bluuebunny/crossref_metadata_2025 huggingface dataset:
Lake Erie fish safe to eat yet afflicted by algal hepatotoxins
Authors: Shahmohamadloo René S. , Bhavsar Satyendra P. , Ortiz Almirall Xavier , Marklevitz Stephen A. C. , Rudman Seth M. , Sibley Paul K.
Published: June 2022

Microcystin toxins from harmful algal blooms (HABs) can accumulate and persist in fish, raising dual concerns about human health risks from consumption and the potential for detrimental impacts on fish populations. However, there are fundamental unknowns about the relationship between HABs and fish populations driven by a lack of field information on toxin accumulation and retention over space and time. We conducted a field study to assess human health risks from consuming fish caught across all life stages of a HAB and to determine the pervasiveness of potentially harmful levels of microcystins on fish populations. We collected 190 fish in 2015 and 2017 from Lake Erie, a large freshwater ecosystem that is highly productive for fisheries and is an epicenter of HABs and microcystin toxicity events. Muscles and livers were analyzed for total microcystins, which was used to conduct a human health risk assessment for comparison against fish consumption advisory benchmarks available for Lake Erie. We find low human health risk from muscle consumption following the World Health Organization’s safety thresholds. However, all fish across capture dates had microcystins in their livers at levels shown to cause adverse effects, suggesting a pervasive and underappreciated toxic stressor. These data demonstrate that microcystins are retained in fish livers well beyond the cessation of HABs and calls for additional research to better understand the effects of sublethal toxic exposures for fish population dynamics, conservation, and related ecosystem services.
Pynoma, PyABraOM and BIOVARS: Towards genetic variant data acquisition and integration
Authors: Carneiro Paola , Colombelli Felipe , Recamonde-Mendoza Mariana , Matte Ursula
Published: June 2022

Motivation

Advances in genomic sequencing of human populations have generated a large amount of genomics data deposited in multiple sources. Programmatic batch searches executed at once are of great scientific interest to ease genomic investigations by retrieving and integrating this massive and decentralized data with little manual intervention.

Results

Pynoma and PyABraOM APIs were developed to offer multiple queries in gnomAD and ABraOM databases, respectively. A centralized search in these databases with data integration is offered by a third API, BIOVARS, which combines the resulting information with statistical and graphical visualizations. The implemented features are demonstrated in a case study using ACE2, ADAM17 and TMPRSS2 genes, which presents a generalizable workflow that shows how our APIs facilitate the access and integration of valuable biological data.

Availability

All the APIs are written in Python 3. Graphical visualizations for the retrieved data are provided by using the R language version 4.1. The source codes are publicly available and hosted on GitHub (github.com/bioinfo-hcpa).

Contact

umatte@hcpa.edu.br

Supplementary information

Supplementary data is available at github@nbioinfo-hcpa.
Efficacy of Parainfluenza Virus 5 (PIV5)-vectored Intranasal COVID-19 Vaccine as a Single Dose Vaccine and as a Booster against SARS-CoV-2 Variants
Authors: Beavis Ashley C. , Li Zhuo , Briggs Kelsey , Huertas-Díaz María Cristina , Wrobel Elizabeth R. , Najera Maria , An Dong , Orr-Burks Nichole , Murray Jackelyn , Patil Preetish , Huang Jiachen , Mousa Jarrod , Hao Linhui , Hsiang Tien-Ying , Gale Michael , Harvey Stephen B. , Tompkins S. Mark , Hogan Robert Jeffrey , Lafontaine Eric R. , Jin Hong , He Biao
Published: June 2022

Immunization with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has greatly reduced coronavirus disease 2019 (COVID-19)-related deaths and hospitalizations, but waning immunity and the emergence of variants capable of immune escape indicate the need for novel SARS-CoV-2 vaccines. An intranasal parainfluenza virus 5 (PIV5)-vectored COVID-19 vaccine CVXGA1 has been proven efficacious in animal models and blocks contact transmission of SARS-CoV-2 in ferrets. CVXGA1 vaccine is currently in human clinical trials in the United States. This work investigates the immunogenicity and efficacy of CVXGA1 and other PIV5-vectored vaccines expressing additional antigen SARS-CoV-2 nucleoprotein (N) or SARS-CoV-2 variant spike (S) proteins of beta, delta, gamma, and omicron variants against homologous and heterologous challenges in hamsters. A single intranasal dose of CVXGA1 induces neutralizing antibodies against SARS-CoV-2 WA1 (ancestral), delta variant, and omicron variant and protects against both homologous and heterologous virus challenges. Compared to mRNA COVID-19 vaccine, neutralizing antibody titers induced by CVXGA1 were well-maintained over time. When administered as a boost following two doses of a mRNA COVID-19 vaccine, PIV5-vectored vaccines expressing the S protein from WA1 (CVXGA1), delta, or omicron variants generate higher levels of cross-reactive neutralizing antibodies compared to three doses of a mRNA vaccine. In addition to the S protein, the N protein provides added protection as assessed by the highest body weight gain post-challenge infection. Our data indicates that PIV5-vectored COVID-19 vaccines, such as CVXGA1, can serve as booster vaccines against emerging variants.

