Filoviridae and Flaviviridae is mediated or enhanced by phosphatidylserine receptors (PSRs). PSRs facilitate the attachment of enveloped viruses to cells by binding to exposed phosphatidylserine (PS) in the viral lipid membrane - a process termed viral apoptotic mimicry. To investigate the role of viral apoptotic mimicry during CHIKV infection, we produced viral particles with discrete amounts of exposed PS on the virion envelope by exploiting the cellular distribution of phospholipids at the plasma membrane. We found that CHIKV particles containing high outer leaflet PS (produced in cells lacking flippase activity) were more infectious in Vero cells than particles containing low levels of outer leaflet PS (produced in cells lacking scramblase activity). However, the same viral particles were similarly infectious in NIH3T3 and HAP1 cells, suggesting PS levels can influence infectivity only in cells with high levels of PSRs. Interestingly, PS-dependent CHIKV entry was observed in mosquito Aag2 cells, but not C6/36 cells. These data demonstrate that CHIKV entry via viral apoptotic mimicry is cell-type dependent. Furthermore, viral apoptotic mimicry has a mechanistic basis to influence viral dynamics in vivo in both the human and mosquito host.

Importance

Outbreaks of Chikungunya virus (CHIKV) have occurred throughout Africa, Asia, and Europe. Climate change permits the expansion of Aedes mosquito vectors into more temperate regions, broadening the geographic range and increasing the frequency of future human outbreaks. The molecular basis underlying the broad host and cellular tropism of CHIKV remains unresolved. While several host molecules have been implicated in CHIKV viral attachment and entry, the role of lipid-mediated attachment (viral apoptotic mimicry) is unclear. We observed that higher levels of externalized phosphatidylserine (PS) in the viral lipid bilayer correlated with enhanced CHIKV infectivity in mammalian cells abundant with PS receptors and lacking alternative attachment factors. Interestingly, CHIKV infection in mosquito Aag2 cells was also affected by viral PS accessibility. This study further delineates the role of virus-cell attachment molecules in CHIKV infection. Viral apoptotic mimicry has potential to influence CHIKV dynamics in vivo in both the human and mosquito host.
EPSTEIN-BARR VIRUS LMP1 ENHANCES LEVELS OF MICROVESICLE-ASSOCIATED PD-L1
Authors: Harb Monica Abou , Sun Li , Meckes David G.
Published: January 2022

Extracellular vesicles (EVs) circulate throughout the body and carry cargo that can be conferred to proximal or distant cells, making them major delivery vehicles for cellular communication. Epstein-Barr virus (EBV) infected cells release EVs that contain viral proteins such as the major viral oncogene, latent membrane protein 1 (LMP1). LMP1 has been shown to regulate the cellular gene expression of programmed cell death protein 1 ligand (PD-L1). PD-L1, a protein that suppresses the immune system by binding to PD-1, (a receptor found on cytotoxic T cells). PD-L1 has been recently found to be packaged into small EVs contributing to immune evasion of lung cancer cells. Recent studies establish that MVs are shed in very large amounts by tumor cells, and that elevated levels of MVs correlate to disease metastasis and cancers being more aggressive. Here, we demonstrate PD-L1 enrichment in MVs released from nasopharyngeal carcinoma cells and an important function of EBV LMP1 in regulating PD-L1 levels in MVs. These PD-L1+ MVs containing LMP1 likely contribute to the immunosuppressive microenvironment found in EBV-associated cancers.

Importance

Accumulating evidence over the past decade supports that viruses utilize EVs and associated pathways to incorporate viral products to evade eliciting an immune response, while concurrently enabling viral spread or persistence within the host. Considering that viral proteins confer very strong antigenic peptides that will be recognized by T cells, the regulation of the PD-1 pathway by the overexpression of MV-associated PD-L1 may be a strong immune evasion tactic utilized by viruses. The discovery that EBV LMP1 increases PD-L1 microvesicle secretion, identifies a new therapeutic target in immune blockade therapy. We expect that our findings will begin to clarify the mechanism of LMP1-mediated enhanced packaging of PD-L1 into MVs and may produce more specific targets to treat EBV-associated cancers. Consequently, identifying whether a disease is of viral origin through predictive MV biomarkers could further allow for more targeted therapies.
Information disclosing willingness in mobile internet contexts
Authors: Gao Bill Ming , Liu Matthew Tingchi , Chu Rongwei
Published: January 2022

Purpose

This paper aims to learn about consumers’ information disclosing patterns in the mobile internet context by investigating how demographic, geographic and psychological factors influence their information disclosing willingness (IDW).

Design/methodology/approach

Drawing on self-disclosure theory, the authors carried out simple linear regression analyses on a Chinese sample of 10,000 participants.

Findings

The results revealed that significant gender differences exist between males and females in their IDW in mobile internet context, and females have higher IDW than males do. And the authors also found that first-tier (third tier) citizens have the lowest (highest) IDW in their mobile internet usage.

Originality/value

This study offers three implications. First, this paper captures the insight of IDW within the mobile internet context, while previous studies mostly focus on the desktop internet context. Second, the results show that females have higher willingness to disclose than males do in the context of mobile internet, which is different from the findings of prior studies that females have higher privacy concerns and lower disclosing willingness in the context of desktop internet. Thirdly, this research introduces city tiers as a new approach to the study of IDW, which is one of the first studies exploring the geographical effect on information privacy.
The role of communication in restaurant crowdfunding success
Authors: Salvi Antonio , Raimo Nicola , Petruzzella Felice , Vitolla Filippo
Published: January 2022

Purpose

In recent years, crowdfunding is assuming an increasingly central role in the development of business projects as an alternative financing tool to traditional sources. This study analyses the role of communication in the success of crowdfunding campaigns in the restaurant sector in the European context.

