bluuebunny/crossref_metadata_2025 huggingface dataset:
Standardised empirical dispersal kernels emphasise the pervasiveness of long-distance dispersal in European birds
Authors: Fandos Guillermo , Talluto Matthew , Fiedler Wolfgang , Robinson Robert A. , Thorup Kasper , Zurell Damaris
Published: November 2021

Dispersal is a key life-history trait for most species and essential to ensure connectivity and gene flow between populations and facilitate population viability in variable environments. Despite the increasing importance of range shifts due to global change, dispersal has proved difficult to quantify, limiting empirical understanding of this phenotypic trait and wider synthesis.

Here we aim to estimate and compare empirical dispersal kernels for European breeding birds considering average dispersal, natal (before first breeding) and breeding dispersal (between subsequent breeding attempts), and test whether different dispersal properties are phylogenetically conserved.

We standardised and analysed data from an extensive volunteer-based bird ring-recoveries database in Europe (EURING) by accounting for biases related to different censoring thresholds in reporting between countries and to migratory movements. Then, we fitted four widely used probability density functions in a Bayesian framework to compare and provide the best statistical descriptions of the average, the natal and the breeding dispersal kernels for each bird species.

The dispersal movements of the 234 European bird species analysed were statistically best explained by heavy-tailed kernels, meaning that while most individuals disperse over short distances, long-distance dispersal is a feature in almost all bird species. The overall phylogenetic signal in both median and long dispersal distances was low (Pagel’s λ < 0.40), implying a high degree of taxonomic generality in our findings. As expected in birds, natal dispersal was 5 Km greater as an average than breeding dispersal for most species (88% species analysed).

Our comprehensive analysis of empirical kernels indicates that long-distance dispersal is common among European breeding bird species and across life stages. The dispersal estimates offer a first guide to selecting appropriate dispersal kernels in range expansion studies and provide new avenues to improve our understanding of the mechanisms and rules underlying dispersal events.
XomicsToModel: Omics data integration and generation of thermodynamically consistent metabolic models
Authors: Preciat German , Wegrzyn Agnieszka B. , Thiele Ines , Hankemeier Thomas , Fleming Ronan M.T.
Published: November 2021

Constraint-based modelling can mechanistically simulate the behaviour of a biochemical system, permitting hypotheses generation, experimental design and interpretation of experimental data, with numerous applications, including modelling of metabolism. Given a generic model, several methods have been developed to extract a context-specific, genome-scale metabolic model by incorporating information used to identify metabolic processes and gene activities in a given context. However, existing model extraction algorithms are unable to ensure that the context-specific model is thermodynamically feasible. This protocol introducesXomicsToModel, a semi-automated pipeline that integrates bibliomic, transcriptomic, proteomic, and metabolomic data with a generic genome-scale metabolic reconstruction, or model, to extract a context-specific, genome-scale metabolic model that is stoichiometrically, thermodynamically and flux consistent. TheXomicsToModelpipeline is exemplified for extraction of a specific metabolic model from a generic metabolic model, but it enables omics data integration and extraction of physicochemically consistent mechanistic models from any generic biochemical network. With all input data fully prepared, algorithmic completion of the pipeline takes ~10 min, however manual review of intermediate results may also be required, e.g., when inconsistent input data lead to an infeasible model.
Low abundance members of the gut microbiome are potent drivers of immune cell education
Authors: Han Geongoo , Luong Hien , Vaishnava Shipra
Published: November 2021

One of the main goals of microbiome research is to identify bacterial members that significantly affect host phenotypes and understand their contributions to disease pathogenesis. Studies identifying bacterial members that dictate host phenotype have focused mainly on the dominant members, and the role of low abundance microbes in determining host phenotypes and pathogenesis of diseases remains unexplored. In this study, we compared the gut bacterial community of mice with wide-ranging microbial exposure to determine if low abundance bacteria vary based on microbial exposure or remain consistent. We noted that similar to the high abundance bacterial community, a core community of low abundance bacteria made up a significant portion of the gut microbiome irrespective of microbial exposure. To determine the effect of low abundance bacteria on community structure and host gene expression, we devised a microbiome dilution strategy to “delete” out low abundance bacteria and engrafted the diluted microbiomes into germ-free mice. Our approach successfully excluded low abundance bacteria from small and large intestinal bacterial communities and induced global changes in microbial community structure and composition in the large intestine. Gene expression analysis of intestinal tissue revealed that loss of low abundance bacteria resulted in a drastic reduction in expression of multiple genes involved MHC class II antigen presentation pathway and T-cell cytokine production in the small intestine. The effect of low abundance bacteria on MHC class II expression was found specific to the intestinal epithelium at an early timepoint post-colonization and correlated with bacteria belonging to the family Erysipelotrichaceae. We conclude that low abundance bacteria have a significantly higher immuno-stimulatory effect compared to dominant bacteria and are thus potent drivers of early immune education in the gut. Therefore, characterizing immune interaction of low abundance bacteria with the host will offer greater insight into the intestinal immune landscape and disease pathogenesis.
A biologically inspired architecture with switching units can learn to generalize across backgrounds
Authors: Voina Doris , Shea-Brown Eric , Mihalas Stefan
Published: November 2021