Importance

With emerging new variants of concern (VOC), SARS-CoV 2 continues to be a major threat to human health. Approved COVID-19 vaccines have been less effective against these emerging VOCs. This work demonstrates the protective efficacy, and strong boosting effect, of a new intranasal viral-vectored vaccine against SARS-CoV-2 variants in hamsters.
Genomics of cold adaptations in the Antarctic notothenioid fish radiation
Authors: Bista Iliana , Wood Jonathan M. D. , Desvignes Thomas , McCarthy Shane A. , Matschiner Michael , Ning Zemin , Tracey Alan , Torrance James , Sims Ying , Chow William , Smith Michelle , Oliver Karen , Haggerty Leanne , Salzburger Walter , Postlethwait John H. , Howe Kerstin , Clark Melody S. , Detrich William H. , Cheng C.-H. Christina , Miska Eric A. , Durbin Richard
Published: June 2022

Numerous novel adaptations characterise the radiation of notothenioids, the dominant fish group in the freezing seas of the Southern Ocean. To improve understanding of the evolution of this iconic fish group, we generated and analysed new genome assemblies for 24 species covering all major subgroups of the radiation. We present a new estimate for the onset of the radiation at 10.7 million years ago, based on a time-calibrated phylogeny derived from genome-wide sequence data. We identify a two-fold variation in genome size, driven by expansion of multiple transposable element families, and use long-read sequencing data to reconstruct two evolutionarily important, highly repetitive gene family loci. First, we present the most complete reconstruction to date of the antifreeze glycoprotein gene family, whose emergence enabled survival in sub-zero temperatures, showing the expansion of the antifreeze gene locus from the ancestral to the derived state. Second, we trace the loss of haemoglobin genes in icefishes, the only vertebrates lacking functional haemoglobins, through complete reconstruction of the two haemoglobin gene clusters across notothenioid families. Finally, we show that both the haemoglobin and antifreeze genomic loci are characterised by multiple transposon expansions that may have driven the evolutionary history of these genes.
Role of TM3 in claudin-15 strand flexibility: a molecular dynamics study
Authors: Fuladi Shadi , McGuinness Sarah , Khalili-Araghi Fatemeh
Published: June 2022

Claudins are cell-cell adhesion proteins within tight junctions that connect epithelial cells together. Claudins polymerize into a network of strand-like structures within the membrane of adjoining cells and create ion channels that control paracellular permeability to water and small molecules. Tight junction morphology and barrier function is tissue specific and regulated by claudin subtypes. Here, we present a molecular dynamics study of claudin-15 strands within lipid membranes and the role of a single-point mutation (A134P) on the third transmembrane helix (TM3) of claudin-15 in determining the morphology of the strand. Our results indicate that the A134P mutation significantly affects the lateral flexibility of the strands, increasing the persistence length of claudin-15 strands by a factor of three. Analyses of claudin-claudin contact in our µsecond-long trajectories show that the mutation does not alter the intermolecular contacts (interfaces) between claudins. However, the dynamics and frequency of interfacial contacts are significantly affected. The A134P mutation introduces a kink in TM3 of claudin-15 similar to the one observed in claudin-3 crystal structure. The kink on TM3 skews the rotational flexibility of the claudins in the strands and limits their fluctuation in one direction. This asymmetric movement in the context of the double rows reduces the lateral flexibility of the strand and leads to higher persistence lengths of the mutant.
Phenotypic trait variation in a long-term, multisite common garden of Scots pine in Scotland
Authors: Beaton Joan , Perry Annika , Cottrell Joan , Iason Glenn , Stockan Jenni , Cavers Stephen
Published: June 2022

Multisite common garden experiments, exposing common pools of genetic diversity to a range of environments, allow quantification of plastic and genetic components of trait variation. For tree species, such studies must be long term as they typically only express mature traits after many years. As well as evaluating standing genetic diversity, these experiments provide an ongoing test of genetic variation against changing environmental conditions and form a vital resource for understanding how species respond to abiotic and biotic variation. Finally, quantitative assessments of phenotypic variation are essential to pair with rapidly accumulating genomic data to advance understanding of the genetic basis of trait variation, and its interaction with climatic change.

We describe a multisite, population-progeny, common garden experiment of the economically and ecologically important tree species, Scots pine, collected from across its native range in Scotland and grown in three contrasting environments. Phenotypic traits, including height, stem diameter and budburst were measured over 14 growing seasons from nursery to field site. The datasets presented have a wide range of applications.
Modeling the Diverse Effects of Divisive Normalization on Noise Correlations
Authors: Weiss Oren , Bounds Hayley A. , Adesnik Hillel , Coen-Cagli Ruben
Published: June 2022

Divisive normalization, a prominent descriptive model of neural activity, is employed by theories of neural coding across many different brain areas. Yet, the relationship between normalization and the statistics of neural responses beyond single neurons remains largely unexplored. Here we focus on noise correlations, a widely studied pairwise statistic, because its stimulus and state dependence plays a central role in neural coding. Existing models of covariability typically ignore normalization despite empirical evidence suggesting it affects correlation structure in neural populations. We therefore propose a pairwise stochastic divisive normalization model that accounts for the effects of normalization and other factors on covariability. We first show that normalization modulates noise correlations in qualitatively different ways depending on whether normalization is shared between neurons, and we discuss how to infer when normalization signals are shared. We then apply our model to calcium imaging data from mouse primary visual cortex (V1), and find that it accurately fits the data, often outperforming a popular alternative model of correlations. Our analysis indicates that normalization signals are often shared between V1 neurons in this dataset. Our model will enable quantifying the relation between normalization and covariability in a broad range of neural systems, which could provide new constraints on circuit mechanisms of normalization and their role in information transmission and representation.