Design/methodology/approach

This study conducts a regression analysis on a sample of 442 European restaurant crowdfunding projects launched on the Kickstarter platform in a time period spanning from 2014 to 2021. More specifically, this study uses a logistic regression model to test the impact of communication on the success of restaurant crowdfunding projects.

Findings

Empirical results suggest a strong impact of communication, declined in its different forms, on the success of restaurant crowdfunding campaigns. More specifically, they highlight a positive impact of the number of images, number of videos, readability and community orientation of the project description, number of comments and number of updates on the success of restaurant crowdfunding projects.

Originality/value

To the best of the authors’ knowledge, this study represents the first research that examines the effect of the communication on the success of restaurant crowdfunding projects conducted in the European context.
Consumer decision journey for online group buying: psychological and intentional procedure perspectives
Authors: Lin Shu-Chiung , Tseng Hsiao-Ting , Shirazi Farid
Published: January 2022

Purpose

This study investigates the relationship between buyers’ psychological antecedent and repurchase intentions in online group buying. Considering and evaluating pre-purchase, the authors measure the buyers’ overall experience of online group buying through their perceived value (PV) and risk. This study examines the influence of PV and perceived risk (PR) on positive electronic word-of-mouth (eWoM) communication and repurchase intention in online group buying.

Design/methodology/approach

The authors verify the research model using SPSS and the structural equation modeling-partial least square (SEM-PLS) to analyze 839 convincing respondents. This quantitative research provides insights into online group buying, including the food industry.

Findings

The results demonstrate that the buyers’ PV of online group buying enhanced positive eWoM communication and repurchase intention. The willingness of buyers to spread positive eWoM indicates their recognition and satisfaction with a product or brand. Thus, they have the behavioral intention to repurchase in online group buying. The study found that while positive eWoM communication significantly impacts repurchase intention, PR negatively affects PV. The research provides theoretical and practical implications at the end of the study.

Research limitations/implications

This study has some limitations. First, the study only used PV and PR to measure consumers’ considerations and evaluations of the initial stage in the consumer decision journey. Future studies can include more dimensions that may further affect these considerations and assessments to verify the research model. Second, the study only used positive eWoM communication to measure the “enjoy-advocate-bond” of consumption and usage in the post-purchase stage.

Originality/value

The study proposes the sequential relationship in the psychological decision procedure of participating in online group buying and provides valuable managerial implications for managers operating online group buying on third-party platforms. The findings provide good knowledge for the food industry to stay connected with customers and develop their satisfaction.
Exploring the remote work challenges in the era of COVID-19 pandemic: review and application model
Authors: Arunprasad P. , Dey Chitra , Jebli Fedwa , Manimuthu Arunmozhi , El Hathat Zakaria
Published: January 2022

Purpose

Remote work (RW) literature is a megatrend in HRM literature, and the COVID-19 pandemic has highlighted the importance of RW as a concept and an organisational practice. Given the large number of papers being published on remote work, there is a need for a critical review of the extant literature using bibliometric analysis. This paper examines the literature on remote working to identify the factors crucial for managing a remote workforce. This study uses the complex adaptive systems theory as a foundation to build a framework that organisations can use to manage their remote workforce, focusing on three outcomes: employee engagement, collaboration and organisational agility.

Design/methodology/approach

Bibliometric analysis was conducted on the research published in Scopus journal in the area of remote work, followed by critical literature analysis.

Findings

The bibliometric analysis identified five clusters that reflect five organisational factors which the management can align to achieve the desired outcomes of engagement, collaboration and agility: technology orientation, leadership, HRM practices, external processes and organisational culture. The present findings have important implications for managing the remote workforce.

Originality/value

The five factors were mapped to propose a conceptual model on engaging individual employees, fostering team collaboration and building organisational agility while working remotely. We also propose an application model for using technology to achieve the outcomes of engagement, collaboration and agility in the organisation. Practitioners could use this framework to focus on the factors that can create a conducive environment to improve work efficiency in a remote workforce.
Liquidity of China’s agricultural futures market: measurement and cross-market dependence
Authors: Xu Yuanyuan , Li Jian , Wang Linjie , Li Chongguang
Published: January 2022

Purpose

This paper aims to present the first empirical liquidity measurement of China’s agricultural futures markets and study time-varying liquidity dependence across markets.

Design/methodology/approach

Based on both high- and low-frequency trading data of soybean and corn, this paper evaluates short-term liquidity adjustment in Chinese agricultural futures market measured by liquidity benchmark and long-term liquidity development measured by liquidity proxies.

Findings

By constructing comparisons, the authors identify the seminal paper of Fong, Holden and Trzcinka (2017) as the best low-frequency liquidity proxy in China’s agricultural futures market and capture similar historical patterns of the liquidity in soybean and corn markets. The authors further employ Copula-generalized autoregressive conditional heteroskedasticity models to investigate liquidity dependence between soybean and corn futures markets. Results show that cross-market liquidity dependence tends to be dynamic and asymmetric (in upper versus lower tails). The liquidity dependence becomes stronger when these markets experience negative shocks than positive shocks, indicating a concern on the contagion effect of liquidity risk under negative financial situations.

Originality/value

The findings of this study provide useful information on the dynamic evolution of liquidity pattern and cross-market dependence of fastest-growing agricultural futures in the largest emerging economy.