Humans and other animals navigate different landscapes and environments with ease, a feat that requires the brain’s ability to rapidly and accurately adapt to different visual domains, generalizing across contexts/backgrounds. Despite recent progress in deep learning applied to classification and detection in the presence of multiple confounds including contextual ones [25, 30], there remain important challenges to address regarding how networks can perform context-dependent computations and how contextually-invariant visual concepts are formed. For instance, recent studies have shown artificial networks that repeatedly misclassified familiar objects set on new backgrounds, e.g. incorrectly labelling known animals when they appeared in a different setting [3]. Here, we show how a bio-inspired network motif can explicitly address this issue. We do this using a novel dataset which can be used as a benchmark for future studies probing invariance to backgrounds. The dataset consists of MNIST digits of varying transparency, set on one of two backgrounds with different statistics: a Gaussian noise or a more naturalistic background from the CIFAR-10 dataset. We use this dataset to learn digit classification when contexts are shown sequentially, and find that both shallow and deep networks have sharply decreased performance when returning to the first background after experience learning the second – thecatastrophic forgettingphenomenon in continual learning. To overcome this, we propose an architecture with additional “ switching” units that are activated in the presence of a new background. We find that the switching network can learn the new context even with very few switching units, while maintaining the performance in the previous context – but that they must berecurrentlyconnected to network layers. When the task is difficult due to high transparency, the switching network trained on both contexts outperforms networks without switching trained on only one context. The switching mechanism leads to sparser activation patterns, and we provide intuition for why this helps to solve the task. We compare our architecture with other prominent learning methods, and find that elastic weight consolidation is not successful in our setting, while progressive nets are more complex but less effective. Our study therefore shows how a bio-inspired architectural motif can contribute to task generalization across context.
Spatial relationships of intra-lesion heterogeneity in Mycobacterium tuberculosis microenvironment, replication status, and drug efficacy
Authors: Lavin Richard C. , Tan Shumin
Published: November 2021

A hallmark of Mycobacterium tuberculosis (Mtb) infection with critical impact on disease development and outcome is the marked heterogeneity that exists, spanning differences in lesion types to changes in microenvironment as the infection progresses1–7. A mechanistic understanding of how this heterogeneity affects Mtb growth and treatment efficacy necessitates single bacterium-level studies in the context of intact host tissue architecture; however, such an evaluation has been technically challenging. Here, we exploit fluorescent reporter Mtb strains and the C3HeB/FeJ murine model in an integrated imaging approach to study microenvironment heterogeneity within a single lesion in situ, and analyze how these differences relate to non-uniformity in Mtb replication state, activity, and drug efficacy. We show that the pH and chloride environments differ spatially in a caseous necrotic lesion, with increased acidity and chloride levels in the lesion cuff versus the necrotic core. Conversely, a higher percentage of Mtb in the necrotic core versus the lesion cuff were in an actively replicating state, and correspondingly active in transcription and translation. Finally, examination of three first-line anti-tubercular drugs showed that efficacy of isoniazid was strikingly poor against bacteria in the lesion cuff. Our study reveals spatial relationships of intra-lesion heterogeneity, sheds light on important considerations in the development of anti-tubercular treatment strategies, and establishes a foundational framework for Mtb infection heterogeneity analysis at the single cell level in situ.
Interpreting ruminant specific conserved non-coding elements by developmental gene regulatory network
Authors: Pan Xiangyu , Ma Zhaoxia , Sun Xinqi , Li Hui , Zhang Tingting , Zhao Chen , Wang Nini , Heller Rasmus , Wong Wing Hung , Wang Wen , Jiang Yu , Wang Yong
Published: November 2021

Background

Biologists long recognized that the genetic information encoded in DNA leads to trait innovation via gene regulatory network (GRN) in development.

Results

Here, we generated paired expression and chromatin accessibility data during rumen and esophagus development in sheep and revealed 1,601 active ruminant-specific conserved non-coding elements (active-RSCNEs). To interpret the function of these active-RSCNEs, we developed a Conserved Non-coding Element interpretation method by gene Regulatory network (CNEReg) to define toolkit transcription factors (TTF) and model its regulation on rumen specific gene via batteries of active-RSCNEs during development. Our developmental GRN reveals 18 TTFs and 313 active-RSCNEs regulating the functional modules of the rumen and identifies OTX1, SOX21, HOXC8, SOX2, TP63, PPARG and 16 active-RSCNEs that functionally distinguish the rumen from the esophagus.

