bluuebunny/crossref_metadata_2025 huggingface dataset:
Disruption of the nuclear localization signal in RBM20 is causative in dilated cardiomyopathy
Authors: Zhang Yanghai , Gregorich Zachery R. , Wang Yujuan , Braz Camila Urbano , Zhang Jibin , Liu Yang , Liu Peiheng , Aori Nanyumuzi , Hacker Timothy A. , Granzier Henk , Guo Wei
Published: December 2022

Human patients carrying genetic mutations in RNA binding motif 20 (RBM20) develop a clinically aggressive dilated cardiomyopathy (DCM). RBM20 is a splicing factor with two canonical domains, an RNA recognition motif (RRM) and an arginine-serine rich (RS) domain. RRM loss-of-function disrupts the splicing of RBM20 target transcripts and leads to systolic dysfunction without overt DCM, while mutations in the RS domain precipitate DCM. We show that mice lacking the RS domain (Rbm20ΔRS) manifest DCM with mis-splicing of RBM20 target transcripts. We found that RBM20 is mis-localized inRbm20ΔRSmice but not in mice lacking the RRM, which are also deficient in RBM20 splicing. We determine that the RS domain, not other domains including the RRM, is critical for RBM20 nuclear import and define the core nuclear localization signal (NLS) within this domain. Mutation analysis of phosphorylation sites within the RS domain indicate that phosphorylation is dispensable for RBM20 nuclear import. Collectively, our findings establish disruption of the NLS in RBM20 as a causative mechanism in DCM through nucleocytoplasmic transport.
Disrupted RNA editing in beta cells mimics early stage type 1 diabetes
Authors: Knebel Udi Ehud , Peleg Shani , Dai Chunhua , Cohen-Fultheim Roni , Glaser Benjamin , Levanon Erez Y. , Powers Alvin C. , Klochendler Agnes , Dor Yuval
Published: December 2022

A major hypothesis for the etiology of type 1 diabetes (T1D) postulates initiation by viral infection, leading to double-stranded RNA (dsRNA)-mediated interferon response; however, a causal virus has not been identified. Here we use a mouse model, corroborated with human data, to demonstrate that endogenous dsRNA in beta-cells can lead to a diabetogenic immune response, thus identifying a virus-independent mechanism for T1D initiation. We found that disruption of the RNA editing enzyme ADAR in beta-cells triggers a massive interferon response, islet inflammation and beta-cell failure, with features bearing striking similarity to early-stage human T1D. Glycolysis via calcium enhances the interferon response, suggesting an actionable vicious cycle of inflammation and increased beta-cell workload.

One sentence summary

Adar inactivation in beta-cells triggers a glucose-dependent interferon response causing insulitis and diabetes
Context-dependent functions of mitochondria protein quality control in lung
Authors: Xu Le , Tan Chunting , Barr Justinn , Talaba Nicole , Verheyden Jamie , Chin Ji Sun , Gaboyan Samvel , Advani Ira , Elgamal Ruth M , Gaulton Kyle J , Lin Grace , Afshar Kamyar , Golts Eugene , Meier Angela , Alexander Laura E Crotty , Borok Zea , Shen Yufeng , Chung Wendy K , McCulley David J , Sun Xin
Published: December 2022

Aside from its role as the universal energy source of the cell, mitochondria also control many aspects of cell behavior. In an intact tissue, whether all cells require mitochondria function to the same extent, and how mitochondria insufficiency impacts cell behavior are poorly understood. Here we show that in the mouse lung epithelium, inactivation of LONP1, an energy ATP-dependent protease that functions in the mitochondria to degrade unfolded and misfolded proteins, led to mitochondria deficiency. In the naïve epithelium of the developing lung, loss ofLonp1obliterated cell proliferation and differentiation. In the adult airway epithelium during homeostasis, loss ofLonp1led to selective death of terminally differentiated multiciliated cells, leading to a cascade of progenitor activation to replace lost cells. In the adult airway epithelium following influenza infection, loss ofLonp1led to failure of airway progenitor migration into the damaged alveolar region. Bulk and single cell transcriptomic analysis revealed that one branch of the ER stress pathways, namely integrated stress response (ISR), is ectopically upregulated in mutants under all three conditions. Inactivation of core ISR transcription factor ATF4 in theLonp1mutant airway reversed abovementioned phenotypes. Taken together, our findings demonstrate that depending on a cellular context, intact mitochondria function is required in either progenitor or progeny cells, and is essential for cell proliferation, survival or migration in the mammalian lung.
wastewaterSPAdes: SARS-CoV-2 strain deconvolution using SPAdes toolkit
Authors: Korobeynikov Anton
Published: December 2022

Motivation

SARS-CoV-2 wastewater samples are extensively collected and studied because it allows quantitatively assess a viral load in surrounding populations. Additionally, SARS-CoV-2 strain deconvolution gives more insights into pandemic dynamics, and the uprising of new strains. Usually, the solution to the strain deconvolution problem starts with read alignment of wastewater short read sequencing data to the SARS-CoV-2 reference genome. After variants are called and their abundances are estimated, a reference database is used to assign variants to strains, select a subset of strains, and infer relative abundance of these strains based on some mathematical model. Assembly-based methods have its own strengths, but currently reside in the shadow of alignment-based methods.