Author Summary

Cortical responses are often variable across identical experimental conditions, and this variability is shared between neurons (noise correlations). These noise correlations have been studied extensively to understand how they impact neural coding and what mechanisms determine their properties. Here we show how correlations relate to divisive normalization, a mathematical operation widely adopted to describe how the activity of a neuron is modulated by other neurons via divisive gain control. We introduce the first statistical model of this relation. We extensively validate the model and investigate parameter inference in synthetic data. We find that our model, when applied to data from mouse visual cortex, outperforms a popular model of noise correlations that does not include normalization, and it reveals diverse influences of normalization on correlations. Our work demonstrates a framework to measure the relation between noise correlations and the parameters of the normalization model, which could become an indispensable tool for quantitative investigations of noise correlations in the wide range of neural systems that exhibit normalization.
Prioritized docking of synaptic vesicles provided by a rapid recycling pathway
Authors: Tran Van , Marty Alain
Published: June 2022

It is known that endocytosis of synaptic vesicles, and docking of these vesicles to their release sites, are regulated in a similar manner, but it has remained unclear whether the two processes are linked together mechanistically. To address this issue, we studied vesicular release during repeated trains of presynaptic action potentials. Synaptic responses decreased whenthe inter-train interval was shortened, indicating a gradual exhaustion of the recycling pool of vesicles, with a resting capacity of about 180 vesicles per active zone. This effect was partially counteracted by activation of a rapid recycling pathway that depended on the activation of myosin light chain kinase and that had a capacity of 200 vesicles per active zone. Vesicles arising from the rapid recycling route were preferentially docked in comparison with vesicles coming from an upstream pool, demonstrating a differential sorting of vesicles inside the readily releasable pool depending on their origin.
Identification of biomarkers and pathways for focal segmental glomerulosclerosis using next generation sequencing data and bioinformatics analysis
Authors: Vastrad Basavaraj , Vastrad Chanabasayya
Published: June 2022

Focal segmental glomerulosclerosis (FSGS) is a renal disease leading threat to human health around the world. Here we aimed to explore novel molecular and potential therapeutic targets in FSGS through adopting integrated bioinformatics tools. Next generation sequencing (NGS) data of GSE197307 was available from Gene Expression Omnibus (GEO) database. Furthermore, differentially expressed genes (DEGs) were screened using the DESeq2 package in R software. Gene ontology (GO) and REACTOME pathway enrichment analyses of DEGs were performed via g:Profiler. Then, the protein-protein interaction (PPI) network, miRNA-hub gene regulatory network and TF-hub gene regulatory network were constructed using the HIPPIE, miRNet and NetworkAnalyst databases. Hub genes were validated using the receiver operating characteristic curve (ROC) analysis. By performing DEGs analysis, 488 up regulated genes and 488 down regulated genes were successfully identified from GSE197307, respectively. And they were mainly enriched in the terms of multicellular organismal process, cell periphery, protein binding, metabolism, immune system process, signaling receptor binding and immune system. Based on the data of protein–protein interaction (PPI), miRNA-hub gene regulatory network and TF-hub gene regulatory network, the top hub genes were ranked, including ILK, DDX5, MATR3, ALB, FOS, MKI67, PLK1, TNF, LCK and GTSE1. Bioinformatics analysis of NGS data identified signaling pathways and hub genes, potentially representing molecular mechanisms for the occurrence, progression, and risk prediction in FSGS.
G307S DNAM-1 mutation exacerbates autoimmune encephalomyelitis via enhancing CD4+ T cell activation
Authors: Murata Rikito , Kinoshita Shota , Matsuda Kenshiro , Kawaguchi Atsushi , Shibuya Akira , Shibuya Kazuko
Published: June 2022

Although rs763361, which causes a non-synonymous glycine-to-serine mutation at residue 307 (G307S mutation) of the DNAM-1 immunoreceptor, is a single-nucleotide polymorphism (SNP) associated with autoimmune disease susceptibility, little is known about how the SNP is involved in pathogenesis. Here, we established CD4+ T cells expressing wild-type or G307S DNAM-1 and showed that the costimulatory signal from G307S DNAM-1 induced greater pro-inflammatory cytokine production and cell proliferation than that from wild-type DNAM-1. The G307S mutation also enhanced the recruitment of the tyrosine kinase Lck and augmented tyrosine phosphorylation at residue 322 (Tyr322) of DNAM-1. However, conversion of Tyr322 of DNAM-1 to phenylalanine (Y322F mutation) canceled the enhanced activation of CD4+ T cell transfectants expressing G307S DNAM-1. Adoptive transfer of myelin-antigen-specific CD4+ T cells expressing G307S DNAM-1 into mice exacerbated experimental autoimmune encephalomyelitis compared with the transfer of cells expressing wild-type DNAM-1. These findings suggest that rs763361 is a gain-of-function mutation that enhances DNAM-1-mediated costimulatory signaling for proinflammatory responses.
Single-cell multi-omics defines the cell-type specific impact of splicing aberrations in human hematopoietic clonal outgrowths
Authors: Gaiti Federico , Chamely Paulina , Hawkins Allegra G. , Cortés-López Mariela , Swett Ariel D. , Ganesan Saravanan , Mouhieddine Tarek H. , Dai Xiaoguang , Kluegel Lloyd , Chen Celine , Batta Kiran , Beaulaurier John , Drong Alexander W. , Hickey Scott , Dusaj Neville , Mullokandov Gavriel , Su Jiayu , Chaligné Ronan , Juul Sissel , Harrington Eoghan , Knowles David A. , Wiseman Daniel H. , Ghobrial Irene M. , Taylor Justin , Abdel-Wahab Omar , Landau Dan A.
Published: June 2022