Conclusions

We argue that CNEReg is an attractive systematic approach to integrate evo-devo concepts with omics data to understand how gene regulation evolves and shapes complex traits.
Learning Feedback Molecular Network Models Using Integer Linear Programming
Authors: Ozen Mustafa , Abdi Ali , Emamian Effat S.
Published: November 2021

Analysis of intracellular molecular networks has many applications in understanding of the molecular bases of some complex diseases and finding the effective therapeutic targets for drug development. To perform such analyses, the molecular networks need to be converted into computational models. In general, network models constructed using literature and pathway databases may not accurately predict and reproduce experimental network data. This can be due to the incompleteness of literature on molecular pathways, the resources used to construct the networks, or some conflicting information in the resources. In this paper, we propose a network learning approach via an integer linear programming formulation that can efficiently incorporate biological dynamics and regulatory mechanisms of molecular networks in the learning process. Moreover, we present a method to properly take into account the feedback paths, while learning the network from data. Examples are also provided to show how one can apply the proposed learning approach to a network of interest. Overall, the proposed methods are useful for reducing the gap between the curated networks and experimental network data, and result in calibrated networks that are more reliable for making biologically meaningful predictions.
NorA, HmpX, and NorB cooperate to reduce NO toxicity during denitrification and plant pathogenesis in Ralstonia solanacearum
Authors: Truchon Alicia N. , Hendrich Connor G. , Bigott Adam F. , Dalsing Beth L. , Allen Caitilyn
Published: November 2021

Ralstonia solanacearum, which causes bacterial wilt disease of many crops, needs denitrifying respiration to succeed inside its plant host. In the hypoxic environment of plant xylem vessels this pathogen confronts toxic oxidative radicals like nitric oxide (NO), which is generated by both bacterial denitrification and host defenses. R. solanacearum has multiple distinct mechanisms that could mitigate this stress, including Repair of Iron Cluster (RIC) homolog NorA, nitric oxide reductase NorB, and flavohaemoglobin HmpX. During denitrification and tomato pathogenesis and in response to exogenous NO, R. solanacearum upregulated norA, norB, and hmpX. Single mutants lacking ΔnorB, ΔnorA, or ΔhmpX increased expression of many iron and sulfur metabolism genes, suggesting that losing even one NO detoxification system demands metabolic compensation. Single mutants suffered only moderate fitness reductions in host plants, possibly because they upregulated their remaining detoxification genes. However, ΔnorA/norB, ΔnorB/hmpX, and ΔnorA/hmpX double mutants grew poorly in denitrifying culture and in planta. Loss of norA, norB, and hmpX may be lethal, since the methods used to construct the double mutants did not generate a triple mutant. Aconitase activity assays showed that NorA, HmpX and especially NorB are important for maintaining iron-sulfur cluster proteins. Additionally, plant defense genes were upregulated in tomatoes infected with the NO-overproducing ΔnorB mutant, suggesting that bacterial detoxification of NO reduces pathogen visibility. Thus, R. solanacearum’s three NO detoxification systems each contribute to and are collectively essential for overcoming metabolic oxidative stress during denitrification, for virulence and growth in tomato, and for evading host plant defenses.

Importance

The soilborne plant pathogen Ralstonia solanacearum (Rs) causes bacterial wilt, a serious and widespread threat to global food security. Rs is metabolically adapted to low oxygen conditions, using denitrifying respiration to survive in the host and cause disease. However, bacterial denitrification and host defenses generate nitric oxide (NO), which is toxic and also alters signaling pathways in both plants and the pathogen. Rs mitigates NO with a trio of mechanistically distinct proteins: NO-reductase NorB, Repair of Iron Centers NorA, and oxidoreductase HmpX. This redundancy, together with analysis of mutants and in-planta dual transcriptomes, indicates that maintaining low NO levels is integral to Rs fitness in tomatoes (because NO damages iron-cluster proteins) and to evading host recognition (because bacterially produced NO can trigger plant defenses).
Characterization of the humoral immune response to BNT162b2 in elderly residents of long-term care facilities five to seven months after vaccination
Authors: Delbrück Marla , Hoehl Sebastian , Toptan Tuna , Schenk Barbara , Grikscheit Katharina , Metzler Melinda , Herrmann Eva , Ciesek Sandra
Published: November 2021

The elderly residing in long-term care facilities (LTCFs) are a group at high risk for COVID-19. Hence, monitoring of the vaccine-based immunity has a pivotal role in identifying strategies to provide optimal protection in this population. We examined the immune response to the mRNA vaccine BNT162b2 against COVID-19 five to seven months after completing a two-dose regimen.

We determined significantly lower anti-SARS-CoV-2 antibody titers in 298 SARS-CoV-2 naïve residents who were at least 75 years of age (mean 51.60 BAU/ml) (median age 87 years, range 75 to 101 years) when compared to health care workers (HCWs) aged 18 to 70 years (mean 156.99 BAU/ml, p < 0.001). Of the SARS-CoV-2 naïve residents, 29 had detectable neutralizing antibodies against the Delta variant (9.5%), and 14 of those (48.3%) only had a borderline titer of 1:10. Of 114 HCWs, 36 (31.6%) had detectable neutralizing antibodies. In a group of 14 elderly residents who had had a PCR-confirmed breakthrough infection, the mean antibody titer was significantly higher than in the other two groups (3199.65 BAU/mL) (p < 0.001), and 12 (85.7%) had detectable neutralizing antibodies against the Delta variant.