Results

In this paper we propose a new assembly-based approach based on SPAdes toolkit codebase ––– wastewaterSPAdes, that is able to deconvolve wastewater without a need of read alignment. Our results show that watewaterSPAdes is able to accurately identify strains presented in a sample, and correctly estimate abundances for most of the samples.

Availability

https://cab.spbu.ru/software/wastewaterspades/

Contact

a.korobeynikov@spbu.ru

Supplementary information

Supplementary data are available atBioinformatics
Get a new perspective on EEG: Convolutional neural network encoders for parametric t-SNE
Authors: Svantesson Mats , Olausson Håkan , Eklund Anders , Thordstein Magnus
Published: December 2022

Background

t-distributed stochastic neighbor embedding (t-SNE) is a method for reducing high-dimensional data to a low-dimensional representation and is mostly used for visualizing data. In parametric t-SNE, a neural network learns to reproduce this mapping. When used for EEG analysis, the data is usually first transformed into a set of features, but it is not known which features are optimal.

New method

The principle of t-SNE was used to train convolutional neural network (CNN) encoders to learn to produce both a high- and a low-dimensional representation, eliminating the need for feature engineering. A simple neighbor distribution based on ranked distances was used for the high-dimensional representation instead of the traditional normal distribution. To evaluate the method, the Temple University EEG Corpus was used to create three datasets with distinct EEG characters: 1) wakefulness and sleep, 2) interictal epileptiform discharges, and 3) seizure activity.

Results

The CNN encoders for the three datasets produced low-dimensional representations of the datasets with a global and local structure that conformed well to the EEG characters and generalized to new data.

Comparison to existing methods

Compared to parametric t-SNE for either a short-time Fourier transforms or wavelet representation of the datasets, the developed CNN encoders performed equally well but generally produced a higher degree of clustering.

Conclusions

The developed principle is promising and could be further developed to create general tools for exploring relations in EEG data, e.g., visual summaries of recordings, and trends for continuous EEG monitoring. It might also be used to generate features for other types of machine learning.
In vitroactivity andin vivoefficacy against non-tuberculous mycobacteria of SPR719, the active moiety of the novel oral benzimidazole prodrug SPR720
Authors: Cotroneo Nicole , Stokes Suzanne S. , Pucci Michael J. , Rubio Aileen , Hamed Kamal , Critchley Ian A.
Published: December 2022

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is increasing globally, withMycobacterium aviumcomplex (MAC) accounting for 80% of cases andMycobacterium abscessusamong the next most prevalent pathogens. Current treatment necessitates long-term administration of poorly tolerated and modestly effective antibiotic combinations, highlighting the need for new oral agents. SPR719, the active moiety of the benzimidazole phosphate prodrug SPR720, inhibits the ATPase subunits of DNA gyrase B, a target with no human homolog and not exploited by current antibiotics. We demonstrated SPR719 activity against MAC (MIC90, 2 µg/mL) andM. abscessusclinical isolates (MIC90, 4 µg/mL), including those resistant to current standard-of-care (SOC) agents.In vivoefficacy of SPR720 was demonstrated againstM. aviumATCC 700898 in a chronic C3HeB/FeJ murine model of pulmonary infection, both as a monotherapy and in combination with clarithromycin, ethambutol and rifabutin. SPR720 monotherapy exhibited a dose-dependent reduction in bacterial burden, with the largest reduction observed when combined with clarithromycin and ethambutol. Efficacy of SPR720 was also demonstrated againstM. abscessussubspeciesabscessus1513, a virulent multidrug-resistant strain in a prolonged acute model of pulmonary infection in mice. SPR720 monotherapy exhibited a dose-dependent reduction in bacterial burden with further reductions when combined with SOC agents, clarithromycin and amikacin ± clofazimine. Taken together, thein vitroactivity of SPR720 against common NTM pathogens in concert with the proof-of-concept efficacy in murine infection models warrants the continued clinical evaluation of SPR720 as a new oral option for the treatment of NTM-PD.
Exploring cognitive, behavioural and autism trait network topology in very preterm and term-born children
Authors: Leoni Marguerite , Vanes Lucy D. , Hadaya Laila , Kanel Dana , Dazzan Paola , Simonoff Emily , Counsell Serena , Happé Francesca , Edwards A. David , Nosarti Chiara
Published: December 2022