RNA splicing factors are recurrently affected by alteration-of-function mutations in clonal blood disorders, highlighting the importance of splicing regulation in hematopoiesis. However, our understanding of the impact of dysregulated RNA splicing has been hampered by the inability to distinguish mutant and wildtype cells in primary patient samples, the cell-type complexity of the hematopoietic system, and the sparse and biased coverage of splice junctions by short-read sequencing typically used in single-cell RNA sequencing. To overcome these limitations, we developed GoT-Splice by integrating Genotyping of Transcriptomes (GoT) with enhanced efficiency long-read single-cell transcriptome profiling, as well as proteogenomics (with CITE-seq). This allowed for the simultaneous single-cell profiling of gene expression, cell surface protein markers, somatic mutation status, and RNA splicing. We applied GoT-Splice to bone marrow progenitors from patients with myelodysplastic syndrome (MDS) affected by mutations in the most prevalent mutated RNA splicing factor – the core RNA splicing factor SF3B1. High-resolution mapping of SF3B1mut vs. SF3B1wt hematopoietic progenitors revealed a fitness advantage of SF3B1mut cells in the megakaryocytic-erythroid lineage, resulting in an expansion of SF3B1mut erythroid progenitor (EP) cells. SF3B1mut EP cells exhibited upregulation of genes involved in regulation of cell cycle and mRNA translation. Long-read single-cell transcriptomes revealed the previously reported increase of aberrant 3’ splicing site usage in SF3B1mut cells. However, the ability to profile splicing within individual cell populations uncovered distinct cryptic 3’ splice site usage across different progenitor populations, as well as stage-specific aberrant splicing during erythroid maturation. Lastly, as splice factor mutations occur in clonal hematopoiesis (CH) with increased risk of neoplastic transformation, we applied GoT-Splice to CH samples. These data revealed that the erythroid lineage bias, as well as cell-type specific cryptic 3’ splice site usage in SF3B1mut cells, precede overt MDS. Collectively, we present an expanded multi-omics single-cell toolkit to define the cell-type specific impact of somatic mutations on RNA splicing, from the earliest phases of clonal outgrowths to overt neoplasia, directly in human samples.
The cell cycle inhibitor RB is diluted in G1 and contributes to controlling cell size in the mouse liver
Authors: Zhang Shuyuan , Zatulovskiy Evgeny , Arand Julia , Sage Julien , Skotheim Jan M.
Published: June 2022

Every type of cell in an animal maintains a specific size, which likely contributes to its ability to perform its physiological functions. While some cell size control mechanisms are beginning to be elucidated through studies of cultured cells, it is unclear if and how such mechanisms control cell size in an animal. For example, it was recently shown that RB, the retinoblastoma protein, was diluted by cell growth in G1 to promote size-dependence of the G1/S transition. However, it remains unclear to what extent the RB-dilution mechanism controls cell size in an animal. We therefore examined the contribution of RB-dilution to cell size control in the mouse liver. The RB-dilution model has two requirements. First, manipulations changing RB concentration drive corresponding changes in cell size, and second, the endogenous RB concentration decreases with cell size in G1. We found that both these requirements were met. Genetic perturbations decreasing RB protein concentrations through inducible shRNA expression or through liverspecific Rb1 knockout reduced hepatocyte size, while perturbations increasing RB protein concentrations in an Fah−/− mouse model increased hepatocyte size. Moreover, RB concentration decreased in larger G1 hepatocytes while the concentrations of the cell cycle activators Cyclin D1 and E2f1 remained relatively constant. Lastly, we tested how Rb1 manipulations affected G1/S cell size control in primary hepatocytes using live cell imaging. Loss of Rb1 weakened cell size control, i.e., reduced the inverse correlation between how much cells grew in G1 and how large they were at birth. Taken together, our results show that an RB- dilution mechanism contributes to cell size control in the mouse liver by linking cell growth to the G1/S transition.
A pan-genome approach to decipher variants in the highly complex tandem repeat ofLPA
Authors: Chin Chen-Shan , Behera Sairam , Metcalf Ginger A. , Gibbs Richard A. , Boerwinkle Eric , Sedlazeck Fritz J.
Published: June 2022

Lp(a) is an important factor in Coronary Heart disease risk, and its expression is correlated with the length of theLPAgene. The KIV-2 region ofLPAconsists of variable tandem repeats whose number is highly variable across individuals. Little is known about the inner diversity of the KIV-2 repeats themselves. Here we utilize a pan-genome graph approach across 47 haplotype resolved assemblies to identify unexpected variation across KIV-2.
NSUN2-mediated mRNA m5C Modification Regulates the Progression of Hepatocellular Carcinoma
Authors: Song Dan , An Ke , Zhai Wen-Long , Feng Lu-Yao , Xu Ying-Jie , Sun Ran , Wang Yue-Qin , Yang Yun-Gui , Kan Quan-Cheng , Tian Xin
Published: June 2022