Our data demonstrate that 90.5% of elderly residents of LTCFs had no detectable neutralization-competent antibodies against the dominant Delta variant five to seven months after vaccination, and that neutralizing antibody titers were restored following a break-through infection. Our results suggest that both residents and health care workers in LTCFs would benefit from a booster vaccine six months after completing the two-dose schedule or earlier.
Cellular and Humoral Immunity to Ebola Zaire Glycoprotein and Viral Vector Proteins Following Immunization with Recombinant Vesicular Stomatitis Virus-Based Ebola Vaccine (rVSVΔG-EBOV-GP)
Authors: Raabe Vanessa , Lai Lilin , Morales Juliet , Xu Yongxian , Rouphael Nadine , Davey Richard T. , Mulligan Mark J.
Published: November 2021

While effective at preventing Zaire ebolavirus (EBOV) disease, cellular immunity to EBOV and vector-directed immunity elicited by the recombinant vesicular stomatitis virus expressing Ebola glycoprotein (rVSVΔG-EBOV-GP) vaccine remains poorly understood. Sera and peripheral blood mononuclear cells were collected from 32 participants enrolled in a prospective multicenter study [ClinicalTrials.govNCT02788227] before vaccination and up to six months post-vaccination. IgM and IgG antibodies, IgG-producing memory B cells, and T cell reactivity to EBOV glycoprotein, vesicular stomatitis virus-Indiana strain (VSV-I) matrix protein, and VSV-I nucleoprotein were measured using ELISA, ELISpot, and intracellular cytokine staining, respectively. Eleven participants previously received a different investigational Ebola vaccine. All participants met positivity criteria for IgG antibodies to, and circulating IgG-producing memory B cells to, EBOV glycoprotein following rVSVΔG-EBOV-GP vaccination. Transient IgM and IgG antibody responses to VSV-I matrix protein (n=1/32 and n=0/32, respectively) and nucleoprotein (n=2/32 and n=1/32, respectively) were infrequently detected, as were IgG-producing memory B cells recognizing VSV-I matrix protein (n=3/31) and nucleoprotein (n=2/31). CD4+ and CD8+ T cell responses to EBOV glycoprotein were present in 15/32 and 19/32 participants at baseline and in 32/32 and 23/32 participants one month post-vaccination, respectively. CD4+ and CD8+ T cell responses to VSV-I matrix protein (n=17/32 and n=16/32, respectively) and VSV-I nucleoprotein (n=23/32 for both CD4+ and CD8+ responses) were common post-vaccination. T cell responses were predominantly mono-cytokine, except CD8+ responses to EBOV glycoprotein among heterologous Ebola vaccine-experienced participants and CD8+ responses to VSV-I nucleoprotein. Overall, rVSVΔG-EBOV-GP elicits robust humoral and memory B cell responses to EBOV glycoprotein in both Ebola vaccine-naïve and heterologous Ebola vaccine-experienced individuals and can generate vector-directed T cell immunity. Further research is needed to understand the significance of pre-existing vector-directed immunity on responses to booster doses of rVSVΔG-EBOV-GP and other rVSV-vectored vaccines.
A novel histone deacetylase inhibitor-based approach to eliminate microglia and retain astrocyte properties in glial cell culture
Authors: He Xi-Biao , Wu Yi , Huang Haozhi , Guo Fang
Published: November 2021

The close association between astrocytes and microglia causes great difficulties to distinguish their individual roles in innate immune responses in central nervous system. Current chemical-based methods to eliminate microglia in glial cell culture introduce various molecular and functional alterations to astrocytes. Here, we describe a novel two-step approach to achieve a complete elimination of microglia without affecting the biological properties of co-cultured astrocytes by temporal treatment of histone deacetylase inhibitor trichostatin A (TSA). We verify TSA as a potent inducer for microglial-specific cell death, which also causes comprehensive gene expression changes in astrocytes. However, withdrawal of TSA not only ensures no microglia repopulation, but also restores all the gene expression changes in terms of astrocyte functions, including neurotrophic factors, glutamate and potassium transporters, and reactive astrocyte subtypes. By contrast, withdrawal of PLX5622, the commonly used colony-stimulating factor 1 receptor inhibitor neither prevents microglia repopulation nor restores the gene expression changes mentioned above. Using this method, we are able to discriminate differential roles of microglia and astrocytes in the induced expression of antiviral and pro-inflammatory cytokines upon various pathological stimuli including the spike protein of SARS-CoV-2. This simple and efficient method can be customized for the understanding of microglia-astrocyte interaction and the development of epigenetic therapies that target over-activated microglia in neuroinflammation-related diseases.
Assessing and enhancing foldability in designed proteins
Authors: Listov Dina , Lipsh-Sokolik Rosalie , Rosset Stéphane , Yang Che , Correia Bruno E , Fleishman Sarel J
Published: November 2021

Recent advances in protein-design methodology have led to a dramatic increase in reliability and scale. With these advances, dozens and even thousands of designed proteins are automatically generated and screened. Nevertheless, the success rate, particularly in design of functional proteins, is low and fundamental goals such as reliable de novo design of efficient enzymes remain beyond reach. Experimental analyses have consistently indicated that a major reason for design failure is inaccuracy and misfolding relative to the design model. To address this challenge, we describe complementary methods to diagnose and ameliorate suboptimal regions in designed proteins: first, we develop a Rosetta atomistic computational mutation scanning approach to detect energetically suboptimal positions in designs (available on a web server https://pSUFER.weizmann.ac.il); second, we demonstrate that AlphaFold2 ab initio structure prediction flags regions that may misfold in designed enzymes and binders; and third, we focus FuncLib design calculations on suboptimal positions in a previously designed low-efficiency enzyme improving its catalytic efficiency by 330 fold. Furthermore, applied to a de novo designed protein that exhibited limited stability, the same approach markedly improved stability and expressibility. Thus, foldability analysis and enhancement may dramatically increase the success rate in design of functional proteins.
Improvement of muscle strength in a mouse model for congenital myopathy treated with HDAC and DNA methyltransferase inhibitors
Authors: Ruiz Alexis , Benucci Sofia , Duthaler Urs , Bachmann Christoph , Franchini Martina , Noreen Faiza , Pietrangelo Laura , Protasi Feliciano , Treves Susan , Zorzato Francesco
Published: November 2021