Compared to full-term (FT) born peers, children who were born very preterm (VPT; <32 weeks’ gestation) are likely to display more cognitive and behavioural difficulties, including inattention, anxiety and socio-communication problems. In the published literature, such difficulties tend to be studied independently, thus failing to account for how different aspects of child development interact. The current study aimed to investigate children’s cognitive and behavioural outcomes as interconnected, dynamically related facets of development that influence one another. Participants were 93 VPT and 55 FT children (median age 8.79 years). IQ was evaluated with the Wechsler Intelligence Scale for Children – 4thedition (WISC-IV), autism spectrum condition (ASC) traits with the Social Responsiveness Scale – 2ndedition (SRS-2), behavioural and emotional problems with the Strengths and Difficulties Questionnaire (SDQ), temperament with the Temperament in Middle Childhood Questionnaire (TMCQ) and executive function with the Behaviour Rating Inventory of Executive Functioning (BRIEF-2). Outcome measures were studied in VPT and FT children using Network Analysis, a method that graphically represents partial correlations between variables and yields information on each variable’s propensity to form abridgebetween other variables. Results showed that VPT and FT children exhibited marked topological differences.Bridges(i.e., the variables most connected to others) in the VPT group network were: SDQ Conduct Problems scale and BRIEF-2 Organisation of Materials scale. In the FT group network, the most importantbridgeswere: the BRIEF-2 Initiate, SDQ Emotional Problems and SDQ Prosocial Behaviours scales. These findings highlight the importance of targeting different aspects of development to support VPT and FT children in person-based interventions.
Lipid Biosynthesis Perturbation Impairs Endoplasmic Reticulum-Associated Degradation
Authors: Turk Samantha M. , Indovina Christopher J. , Overton Danielle L. , Runnebohm Avery M. , Orchard Cade J. , Doss Ellen M. , Richards Kyle A. , Irelan Courtney Broshar , Daraghmi Mahmoud M. , Bailey Connor G. , Miller Jacob M. , Niekamp Julia M. , Gosser Samantha K. , Tragesser-Tiña Mary E. , Claypool Kieran P. , Engle Sarah M. , Buchanan Bryce W. , Woodruff Kelsey A. , Olesen James B. , Smaldino Philip J. , Rubenstein Eric M.
Published: December 2022

The relationship between lipid homeostasis and protein homeostasis (proteostasis) is complex and remains incompletely understood. We conducted a screen for genes required for efficient degradation ofDeg1-Sec62, a model aberrant translocon-associated substrate of the endoplasmic reticulum (ER) ubiquitin ligase Hrd1, inSaccharomyces cerevisiae. This screen revealed thatINO4is required for efficientDeg1-Sec62 degradation.INO4encodes one subunit of the Ino2/Ino4 heterodimeric transcription factor, which regulates expression of genes required for lipid biosynthesis.Deg1-Sec62 degradation was also impaired by mutation of genes encoding several enzymes mediating phospholipid and sterol biosynthesis. The degradation defect inino4Δ yeast was rescued by supplementation with metabolites whose synthesis and uptake are mediated by Ino2/Ino4 targets. Stabilization of a panel of substrates of the Hrd1 and Doa10 ER ubiquitin ligases byINO4deletion indicates ER protein quality control is generally sensitive to perturbed lipid homeostasis. Further, loss ofINO4sensitized yeast to proteotoxic stress, suggesting a broad requirement for lipid homeostasis in maintaining proteostasis. Abundance of the ER ubiquitin-conjugating enzyme Ubc7 was reduced in the absence ofINO4, consistent with a model whereby perturbed lipid biosynthesis alters the abundance of critical protein quality control mediators, with broad consequences for ER proteostasis. A better understanding of the dynamic relationship between lipid homeostasis and proteostasis may lead to improved understanding and treatment of several human diseases associated with altered lipid biosynthesis.
Inhibitory stabilized network behaviour in a balanced neural mass model of a cortical column
Authors: Eskikand Parvin Zarei , Soto-Breceda Artemio , Cook Mark J. , Burkitt Anthony N. , Grayden David B.
Published: December 2022

Strong inhibitory recurrent connections can reduce the tendency for a neural network to become unstable. This is known as inhibitory stabilization; networks that are unstable in the absence of strong inhibitory feedback because of their unstable excitatory recurrent connections are known as Inhibition Stabilized Networks (ISNs). One of the characteristics of ISNs is their “paradoxical response”, where perturbing the inhibitory neurons with additional excitatory input results in a decrease in their activity after a temporal delay instead of increasing their activity. Here, we develop a model of populations of neurons across different layers of cortex. Within each layer, there is one population of inhibitory neurons and one population of excitatory neurons. The connectivity weights across different populations in the model are derived from a synaptic physiology database provided by the Allen Institute. The model shows a gradient of excitation-inhibition balance across different layers in the cortex, where superficial layers are more inhibitory dominated compared to deeper layers. To investigate the presence of ISNs across different layers, we measured the membrane potentials of neural populations in the model after perturbing inhibitory populations. The results show that layer 2/3 in the model does not operate in the ISN regime but layers 4 and 5 do operate in the ISN regime. These results accord with neurophysiological findings that explored the presence of ISNs across different layers in the cortex. The results show that there may be a systematic macroscopic gradient of inhibitory stabilization across different layers in the cortex that depends on the level of excitation-inhibition balance, and that the strength of the paradoxical response increases as the model moves closer to bifurcation points.