RNA modification affects many biological processes and physiological diseases. The 5-methylcytosine (m5C) modification regulates the progression of multiple tumors. However, its characteristics and functions in hepatocellular carcinoma (HCC) remain largely unknown. Here, we found that HCC tissues had a higher m5C methylation level than the adjacent normal tissues. Transcriptome analysis revealed that a major fraction of the hypermethylated genes participated in the phosphokinase signaling pathways, such as the Ras and PI3K-Akt pathways. The m5C methyltransferase NSUN2 was highly expressed in HCC tissues consistently. Interestingly, the expression of many oncogenes was positively correlated with the expression of NSUN2, including GRB2, RNF115, AATF, ADAM15, RTN3, and HDGF. Real-time PCR assays further revealed that the expression of the mRNA of GRB2, RNF115, and AATF decreased significantly with the depletion of NSUN2 in HCC cells. Furthermore, NSUN2 could regulate the cellular sensitivity of HCC cells to sorafenib via modulating the Ras signaling pathway. Moreover, knocking down NSUN2 caused cell cycle arrest. Our study demonstrated a vital role of NSUN2 in the progression of HCC.
An atypical F-actin capping protein modulates cytoskeleton behaviors crucial to colonization of Trichomonas vaginalis
Authors: Wang Kai-Hsuan , Chang Jing-Yang , Li Fu-An , Chen Yen-Ju , Wu Kuan-Yi , Chu Tse-Ling , Lin Jessica , Hsu Hong-Ming
Published: June 2022

Cytoadherence and consequential migration are crucial for pathogens to establish colonization in the host. In contrast to the nonadherent isolate of Trichomonas vaginalis, the adherent one expresses more actin-related machinery proteins with more active flagellate-amoeboid morphogenesis, amoeba migration, and cytoadherence, activities that were abrogated by an actin assembly blocker. By immunoprecipitation coupled with label-free quantitative proteomics, an F-actin capping protein (TvFACPα) was identified from the actin-centric interactome, with an atypically greater binding preference to G-actin than F-actin. TvFACPα partially colocalized with F-actin at the parasite pseudopodia protrusion and formed the protein complexes with α-actin through its c-terminal domain. Meanwhile, TvFACPα overexpression suppresses F-actin polymerization, amoeboid morphogenesis, and cytoadherence in this parasite. Ser2 phosphorylation of TvFACPα enriched in the amoeboid stage of adhered trophozoites was reduced by a CKII inhibitor. The site-directed mutagenesis and CKII inhibitor treatment revealed that Ser2 phosphorylation acts as a switching signal to alter TvFACPα actin-binding activity and consequent actin cytoskeleton behaviors. Through CKII signaling, TvFACPα also controls the conversion of adherent trophozoite from amoeboid migration to flagellate form with axonemal motility. Together, CKII-dependent Ser2 phosphorylation regulates TvFACPα binding actin to fine-tune cytoskeleton dynamics and drive crucial behaviors underlying host colonization of T. vaginalis.
Non-standard viral genome-derived RNA activates TLR3 and type I IFN signaling to induce cDC1-dependent CD8+ T-cell responses during vaccination in mice
Authors: Fisher Devin G. , Holthausen David J. , López Carolina B.
Published: June 2022

There is a critical need to develop vaccine adjuvants that induce robust immune responses able to protect against intracellular pathogens, including viruses. Previously, we described the virus-derived adjuvant, defective viral genome-derived oligonucleotide (DDO), as a strong inducer of type 1 immune responses, including protective Th1 CD4+ T-cells and effector CD8+ T-cells in mice. Here we unravel the early innate response required for this type 1 immunity induction. Upon DDO subcutaneous injection, type 1 conventional dendritic cells (cDC1s) accumulate rapidly in the draining lymph node in a type I interferon (IFN)-dependent manner. cDC1 accumulation in the lymph node is required for antigen-specific CD8+ T-cell responses. Notably, in contrast to poly I:C, DDO administration resulted in type I IFN expression at the injection site, but not in the draining lymph node. Additionally, DDO induced an inflammatory cytokine profile distinct from that induced by poly I:C. Therefore, DDO represent a powerful new adjuvant to be used during vaccination against intracellular pathogens.

IMPORTANCE

There is a paucity of vaccine adjuvants able to trigger effective and safe protective responses to many intracellular pathogens. Defining the minimal requirements to achieve type 1 immunity, which includes antigen specific CD8+ T cells capable of eliminating infected cells, is essential for the development of adjuvants that lead to optimal protective immune responses during vaccination against intracellular pathogens. We use a virus-derived immunostimulatory molecule, defective viral genome-derived oligonucleotide (DDO), to provide insights into how type 1 immune responses are triggered during vaccination using an inactivated influenza vaccine model. Understanding the mechanism of action of vaccine adjuvants not only aids in the advancement of vaccine development, but also in understanding specific immune pathways required for efficient induction of adaptive immune responses to infections.
Intracellular mechanics and TBX3 expression jointly dictate the spreading mode of melanoma cells in 3D environments
Authors: Higgins Ghodeejah , Higgins Faatiemah , Peres Jade , Lang Dirk M , Abdalrahman Tamer , Zaman Muhammad H. , Prince Sharon , Franz Thomas
Published: June 2022