To date there are no therapies for patients with congenital myopathies, muscle disorders causing poor quality of life of affected individuals. In approximately 30% of the cases, patients with congenital myopathies carry either dominant or recessive mutations in the RYR1 gene; recessive RYR1 mutations are accompanied by reduction of RyR1 expression and content in skeletal muscles and are associated with fiber hypotrophy and muscle weakness. Importantly, muscles of patients with recessive RYR1 mutations exhibit increased content of class II histone de-acetylases and of DNA genomic methylation. We recently created a mouse model knocked-in for the p.Q1970fsX16+p.A4329D RyR1 mutations, which are isogenic to those carried by a severely affected child suffering from a recessive form of RyR1-related multi-mini core disease. The phenotype of the RyR1 mutant mice recapitulates many aspects of the clinical picture of patients carrying recessive RYR1 mutations. We treated the compound heterozygous mice with a combination of two drugs targeting DNA methylases and class II histone de-acetylases. Here we show that treatment of the mutant mice with drugs targeting epigenetic enzymes improves muscle strength, RyR1 protein content and muscle ultrastructure. This study provides proof of concept for the pharmacological treatment of patients with congenital myopathies linked to recessive RYR1 mutations.
Sequestration of LINE-1 in novel cytosolic bodies by MOV10 restricts retrotransposition
Authors: Arora Rajika , Bodak Maxime , Penouty Laura , Hackman Cindy , Ciaudo Constance
Published: November 2021

LINE-1 (L1) are autonomous retroelements that have retained their ability to mobilize. Mechanisms regulating L1 mobility include DNA methylation in somatic cells and the Piwi-interacting RNA pathway in the germline. During pre-implantation stages of mouse embryonic development, however, both pathways are inactivated leading to a critical window necessitating alternate means of L1 regulation. We previously reported an increase in L1 levels in Dicer_KO mouse embryonic stem cells (mESCs). Intriguingly this was accompanied by only a marginal increase in retrotransposition, suggestive of additional mechanisms suppressing L1 mobility. Here, we demonstrate that L1 Ribonucleoprotein complexes (L1 RNP) accumulate as aggregates in Dicer_KO cytoplasm along with the RNA helicase MOV10. The combined overexpression of L1 RNAs and MOV10 is sufficient to create L1 RNP aggregates in stem cells. In Dicer_KO mESCs, MOV10 is upregulated due to the loss of its direct regulation by miRNAs. The newly discovered post-transcriptional regulation of Mov10 expression, and its role in preventing L1 retrotransposition by driving novel cytosolic aggregation affords alternate routes to explore for therapy and disease progression.
Deep and fast label-free Dynamic Organellar Mapping
Authors: Schessner Julia P. , Albrecht Vincent , Davies Alexandra K. , Sinitcyn Pavel , Borner Georg H.H.
Published: November 2021

The Dynamic Organellar Maps (DOMs) approach combines cell fractionation and shotgun-proteomics for global profiling analysis of protein subcellular localization. Here, we have drastically enhanced the performance of DOMs through data-independent acquisition (DIA) mass spectrometry (MS). DIA-DOMs achieve twice the depth of our previous workflow in the same MS runtime, and substantially improve profiling precision and reproducibility. We leveraged this gain to establish flexible map formats scaling from rapid analyses to ultra-deep coverage. Our fastest format takes only ∼2.5h/map and enables high-throughput experimental designs. Furthermore, we introduce DOM-QC, an open-source software tool for in-depth standardized analysis of DOMs and other profiling data. We then applied DIA-DOMs to capture subcellular localization changes in response to starvation and disruption of lysosomal pH in HeLa cells, which revealed a subset of Golgi proteins that cycle through endosomes. DIA-DOMs offer a superior workflow for label-free spatial proteomics as a systematic phenotype discovery tool.
Salmonella Outer Membrane Vesicles contain tRNA Fragments (tRFs) that Inhibit Bacteriophage P22 infection
Authors: Houserova Dominika , Huang Yulong , Kasukurthi Mohan V. , Watters Brianna C. , Khan Fiza F. , Mehta Raj V. , Chaudhary Neil Y. , Roberts Justin T. , DeMeis Jeffrey D. , Hobbs Trevor K. , Ghee Kanesha R. , McInnis Cameron H. , Johns Nolan P. , Kegler Abrianna J. , Coley Alexander B. , Brown Cana L. , Hewes Jenny L. , McElyea Marie M. , Reeves Monica N. , Tran Tuan M. , Bauer Natalie R. , Huang Jingshan , Audia Jonathon P. , Foster John W. , Borchert Glen M.
Published: November 2021