Author summary

Strong feedback inhibition prevents neural networks from becoming unstable. Inhibition Stabilized Networks (ISNs) have strong inhibitory connections combined with high levels of unstable excitatory recurrent connections. In the absence of strong inhibitory feedback, ISNs become unstable. ISNs demonstrate a paradoxical effect: perturbing inhibitory neurons in an ISN by increasing their excitatory input results in a decrease in their activity after a temporal delay instead of increasing their activity. Here, we developed a neural mass model of a cortical column based on neurophysiological data. The model shows a gradual change in inhibitory stabilization across different layers in the cortex where layer 2/3 is less inhibitory stabilized and shows no paradoxical effect in contrast to layer 4 and layer 5, which operate in the ISN regime and show paradoxical responses to perturbation.
The ribosome-associated chaperone Zuo1 controls translation upon TORC1 inhibition
Authors: Black Ailsa , Williams Thomas D , Zhou Houjiang , Rousseau Adrien
Published: December 2022

Eukaryotic cells achieve proteostasis by ensuring their protein requirements are met through tight control of TORC1 activity. Upon TORC1 inhibition, degradative activity is increased, and protein synthesis is reduced through inhibition of translation initiation, to maintain cell viability. Here, we show that the ribosome-associated complex (RAC)/Ssb chaperone system is required to maintain proteostasis and cell viability under TORC1 inhibition, in yeast. In the absence of the Hsp40 cochaperone Zuo1, translation does not decrease in response to loss of TORC1 activity. The functional interaction between Zuo1 and its Hsp70 partner, Ssb, is required for proper translational control and proteostasis maintenance upon TORC1 inhibition. Further, we have found that the rapid degradation of eIF4G following TORC1 inhibition is prevented inzuo1Δcells, contributing to decreased survival in these conditions. Our findings suggest a new role for RAC/Ssb in regulating translation in response to changes in TORC1 signalling.
Parental effects in a filamentous fungus: phenotype, fitness, and mechanism
Authors: Villalba de la Peña Mariana , Summanen Pauliina A. M. , Moghadam Neda N. , Kronholm Ilkka
Published: December 2022

Adaptation to changing environments often requires meaningful phenotypic modifications to match the current conditions. However, obtaining information about the surroundings during an organism’s own lifetime may only permit accommodating relatively late developmental modifications. Therefore, it may be advantageous to rely on inter-generational or trans-generational cues that provide information about the environment as early as possible to allow development along an optimal trajectory. Transfer of information or resources across generations, known as parental effects, is well documented in animals and plants but not in other eukaryotes, such as fungi. Understanding parental effects and their evolutionary consequences in fungi is of vital importance as they perform crucial ecosystem functions. In this study, we investigated whether parental effects are present in the filamentous fungusNeurospora crassa, how long do they last, are the effects adaptive, and what is their mechanism. We performed a fully factorial match / mismatch experiment for a good and poor quality environment, in which we measured mycelium size of strains that experienced either a matched or mismatched environment in their previous generation. We found a strong silver spoon effect in initial mycelium growth, which lasted for one generation, and increased fitness during competition experiments. By using deletion mutants that lacked key genes in epigenetic processes, we show that epigenetic mechanisms are not involved in this effect. Instead, we show that spore glycogen content, glucose availability and a radical transcription shift in spores are the main mechanisms behind this parental effect.
Targeted and untargeted nanopore sequencing approaches to profile the gut microbiota of mice infants exposed to ethanolin utero
Authors: Pedroso-Roussado Cristiano , Guppy Fergus , Brissett Nigel , Bowler Lucas , Inacio Joao
Published: December 2022

The gut microbiome plays a vital role in host homeostasis and understanding of its biology is essential for a better comprehension of the etiology of disorders such as foetal alcohol spectrum disorders. Here we assessed the effectiveness of targeted and untargeted (metagenomic) nanopore sequencing approaches to profile the gut microbiota of infant mice exposed to ethanolin utero. DNA extracts from the gut content of 12 infant mice exposed to ethanol in utero were analysed using one untargeted and two targeted (full-length 16S rRNA gene and the 16S-ITS-23S region of the ribosomal RNA operon) nanopore sequencing approaches. The targeting of the full-length 16S rRNA gene provided the most comprehensive analysis of the mouse gut microbiota. The differences in diversity between approaches were accounted by the sequencing target (p-value < 0.001). Faecalibaculum rodentium and Duncaniella sp. were the two most prevalent taxa detected using targeted sequencing approaches, while bacterial taxa were more evenly represented when using the metagenomic approach. Full-length 16S rRNA gene nanopore sequencing provides the most discriminatory microbiota compositional analysis of mice faecal samples. However, using nanopore sequencing approaches targeting the metagenome or different taxonomically-informative DNA region appears to introduce significant target-related biases.