Cell stiffness and T-box transcription factor 3 (TBX3) expression have been identified as biomarkers of melanoma metastasis in 2D environments. This study aimed to determine how mechanical and biochemical properties of melanoma cells change during cluster formation in 3D environments. Vertical growth phase (VGP) and metastatic (MET) melanoma cells were embedded in 3D collagen matrices of 2 and 4 mg/ml collagen concentrations, representing low and high matrix stiffness. Mitochondrial fluctuation, intracellular stiffness, and TBX3 expression were quantified before and during cluster formation. In isolated cells, mitochondrial fluctuation decreased and intracellular stiffness increased with increase in disease stage from VGP to MET and increased matrix stiffness. TBX3 was highly expressed in soft matrices but diminished in stiff matrices for VGP and MET cells. Cluster formation of VGP cells was excessive in soft matrices but limited in stiff matrices, whereas for MET cells it was limited in soft and stiff matrices. In soft matrices, VGP cells did not change the intracellular properties, whereas MET cells exhibited increased mitochondrial fluctuation and decreased TBX3 expression. In stiff matrices, mitochondrial fluctuation and TBX3 expression increased in VGP and MET, and intracellular stiffness increased in VGP but decreased in MET cells. The findings suggest that soft extracellular environments are more favourable for tumour growth, and high TBX3 levels mediate collective cell migration and tumour growth in the earlier VGP disease stage but play a lesser role in the later metastatic stage of melanoma.

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Distinct patterns of cortical manifold expansion and contraction underlie human sensorimotor adaptation
Authors: Gale Daniel J. , Areshenkoff Corson N. , Standage Dominic P. , Nashed Joseph Y. , Markello Ross D. , Flanagan J. Randall , Smallwood Jonathan , Gallivan Jason P.
Published: June 2022

Sensorimotor learning is a dynamic, systems-level process that involves the combined action of multiple neural systems distributed across the brain. Although we understand a great deal about the specialized cortical systems that support specific components of action (such as reaching), we know less about how cortical systems function in a coordinated manner to facilitate adaptive behaviour. To address this gap in knowledge, our study measured human brain activity using functional MRI (fMRI) while participants performed a classic sensorimotor adaptation task, and used a manifold learning approach to describe how behavioural changes during adaptation relate to changes in the landscape of cortical activity. During early adaptation, we found that areas in parietal and premotor cortex exhibited significant contraction along the cortical manifold, which was associated with their increased covariance with regions in higher-order association cortex, including both the default mode and fronto-parietal networks. By contrast, during late adaptation, when visuomotor errors had been largely reduced, we observed a significant expansion of visual cortex along the cortical manifold, which was associated with its reduced covariance with association cortex and its increased intraconnectivity. Lastly, we found that individuals who learned more rapidly exhibited greater covariance between regions in the sensorimotor and association cortices during early adaptation. Together, these findings are consistent with a view that sensorimotor adaptation depends on changes in the integration and segregation of neural activity across more specialized regions of unimodal cortex with regions in association cortex implicated in higher-order processes. More generally, they lend support to an emerging line of evidence implicating regions of the default mode network in task-based performance.
The restriction factor pastrel is associated with host vigor, viral titer, and variation in disease tolerance during Drosophila C Virus infection
Authors: Kutzer Megan A.M. , Gupta Vanika , Neophytou Kyriaki , Doublet Vincent , Monteith Katy M. , Vale Pedro F.
Published: June 2022

Genetic variation for both resistance and disease tolerance has been described in a range of species infected with bacterial, viral and fungal pathogens. In Drosophila melanogaster, genetic variation in mortality following systemic Drosophila C Virus (DCV) infection has been shown to be driven by large effect polymorphisms in the viral restriction factor pastrel (pst). However, it is unclear if pst impacts variation in DCV titres (i.e. resistance), or if it also contributes to disease tolerance. We investigated systemic infection across a range of DCV challenge doses spanning nine orders of magnitude, in males and females of ten Drosophila Genetic Reference Panel (DGRP) lines carrying either a susceptible (S) or resistant (R) pst allele. Our results uncover among-line variation in fly survival, viral titers, and disease tolerance measured both as the ability to maintain survival (mortality tolerance) and reproduction (fecundity tolerance). We confirm the role of pst in resistance, as fly lines with the resistant (R) pst allele experienced lower viral titers, and we uncover novel effects of pst on host vigor, as flies carrying the R allele exhibited higher survival and fecundity even in the absence of infection. Finally, we found significant variation in the expression of the JAK-STAT ligand upd3 and the epigenetic regulator of JAK-STAT G9a. While G9a has been previously shown to mediate tolerance of DCV infection, we found no correlation between the expression of either upd3 or G9a on fly tolerance or resistance. Our work highlights the importance of both resistance and tolerance in viral defence.
Chiral growth of adherent filopodia
Authors: Li Wenhong , Chung Wen-Lu , Kozlov Michael M. , Medalia Ohad , Geiger Benjamin , Bershadsky Alexander D.
Published: June 2022

Adherent filopodia are elongated finger-like membrane protrusions, extending from the edges of diverse cell types and participating in cell adhesion, spreading, migration and environmental sensing. The formation and elongation of filopodia are driven by the polymerization of parallel actin filaments, comprising the filopodia cytoskeletal core. Here, we report that adherent filopodia, formed during the spreading of cultured cells on galectin-8-coated substrates, tend to change the direction of their extension in a chiral fashion, acquiring a left-bent shape. Cryo-electron tomography examination indicated that turning of the filopodia tip to the left is accompanied by the displacement of the actin core bundle to the right of the filopodia midline. Reduction of the adhesion to galectin-8 by treatment with thiodigalactoside abolished the filopodia chirality. By modulating the expression of a variety of actin-associated filopodia proteins, we identified myosin-X and formin DAAM1 as major filopodia chirality promoting factors. Formin mDia1, actin filament elongation factor VASP, and actin filament crosslinker fascin were also shown to be involved. Thus, the simple actin cytoskeleton of filopodia, together with a small number of associated proteins are sufficient to drive a complex navigation process, manifested by the development of left-right asymmetry in these cellular protrusions.
Deep thermal proteome profiling for detection of proteoforms and drug sensitivity biomarkers
Authors: Kurzawa Nils , Stahl Matthias , Leo Isabelle , Kunold Elena , Becher Isabelle , Audrey Anastasia , Mermelekas Georgios , Huber Wolfgang , Mateus André , Savitski Mikhail M. , Jafari Rozbeh
Published: June 2022