Salmonella Outer Membrane Vesicles (OMVs) were recently shown to inhibit P22 bacteriophage infection. Furthermore, despite there being several published reports now independently describing (1) the marked prevalence of tRFs within secreted vesicle transcriptomes and (2) roles for specific tRFs in facilitating/inhibiting viral replication, there have been no examinations of the effects of vesicle-secreted tRFs on viral infection reported to date. Notably, while specific tRFs have been reported in a number of bacteria, the tRFs expressed by salmonellae have not been previously characterized. As such, we recently screened small RNA-seq datasets for the presence of recurrent, specifically excised tRFs and identified 31 recurrent, relatively abundant tRFs expressed by Salmonella enterica serovar Typhimurium (SL1344). What’s more, we find S. Typhimurium OMVs contain significant levels of tRFs highly complementary to known Salmonella enterica-infecting bacteriophage with 17 of 31 tRFs bearing marked complementarity to at least one known Salmonella enterica-infecting phage (averaging 97.4% complementarity over 22.9 nt). Most notably, tRNA-Thr-CGT-1-1, 44-73, bears 100% sequence complementary over its entire 30 nt length to 29 distinct, annotated Salmonella enterica-infecting bacteriophage including P22. Importantly, we find inhibiting this tRF in secreted OMVs improves P22 infectivity in a dose dependent manner whereas raising OMV tRF levels conversely inhibits P22 infectivity. Furthermore, we find P22 phage pre-incubation with OMVs isolated from naïve, control SL1344 S. Typhimurium, successfully rescues the ability of S. Typhimurium transformed with a specific tRNA-Thr-CGT-1-1, 44-73 tRF inhibitor to defend against P22. Collectively, these experiments confirm tRFs secreted in S. Typhimurium OMVs are directly involved with and required for the ability of OMVs to defend against bacteriophage predation. As we find the majority of OMV tRFs are highly complementary to an array of known Salmonella enterica-infecting bacteriophage, we suggest OMV tRFs may primarily function as a broadly acting, previously uncharacterized innate antiviral defense.
Platelets are dispensable for the ability of CD8+ T cells to accumulate, patrol, kill and reside in the liver
Authors: O’Connor James H. , McNamara Hayley A. , Cai Yeping , Coupland Lucy A. , Gardiner Elizabeth E. , Parish Christopher R. , McMorran Brendan J. , Ganusov Vitaly V. , Cockburn Ian A.
Published: November 2021

Effector and memory CD8+ T cells accumulate in large numbers in the liver where they play key roles in the control of liver pathogens includingPlasmodium. It has also been proposed that liver may act as the main place for elimination of effector CD8+ T cells at the resolution of immune responses. Platelets and the integrin LFA-1 have been proposed to be critical for the accumulation of protective CD8+ T cells in the liver; conversely, asialo-glycoprotein (ASGP) expression on the surface of CD8+ T cells has been proposed to assist in elimination of effector T cells in the liver. Here we investigated the contributions of these interactions in the accumulation of CD8+ T cells activatedin vitroorin vivoby immunization withPlasmodiumparasites. UsingMpl-/-mice with constitutive thrombocytopaenia and antibody-mediated platelet depletion models we found that severe reduction in platelet concentration in circulation did not strongly influence the accumulation and protective function of CD8+ T cells in the liver in these models. Surprisingly, inhibition of ASGP receptors did not inhibit the accumulation of effector cells in the liver, but instead prevented these cells from accumulating in the spleen. We further found that enforced expression of ASGP on effector CD8+ T cells using ST3GalI knockout cells lead to their loss from the spleen. These data suggest that platelets play a marginal role in CD8+ T cell function in the liver. Furthermore, ASGP-expressing effector CD8+ T cells are retained in the liver but are lost from the spleen.
Novel genetic basis of resistance to Bt toxin Cry1Ac inHelicoverpa zea
Authors: Benowitz Kyle M. , Allan Carson W. , Degain Benjamin A. , Li Xianchun , Fabrick Jeffrey A. , Tabashnik Bruce E. , Carrière Yves , Matzkin Luciano M.
Published: November 2021