Importance

Current nanopore approaches have not been standardized which may confound the biological interpretations of hight-throughput sequencing datasets. Additionally, nanopore sequencing still present a high error-rate compared to other more mature sequencing technologies, such as Illumina sequencing. These technological handicaps create the need to study and optimize nanopore sequencing approaches to answer biological questions, such as interrogations of the microbial composition and abundance of clinical and environmental samples. In this work, three nanopore sequencing approaches were designed and attempted to optimize fungal and bacterial profiling sequencing methodologies. Two targeted methods based on the bacterial 16S rRNA gene, and 16S-ITS-23Srrnoperon region, and one untargeted shotgun/metagenomic approach were tested. Despite potential experimental and/or bioinformatical biases were found, the 16S rRNA gene-targeted nanopore sequencing was the most comprehensive approach to study the microbial composition of the infant mice gut microbiotas.
Paenibacillus xylinteritussp. nov., a novel bacterial species isolated from grapevine wood
Authors: Haidar Rana , Antonielli Livio , Compant Stéphane , Sauer Ursula , Pandin Caroline , Gassie Claire , Yacoub Amira , Chrysovergi Maria , Attard Eléonore , Rey Patrice , Guyoneaud Rémy
Published: December 2022

Bacteria naturally colonize grapevine wood, and some populations interact synergistically with fungal pathogens to promote wood degradation. In this study, we characterized a bacterial strain, designated S150T, isolated from the wood of grapevine cultivar Sauvignon Blanc. The strain was previously known as promoting wood degradation caused by the causal agent of white-rot,Fomitiporia mediterranea. Phylogenetic analysis based on the full-length 16S rRNA gene sequence showed that the strain S150Tbelonged to the genusPaenibacillus. Based on 16S rRNA gene sequences, S150Tshared low sequence similarity values (between 96.5 and 97.5%) with closed recognized members of the genus (P. jilunliiBe17,P. tepidiphilusSYSU G01001,P. tengchongensisSYSU-G-01003,P. sonchiX19-5,P. helianthiP26E). The cell wall peptidoglycan of S150 contains meso-diaminopimelate. MK6 and MK7 are the two respiratory quinones. The main cellular fatty acids are iso-C16:0and anteiso-C15:0. The polar lipids are diphosphatidylglycerol, phosphatidylethanolamine, three amino phospholipids, two phospholipids and three polar lipids. The whole-genome is 7.45 Mb, with a G+C content of 52.54%. The average nucleotide identity (ANI) value between S150Tand the closely relatedPaenibacillusmember (P. sonchiX19-5) was 85.06%. Biochemical and physiological analyses revealed that strain S150Thas different characteristics from reference strainsPaenibacillusspp.. Phenotypic, phylogenetic and chemotaxonomic analyses show strain S150Tis a novel species of the genusPaenibacillus, for which the namePaenibacillus xylinteritusis proposed.
Mre11 liberates cGAS from nucleosome sequestration during tumorigenesis
Authors: Cho Min-Guk , Kumar Rashmi J. , Lin Chien-Chu , Boyer Joshua A. , Shahir Jamshaid A. , Fagan-Solis Katerina , Simpson Dennis A. , Fan Cheng , Foster Christine E. , Goddard Anna M. , Wang Qinhong , Wang Ying , Ho Alice Y. , Liu Pengda , Perou Charles M. , Zhang Qi , McGinty Robert K. , Purvis Jeremy E. , Gupta Gaorav P.
Published: December 2022

Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS/STING-mediated innate immune signaling and tumor suppression1-3. However, the mechanism for cGAS activation by endogenous DNA damage remains enigmatic, particularly given the constitutive inhibition of cGAS by high-affinity histone acidic patch (AP) binding4-10. Here we report anin vivoCRISPR screen that identified the DNA double strand break sensor Mre11 as a suppressor of mammary tumorigenesis induced by Myc overexpression and p53 deficiency. Mre11 antagonizes Myc-induced proliferation through cGAS/STING activation. Direct binding of the Mre11-Rad50-Nbn (MRN) complex to nucleosomes displaces cGAS from AP sequestration, which is required for DNA damage-induced cGAS mobilization and activation by cytosolic DNA. Mre11 is thereby essential for cGAS activation in response to oncogenic stress, cytosolic DNA transfection, and ionizing radiation. Furthermore, we show Mre11-dependent cGAS activation suppresses Myc-induced proliferation through ZBP1/RIPK3/MLKL-mediated necroptosis. In human triple-negative breast cancer, ZBP1 downregulation correlates with increased genome instability, decreased immune infiltration, and poor patient prognosis. These findings establish Mre11 as a critical link between DNA damage and cGAS activation that regulates tumorigenesis through ZBP1-dependent necroptosis.

One-sentence summary

Mre11 is required for cGAS activation during oncogenic stress and promotes ZBP1-dependent necroptosis.
Tryptophan-like side chain holding aptamers inhibit respiratory syncytial virus infection of lung epithelial cells
Authors: Percze Krisztina , Tolnai Zoltán János , Eleveld Marc , Ou Li , Du Haijuan , Olia Adam S. , Kwong Peter D. , de Jonge Marien I. , Mészáros Tamás
Published: December 2022