The complexity of the functional proteome extends significantly beyond the protein coding genome resulting in millions of proteoforms. Investigation of proteoforms and their functional roles is important to understand cellular physiology and its deregulation in diseases, but challenging to perform systematically. Here, we apply thermal proteome profiling with deep peptide coverage to detect functional proteoforms in acute lymphoblastic leukemia cell lines with different cytogenetic aberrations. We detect 15,846 proteoforms, capturing differently spliced, post-translationally modified, and cleaved proteins expressed from 9,290 genes. We identify differential coaggregation of proteoform pairs and establish links to disease biology. Moreover, we systematically make use of measured biophysical proteoform states to find specific biomarkers of drug sensitivity. Our approach thus provides a powerful and unique tool for systematic detection and functional annotation of proteoforms.
Keap1-resistant ΔN-Nrf2 isoform does not translocate to the nucleus upon electrophilic stress
Authors: Mikac Sara , Dziadosz Alicja , Padariya Monikaben , Kalathiya Umesh , Fahraeus Robin , Marek-Trzonkowska Natalia , Chruściel Elżbieta , Urban-Wójciuk Zuzanna , Papak Ines , Arcimowicz Łukasz , Marjanski Tomasz , Rzyman Witold , Sznarkowska Alicja
Published: June 2022

The Nrf2 pathway is an essential defense pathway in a cell. It responds to oxidative and electrophilic stress via derepression of Nrf2 from Keap1-Cul3-mediated degradation, accumulation of Nrf2 in the nucleus and transcriptional activation of a number of detoxifying and cell protective Nrf2 target genes. Here we report that normal and cancer cells also express the N-terminally truncated Nrf2 isoform (ΔN-Nrf2), which originates from an alternative promoter. Co-immunoprecipitation together with molecular dynamics simulation showed that the binding between ΔN-Nrf2 and Keap1 is impaired, resulting in the much higher stability of this form. ΔN-Nrf2 is retained in the cytoplasm in response to electrophilic stress, indicating that it does not regulate transcription under the same stress stimuli as the full-length Nrf2. Altogether this data suggests that Nrf2 has other functions in cells than transcriptional activation of genes, which most probably rely on the protein-protein interactions in the cytoplasm. The regulation between these functions takes place on the level of transcription.

Significance Statement

This work signifies the importance of alternative transcription in assigning the function to the produced protein. Nrf2 transcripts produced from the second promoter of the Nrf2 gene give rise to the N-terminally truncated Nrf2 form (ΔN-Nrf2), which is retained in the cytoplasm upon stress, thus it has a different role in cells than transcriptional regulation. ΔN-Nrf2 is resistant to the Keap1-Cul3 degradation pathway and is highly expressed in all tested cell types. This work points to the new, cytoplasmic role of Nrf2 in cells, determined at the level of transcription.
On the termination of the X-ray constrained wavefunction procedure: reformulation of the method for an unequivocal determination of λ
Authors: Genoni Alessandro
Published: June 2022

The X-ray constrained/restrained wavefunction (XCW/XRW) approach of quantum crystallography is revisited by introducing the stationary condition of the Jayatilaka functional with respect to the Lagrange multiplier λ. The theoretical derivation has unequivocally shown that the right value of λ is a maximum stationary point of the functional to optimize, thus enabling the solution of the longstanding problem of establishing the point at which to halt the XCW/XRW procedure. Based on the new finding, a reformulation of the X-ray constrained wavefunction algorithm is proposed and its implementation is envisaged. In addition to relying on more solid mathematical grounds, the new variant of the method will be intrinsically more physically meaningful, allowing a straightforward evaluation of the highest level of confidence with which the experimental X-ray diffraction data can be possibly reproduced.
Synthesis and crystal structure of rac-2-(1,3-dioxoisoindolin-2-yl)ethyl 4-methyl-N-phenyl-N′-(triisopropylsilyl)benzenesulfondiimidoate: the first member of a new substance class
Authors: Friedrich Erik , Heinrich Timo , Rosenberger Lara , Krier Mireille , Marek Stephanie , Reggelin Michael
Published: June 2022

The title compound {systematic name: rac-2-[7-methyl-4-(4-methylphenyl)-4-(phenylimino)-6,6-bis(propan-2-yl)-3-oxa-4λ6-thia-5-aza-6-silaoct-4-en-1-yl]-2,3-dihydro-1H-isoindole-1,3-dione}, C32H41N3O3SSi, was synthesized by desoxychlorination of 4-methyl-N-phenyl-N′-(triisopropylsilyl)benzenesulfonimidamide and subsequent reaction with 2-(2-hydroxyethyl)isoindoline-1,3-dione. The racemic compound was crystallized from isopropanol. The structural characterization by single-crystal X-ray diffraction revealed two double-bonded nitrogen atoms to the central sulfur atom and an overall crystal packing driven by its aromatic interactions.
Crystal-structure studies of 4-phenylpiperazin-1-ium 4-ethoxybenzoate monohydrate, 4-phenylpiperazin-1-ium 4-methoxybenzoate monohydrate, 4-phenylpiperazin-1-ium 4-methylbenzoate monohydrate and 4-phenylpiperazin-1-ium trifluoroacetate 0.12-hydrate
Authors: Mahesha Ninganayaka , Kumar Haruvegowda Kiran , Akkurt Mehmet , Yathirajan Hemmige S. , Foro Sabine , Abdelbaky Mohammed S. M. , Garcia-Granda Santiago
Published: June 2022