Crops genetically engineered to produce insecticidal proteins from the bacteriumBacillus thuringiensis(Bt) have advanced pest management, but their benefits are diminished when pests evolve resistance. Elucidating the genetic basis of pest resistance to Bt toxins can improve resistance monitoring, resistance management, and design of new insecticides. Here, we investigated the genetic basis of resistance to Bt toxin Cry1Ac in the lepidopteranHelicoverpa zea, one of the most damaging crop pests in the United States. To facilitate this research, we built the first chromosome-level genome assembly for this species, which has 31 chromosomes containing 375 Mb and 15,482 predicted proteins. Using a genome-wide association study, fine-scale mapping, and RNA-seq, we identified a 250-kb quantitative trait locus (QTL) on chromosome 13 that was strongly associated with resistance in a strain ofH. zeathat had been selected for resistance in the field and lab. The mutation in this QTL contributed to but was not sufficient for resistance, which implies alleles in more than one gene contributed to resistance. This QTL contains no genes with a previously reported role in resistance or susceptibility to Bt toxins. However, in resistant insects, this QTL has a premature stop codon in a kinesin gene which is a primary candidate as a mutation contributing to resistance. We found no changes in gene sequence or expression consistently associated with resistance for 11 genes previously implicated in lepidopteran resistance to Cry1Ac. Thus, the results reveal a novel and polygenic basis of resistance.
Fibroblast-expressed LRRC15 suppresses SARS-CoV-2 infection and controls antiviral and antifibrotic transcriptional programs
Authors: Loo Lipin , Waller Matthew A. , Moreno Cesar L. , Cole Alexander J. , Stella Alberto Ospina , Pop Oltin-Tiberiu , Jochum Ann-Kristin , Ali Omar Hasan , Denes Christopher E. , Hamoudi Zina , Chung Felicity , Aggarwal Anupriya , Low Jason K. K. , Patel Karishma , Siddiquee Rezwan , Kang Taeyoung , Mathivanan Suresh , Mackay Joel P. , Flatz Lukas , Hesselson Daniel , Turville Stuart , Neely G. Gregory
Published: November 2021

Although ACE2 is the primary receptor for SARS-CoV-2 infection, a systematic assessment of host factors that regulate binding to SARS-CoV-2 spike protein has not been described. Here we use whole genome CRISPR activation to identify host factors controlling cellular interactions with SARS-CoV-2. Our top hit was aTLR-related cell surface receptor calledleucine-rich repeat-containing protein 15(LRRC15).LRRC15expression was sufficient to promote SARS-CoV-2 Spike binding where they form a cell surface complex.LRRC15mRNA is expressed in human collagen-producing lung myofibroblasts and LRRC15 protein is induced in severe COVID-19 infection where it can be found lining the airways. Mechanistically, LRRC15 does not itself support SARS-CoV-2 infection, but fibroblasts expressing LRRC15 can suppress both pseudotyped and authentic SARS-CoV-2 infection intrans. Moreover, LRRC15 expression in fibroblasts suppresses collagen production and promotes expression of IFIT, OAS, and MX-family antiviral factors. Overall, LRRC15 is a novel SARS-CoV-2 spike-binding receptor that can help control viral load and regulate antiviral and antifibrotic transcriptional programs in the context of COVID-19 infection.
Genomic landscape of SARS-CoV-2 pandemic in Brazil suggests an external P.1 variant origin
Authors: Perico Camila P. , De Pierri Camilla R. , Neto Giuseppe P. , Fernandes Danrley R. , Pedrosa Fabio O. , de Souza Emanuel M. , Raittz Roberto T.
Published: November 2021

Brazil was the epicenter of worldwide pandemics at the peak of its second wave. The genomic/proteomic perspective of the COVID-19 pandemic in Brazil can bring new light to understand the global pandemics behavior. In this study, we track SARS-CoV-2 molecular information in Brazil using real-time bioinformatics and data science strategies to provide a comparative and evolutive panorama of the lineages in the country. SWeeP vectors represented the Brazilian and worldwide genomic/proteomic data from GISAID between 02/2020 – 08/2021. Clusters were analyzed and compared with PANGO lineages. Hierarchical clustering provided phylogenetic and evolutionary analysis of the lineages, and we tracked the P.1 (Gamma) variant origin. The genomic diversity based on Chao’s estimation allowed us to compare richness and coverage among Brazilian states and other representative countries. We found that epidemics in Brazil occurred in two distinct moments, with different genetic profiles. The P.1 lineages emerged in the second wave, which was more aggressive. We could not trace the origin of P.1 from the variants present in Brazil in 2020. Instead, we found evidence pointing to its external source and a possible recombinant event that may relate P.1 to the B.1.1.28 variant subset. We discussed the potential application of the pipeline for emerging variants detection and the stability of the PANGO terminology over time. The diversity analysis showed that the low coverage and unbalanced sequencing among states in Brazil could have allowed the silenty entry and dissemination of P.1 and other dangerous variants. This comparative and evolutionary analysis may help to understand the development and the consequences of the entry of variants of concern (VOC).
Unexposed populations and potential COVID-19 burden in European countries as of 21st November 2021
Authors: Chapman Lloyd A C , Barnard Rosanna C , Russell Timothy W , Abbott Sam , Van Zandvoort Kevin , Davies Nicholas G , Kucharski Adam J
Published: November 2021

We estimate the potential remaining COVID-19 burden in 19 European countries by estimating the proportion of each country’s population that has acquired immunity to severe disease through infection or vaccination. Our results suggest that many European countries could still face a substantial burden of hospitalisations and deaths, particularly those with lower vaccination coverage, less historical transmission, and/or older populations. Continued non-pharmaceutical interventions and efforts to achieve high vaccination coverage are required in these countries to limit severe COVID-19 outcomes.
Mitochondrial calcium uptake regulates tumour progression in embryonal rhabdomyosarcoma
Authors: Chiu Hsin Yao , Loh Amos Hong Pheng , Taneja Reshma
Published: November 2021