Respiratory syncytial virus (RSV) is a leading cause of serious and even fatal acute lower respiratory tract infections in infants and in the elderly. Potent RSV neutralization has been achieved by antibodies that selectively bind the prefusion form of the viral fusion (F) protein. We hypothesised that similar potent neutralization could be achieved using F protein targeting aptamers. Aptamers have yet to reach their translational potential for therapeutics or diagnostics due to their short half-life and limited range of target-aptamer interactions; these shortcomings can, however, be ameliorated by application of amino acid-like side chain holding nucleotides. In this study, a stabilized version of the prefusion RSV F protein was targeted by aptamer selection using an oligonucleotide library holding a tryptophan-like side chain. This process resulted in aptamers that bound the F protein with high affinity and differentiated between pre- and postfusion conformation. Identified aptamers inhibited viral infection of lung epithelial cells. Moreover, introduction of modified nucleotides extended aptamer half-lives. Our results suggest that targeting aptamers to the surface of viruses could yield effective drug candidates, which could keep up with the pace of the continuously evolving pathogens.
p38γ and p38δ modulate innate immune response by regulating MEF2D activation
Authors: Escós Alejandra , Díaz-Mora Ester , Pattison Michael , Fajardo Pilar , González-Romero Diego , Risco Ana , Martín-Gómez José , Bonneil Éric , Sonenberg Nahum , Jafarnejad Seyed Mehdi , Sanz-Ezquerro Juan José , Ley Steven C. , Cuenda Ana
Published: December 2022

Evidence implicating p38γ and p38δ (p38γ/p38δ) in inflammation are mainly based on experiments using p38γ/p38δ deficient (p38γ/δ-/-) mice, which show low levels of TPL2, the kinase upstream of MKK1-ERK1/2 in myeloid cells. This could obscure p38γ/p38δ roles, since TPL2 is essential for regulating inflammation. Here we generated a p38γD171A/D171A/p38δ-/-(p38γ/δKIKO) mouse, expressing kinase-inactive p38γ and lacking p38δ. This mouse exhibited normal TPL2 levels, making it an excellent tool to elucidate specific p38γ/p38δ functions. p38γ/δKIKO mice showed a reduced inflammatory response and less susceptibility to LPS-induced septic shock andCandida albicansinfection than wild-type mice. Gene expression analyses in LPS-activated WT and p38γ/δKIKO macrophages revealed that p38γ/p38δ regulated numerous genes implicated in innate immune response. Additionally, phospho-proteomic analyses andin vitrokinase assays showed that the transcription factor myocyte enhancer factor-2D (MEF2D) was phosphorylated at Ser444 via p38γ/p38δ. Mutation of MEF2D Ser444 to the non-phosphorylatable residue Ala increased its transcriptional activity and the expression ofiNOSandIL-1βmRNA. These results suggest that p38γ/p38δ govern innate immune responses by regulating MEF2D phosphorylation and transcriptional activity.
Antimicrobial susceptibility testing for diverseMalasseziaspecies
Authors: Rathie Brooke , Theelen Bart , Laurence Martin , Shapiro Rebecca S.
Published: December 2022

The genusMalasseziais an opportunistic lipid-dependent yeast that is associated with common skin diseases and has recently been associated with Crohn’s disease and certain cancers. Understanding the susceptibility ofMalasseziato diverse antimicrobial agents is crucial for identifying effective antifungal therapies. Here, we tested the efficacy of isavuconazole, itraconazole, terbinafine and artemisinin against threeMalasseziaspecies:M. restricta, M. slooffiae, andM. sympodialis, using microbroth dilution techniques. We found antifungal properties for the two previously-unstudied antimicrobials: isavuconazole and artemisinin. Overall allMalasseziaspecies were particularly susceptible to itraconazole, with a MIC range from 0.0015 to 0.1562 μM.

Importance

TheMalasseziagenus is known to be a cause of skin conditions and has recently been associated with diseases such as Crohn’s disease, pancreatic ductal carcinoma and breast cancer. This work was completed to assess the susceptibility to a variety of antimicrobial drugs on diverseMalasseziaspecies, in particularMalassezia restricta.
Frequent first-trimester pregnancy loss in rhesus macaques infected with African-lineage Zika virus
Authors: Rosinski Jenna R. , Raasch Lauren E. , Tiburcio Patrick Barros , Breitbach Meghan E. , Shepherd Phoenix M. , Yamamoto Keisuke , Razo Elaina , Krabbe Nicholas P. , Bliss Mason I. , Richardson Alexander D. , Einwalter Morgan A. , Weiler Andrea M. , Sneed Emily L. , Fuchs Kerri B. , Zeng Xiankun , Noguchi Kevin K. , Morgan Terry K. , Alberts Alexandra J. , Antony Kathleen M. , Kabakov Sabrina , Ausderau Karla K. , Bohm Ellie K. , Pritchard Julia C. , Spanton Rachel V. , Ver Hoove James N. , Kim Charlene B. Y. , Nork T. Michael , Katz Alex W. , Rasmussen Carol A. , Hartman Amy , Mejia Andres , Basu Puja , Simmons Heather A. , Eickhoff Jens C. , Friedrich Thomas C. , Aliota Matthew T. , Mohr Emma L. , Dudley Dawn M. , O’Connor David H. , Newman Christina M.
Published: December 2022