In this study, four new piperazinium salts, namely, 4-phenylpiperazin-1-ium 4-ethoxybenzoate monohydrate, C9H9O3·C10H15N2·H2O (I); 4-phenylpiperazin-1-ium 4-methoxybenzoate monohydrate, C10H15N2·C8H7O3·H2O (II); 4-phenylpiperazin-1-ium 4-methylbenzoate monohydrate, C10H15N2·C8H7O2·H2O (III); and 4-phenylpiperazin-1-ium trifluoroacetate 0.12 hydrate, C10H15N2·C2F3O2·0.12H2O (IV), have been synthesized. The single-crystal structures of these compounds reveal that all of them crystallize in the triclinic P\overline{1} space group and the crystal packing of (I)–(III) is built up of ribbons formed by a combination of hydrogen bonds of type N—H...O, O—H...O and other weak interactions of type C—H...O and C—H...π, leading to a three-dimensional network. In the crystal of (IV), the cations and the anions are connected by C—H...O, N—H...O and C—H...F hydrogen bonds and by C—H...π interactions, forming sheets which in turn interact to maintain the crystal structure by linking through the oxygen atoms of water molecules and van der Waals interactions, giving the whole structure.
The effects of workplace resources on employees’ decision to provide instrumental help to their colleagues
Authors: Zampetakis Leonidas A.
Published: June 2022

Purpose

The purpose of this research is to establish a hierarchy among different workplace resources in terms of their relative contribution to employee decision to provide instrumental help.

Design/methodology/approach

A within-person survey experiment was conducted and the data were analyzed using multilevel regression. The data are based on a random sample of 94 employees working in medium-sized companies in Crete, Greece.

Findings

Results suggest that for employees’ decision to provide instrumental help, some job resources are perceived as more important than others. Workplace resources that are closer to employees (i.e. coworkers’ social support and manager–subordinate relationship) are perceived as more important compared to leadership style and the manager use of humor.

Practical implications

Findings suggest that organizations can successfully improve instrumental helping through interventions primarily aimed at building group-level resources.

Originality/value

The study highlights the importance of workplace resources for employees’ decision to provide instrumental help. However not all job resources are perceived as equally important. Theoretically, the study extends influential resource-based theories.
The role of artificial intelligence in effective business operations during COVID-19
Authors: Chen Yasheng , Biswas Mohammad Islam , Talukder Md. Shamim
Published: June 2022

Purpose

The pressure to survive in a highly competitive market by using artificial intelligence (AI) has further demonstrated the need for automation in business operations during a crisis, such as COVID-19. Prior research finds managers' mixed perceptions about the use of technology in business, which underscores the need to better understand their perceptions of adopting AI for automation in business operations during COVID-19. Based on social exchange theory, the authors investigated managers' perceptions of using AI in business for effective operations during the COVID-19 pandemic.

Design/methodology/approach

This study collected data through a survey conducted in China (N = 429) and ran structural equation modeling to examine the proposed research model and structural relationships using Smart PLS software.

Findings

The results show that using AI in supply chain management, inventory management, business models, and budgeting are positively associated with managers' satisfaction. Further, the relationship between managers' satisfaction and effective business operations was found to be positively significant. In addition, the findings suggest that top management support and the working environment have moderating effects on the relationship between managers' satisfaction and effective business operations.

Practical implications

The results of this study can guide firms to adopt an AI usage policy and execution strategy, according to managers' perceptions and psychological responses to AI.

Social implications

The study can be used to manage the behavior of managers within organizations. This will ultimately improve society's perception of the employment of AI in business operations.

Originality/value

The study's outcomes provide valuable insights into business management and information systems with AI application as a business response to any crisis in the future.
TMT's decision-making on adoption of management innovation
Authors: Li Ruida , Zheng Li , Yuan Ling
Published: June 2022

Purpose

External environment drives established enterprises to employ management innovation. Drawing on dual-process theories, this paper purports to investigate TMT's intuitive and rational decision-making styles as mediating roles between perceived environmental turbulences and management innovation, and explain how organizational slack play an critical moderating role.

Design/methodology/approach

SPSS 25 is used to test 120 established enterprises' top management team (TMT) samples in China, and the moderated mediation model is empirically tested by using hierarchical regression analysis and conditional process analysis.

Findings

Perceived environmental turbulences promotes management innovation. Organizational slack as contextual variable influences the relationship between technology turbulence and TMT's decision-making styles. Interestingly, only perceived technology turbulence indirectly affects management innovation through TMT's intuitive decision-making when moderated by organizational slack. However, the indirect effect from perceived market turbulence to management innovation through TMT's rational decision-making is not significant when moderated by organizational slack.

Originality/value

Based on management innovation's human agency perspective, TMT's decision-making styles have not been discussed in research on management innovation. This paper sheds light on TMT's decision-making styles as mediating role.