Embryonal rhabdomyosarcoma (ERMS) is characterized by a failure of cells to complete skeletal muscle differentiation. Although ERMS cells are vulnerable to oxidative stress, the relevance of mitochondrial calcium homeostasis in oncogenesis is unclear. Here, we show that ERMS cell lines as well as primary tumours exhibit elevated expression of the Mitochondrial Calcium Uniporter (MCU). MCU knockdown resulted in impaired mitochondrial calcium uptake and a reduction in mitochondrial reactive oxygen species (mROS) levels. Phenotypically, MCU knockdown cells exhibited reduced cellular proliferation and motility, with an increased propensity to differentiatein vitroandin vivo. RNA-sequencing of MCU knockdown cells revealed a significant reduction in genes involved in TGFβ signalling that play prominent roles in oncogenesis and inhibition of myogenic differentiation. Interestingly, modulation of mROS production impacted TGFβ signalling. Our study elucidates mechanisms by which mitochondrial calcium dysregulation promotes tumour progression and suggests that targeting the MCU complex to restore mitochondrial calcium homeostasis could be a therapeutic avenue in ERMS.
Exploring the relationship between lifestyle, digital financial element and digital financial services experience
Authors: Bapat Dhananjay
Published: November 2021

Purpose

The purpose of this study is to explore digital financial services experience, investigate the antecedents to digital financial services experience and examine familiarity as a moderator.

Design/methodology/approach

The study uses dual methods: qualitative and quantitative. Multiple case studies are applied as a qualitative method to explore and capture recent development in rapidly changing digital finance. An empirical, survey-based approach is used to collect data from 258 respondents about their experiences with digital financial services experience using constructs, such as perceived ease of use, timeliness, lifestyle and digital financial element. The study used structural equation modeling using smart-PLS.

Findings

Using word count, hierarchy chart, items clustered by similarity and qualitative analysis by applying NVivo 12, the study validates the constructs and captures recent developments. Using smart PLS, the structural equation model reveals that the digital functional element positively affects the digital financial services experience. It is observed that lifestyle mediated between perceived ease of use and timeliness with digital financial services experience. Further, familiarity moderates the relationship between the digital financial element and digital financial services experience. Moreover, while this research analyzed the relationship regarding financial services customers, we suggest a comparative study between different entities.

Originality/value

The study can be considered one of its kind using qualitative and quantitative research methods. It integrates theory from both the information system and marketing domain. As the increased number of digital channels and interfaces has increased, companies need to understand how to improve the digital financial services experience.
A gardening and woodwork group in mental health: a step towards recovery
Authors: Sinnott Róisín , Rowlís Maria
Published: November 2021

Purpose

This paper aims to evaluate the impact of an eight-week gardening and woodwork group programme on individuals’ recovery goals in an adult community mental health setting.

Design/methodology/approach

Seven individuals participated in the research. The programme was designed and facilitated by two occupational therapists (the authors) and one horticulture and trade skills facilitator. The goal attainment scale was used as a quantitative outcome measure as it allowed individuals to collaboratively set occupation-focused recovery-oriented goals. Due to the small sample size, descriptive statistics were used to analyse this data. Qualitative feedback was gathered through participant feedback forms when the programme ended.

Findings

Quantitative findings indicate positive results for individuals’ progression towards their recovery goals, with six out of seven participants either achieving or exceeding their goals. One person who attended only one out of eight groups had “worse than expected” goal achievement.

Originality/value

While there is evidence for the use of gardening and woodwork group therapy in mental health settings, most studies have relied on symptom-focused questionnaires or qualitative results rather than quantifiable recovery-oriented measures (Cipriani et al., 2017; Kamioka et al., 2014; Parkinson et al., 2011). It is hoped that this paper begins to bridge that gap and also outlines how recovery principles, gardening and woodwork can be incorporated into occupational therapy group programmes. This is of particular merit during the COVID-19 pandemic, which has led to a greater need for group intervention in outdoor settings, where social distancing can be comfortably facilitated.
What contributes to online communities' prosperity? Understanding value co-creation in product-experience-shared communities (PESCs) from the view of resource integration
Authors: Wang Yu , Zhang Mingli , Ming Yaxin
Published: November 2021

Purpose

The purpose of this paper is to understand the factors influencing content generation and community initiative in PESCs. Taking advantage of an emerging PESC – Xiaohongshu APP, the study identifies three antecedent resources, including customer-owned knowledge, harmonious passion to shopping and perceived information usefulness, that affect content generating and further community initiative.

Design/methodology/approach

Based on the service-dominant (S-D) logic model and resource integration related work, the authors proposed a conceptual framework empirically tested using data of a survey and the real content-generating behavior from 347 respondents.

Findings

This paper identifies three resource antecedents of content generating behavior with significant influence. Furthermore, there is a moderating effect of perceived information usefulness among these three resources, which echoes the concept of resource integration. Content generating has a significant and positive influence on community initiative.

Originality/value

First, the paper identified customer and platform resources promoting the prosperity of PESCs, enhancing the research on antecedents of community prosperity. Second, the paper empirically quantifies the process and outcome of resource integration conceptual model. Third, it enriches the understanding of C2C interaction by investigating the value creation process on PESCs. Moreover, findings in the study provide insights for community managers to improve the operation of PESCs.