In the 2016 Zika virus (ZIKV) pandemic, a previously unrecognized risk of birth defects surfaced in babies whose mothers were infected with Asian-lineage ZIKV during pregnancy. Less is known about the impacts of gestational African-lineage ZIKV infections. Given high human immunodeficiency virus (HIV) burdens in regions where African-lineage ZIKV circulates, we evaluated whether pregnant rhesus macaques infected with simian immunodeficiency virus (SIV) have a higher risk of African-lineage ZIKV-associated birth defects. Remarkably, in both SIV+ and SIV-animals, ZIKV infection early in the first trimester caused a high incidence (78%) of spontaneous pregnancy loss within 20 days. These findings suggest a significant risk for early pregnancy loss associated with African-lineage ZIKV infection and provide the first consistent ZIKV-associated phenotype in macaques for testing medical countermeasures.
Core PCP mutations affect short time mechanical properties but not tissue morphogenesis in theDrosophilapupal wing
Authors: Piscitello-Gómez Romina , Gruber Franz S , Krishna Abhijeet , Duclut Charlie , Modes Carl D , Popović Marko , Jülicher Frank , Dye Natalie A , Eaton Suzanne
Published: December 2022

How morphogenetic movements are robustly coordinated in space and time is a fundamental open question in biology. We study this question using the wing ofDrosophila melanogaster, an epithelial tissue that undergoes large-scale tissue flows during pupal stages. We showed previously (Etournay et al., 2015) that pupal wing morphogenesis involves both cellular behaviors that allow relaxation of mechanical tissue stress, as well as cellular behaviors that appear to be actively patterned. The core planar cell polarity (PCP) pathway influences morphogenetic cell movements in many other contexts, which suggests that it could globally pattern active cellular behaviors during pupal wing morphogenesis. We show here, however, that this is not the case: there is no significant phenotype on the cellular dynamics underlying pupal morphogenesis in mutants of core PCP. Furthermore, using laser ablation experiments, coupled with a rheological model to describe the dynamics of the response to laser ablation, we conclude that while core PCP mutations affect the fast timescale response to laser ablation, they do not affect overall tissue mechanics. In conclusion, our work shows that cellular dynamics and tissue shape changes duringDrosophilapupal wing morphogenesis are independent of one potential chemical guiding cue, core PCP.
Primary Cilia are WNT Transducing Organelles whose Biogenesis is Regulated by a WNT┫ PP1 axis
Authors: Zhang Kaiqing , Da Silva Fabio , Seidl Carina , Wilsch-Bräuninger Michaela , Herbst Jessica , Huttner Wieland B. , Niehrs Christof
Published: December 2022

WNT signalling is of paramount importance in development, stem cell maintenance, and disease. WNT ligands typically signal via receptor activation at the plasma membrane to induce β-catenin-dependent gene activation. Here we show that in primary cilia, WNT receptors relay a WNT/GSK3 signal that β-catenin-independently promotes ciliogenesis. Innovations supporting this conclusion are monitoring acute WNT co-receptor activation (phospho-LRP6) and identifying and mutating the LRP6 ciliary targeting sequence. Ciliary WNT signalling inhibits protein phosphatase 1 (PP1) activity, a negative regulator of ciliogenesis, by decommissioning GSK3-mediated phosphorylation of the PP1 regulatory inhibitor subunit PPP1R2. Accordingly, deficiency of WNT/GSK3 signalling by depletion of cyclin Y and cyclin-Y-like protein 1 induces widespread primary cilia defects in mouse embryonic neuronal precursors, kidney proximal tubules, and adult mice preadipocytes. We conclude that primary cilia are WNT ┫ PP1 signalling organelles.

Graphical Abstract

A Localized WNT ┫ PP1 Signalling Axis Promotes CiliogenesisThe WNT co-receptor LRP6 localizes to the ciliary membrane, where it is phospho-primed via a CCNY/L1-dependent CDK (not shown). WNT signalling inhibits GSK3 (not shown) and leads to inhibition of Protein phosphatase 1, a negative regulator of ciliogenesis. Right, CCNY/L1 deficiency disrupts the WNT ┫ PP1 signalling axis, leading to ciliary defects.
Exploring consumers' motives for electric vehicle adoption: bridging the attitude–behavior gap
Authors: Chaturvedi Pallavi , Kulshreshtha Kushagra , Tripathi Vikas , Agnihotri Durgesh
Published: December 2022

Purpose

The current study aims to investigate the various consumption motives (hedonic, gain and normative) responsible for strengthening consumers' intentions toward purchase behavior for electric vehicle (EV).

Design/methodology/approach

A total of 411 valid survey responses were collected using a structured questionnaire. Data were analyzed using confirmatory factor analysis and structural equation modeling to investigate the empirical fit of the hypothesized framework.

Findings

The results of structural equation modeling revealed that all three motives were positively correlated with purchase intentions for EV. Hedonic motives were found to have the strongest influence on purchase intentions. In addition, gain and normative motives were also found to be significant predictors of EV buying behavior. Further analysis revealed a positive correlation between gain, normative and hedonic motives. Moreover, personal moral standards seem to have a significant and positive impact on the positive emotions associated with buying EV.

Practical implications

The results of current research can be useful for marketers while designing promotional strategies for all the high-involvement green products. Marketing professionals and policymakers can use these results to build effective marketing strategies for EVs and reduce greenhouse gas emissions resulting from personal vehicle use.

Originality/value

To the best of the authors' knowledge, this is the first study in the South Asian region that explores consumers' motives for EV purchase behavior. Further, this is among a few studies, which have attempted to investigate the impact of hedonic, gain and normative motives on green purchase behavior in the context of high involvement green products.
Pay transparency, job turnover intentions and the mediating role of perceived organizational support and organizational justice
Authors: Stofberg Rosanna , Bussin Mark , Mabaso Calvin M.
Published: December 2022

Purpose

Despite widespread media attention and growing interest from researchers, pay transparency remains an under-studied field of research and its impact on organizational outcomes like job turnover is not well understood. This study explores the impact of pay transparency on job turnover intentions through the mediating effect of perceived organizational support (POS) and organizational justice.

Design/methodology/approach

Data from quantitative surveys conducted with 299 employees at four South African organizations with different pay transparency practices were used to test the conceptual model of pay transparency impacting job turnover intentions through the mediators of POS and organizational justice.

Findings

The authors found a weak negative relationship between pay transparency and job turnover intentions and the role of the mediating variables was confirmed. Unexpectedly, the role of the organization emerged as a key variable. Controlling for organization type showed that the direct effect of pay transparency on turnover intentions became insignificant, indicating a stronger effect from organizational factors, of which pay transparency practices are just one.

Originality/value

Identifying a contextual (organizational) dimension to pay transparency practices extends the understanding of this concept and has implications for practice. The study also makes a methodological contribution by demonstrating the value of linking respondent data to a particular organization when researching pay transparency.
Local heat flux estimation inside tubes through conjugate gradient method with adjoint operator: application to the pulsating heat pipes case
Authors: Colaço Marcelo , Bozzoli Fabio , Cattani Luca , Pagliarini Luca
Published: December 2022

Purpose

The purpose of this paper is to apply the conjugate gradient (CG) method, together with the adjoint operator (AO) to the pulsating heat pipe problem, including some quite interesting experimental results. The CG method, together with the AO, was able to estimate the unknown functions more efficiently than the other techniques presented in this paper. The estimation of local heat transfer coefficients, rather than the global ones, in pulsating heat pipes is a relatively new subject and presenting a robust, efficient and self-regularized inverse tool to estimate it, supported also by some experimental results, is the main purpose of this paper. To also increase the visibility and the general use of the paper to the heat transfer community, the authors include, as supplemental material, all numerical and experimental data used in this paper.

Design/methodology/approach

The approach was established on the solution of the inverse heat conduction problem in the wall by using as starting data the temperature measurements on the outer surface. The procedure is based on the CG method with AO. The here proposed approach was first verified adopting synthetic data and then it was validated with real cases regarding pulsating heat pipes.

Findings

An original fast methodology to estimate local convective heat flux is proposed. The procedure has been validated both numerically and experimentally. The procedure has been compared to other classical methods presenting some peculiar benefits.

Practical implications

The approach is suitable for pulsating heat pipes performance evaluation because these devices present a local heat flux distribution characterized by an important variation both in time and in space as a result of the complex flow patterns that are generated in this type of devices.

Originality/value

The procedure here proposed shows these benefits: it affords a general model of the heat conduction problem that is effortlessly customized for the particular case, it can be applied also to large datasets and it presents reduced computational expense.
Exploring mobile banking adoption and service quality features through user-generated content: the application of a topic modeling approach to Google Play Store reviews
Authors: Çallı Levent
Published: December 2022

Purpose

The primary purpose of this research is to analyze the online user reviews, where real customer experiences can be observed, with text mining and machine learning approaches, which are seen as a gap in the related literature. This study aims to compare the latent themes uncovered by the topic modeling approach with studies focused on both mobile banking (m-banking) adaptation and service quality features, suggest new aspects and examine the effect of latent topics on customer satisfaction.

Design/methodology/approach

This study analyzed 21,526 reviews posted by customers of private and state banks operating in Türkiye. An unsupervised machine learning method, Latent Dirichlet algorithm (LDA), was conducted to reveal topics, and the distribution of all reviews was visualized with the t-SNE algorithm. Random Forest, logistic regression, k-nearest neighbors (kNN) and Naive Bayes algorithms were utilized to predict user satisfaction through the given score.

Findings

In total, 11 topics were revealed by considering user reviews based on their experience. Among these topics, perceived usefulness and convenience and time-saving are much more important in the scoring given to m-banking apps. Furthermore, in more detail, seven topics have been identified related to technical and security problems related to m-banking apps.

Originality/value

This paper is a pioneer study regarding the method used and sample size reached in the m-banking literature. The findings also provide fresh insight into the post-Covid-19 era, both academically and practically, by providing new features for mobile bank adoption.
Competition or collaboration for human–robot relationship: a critical reflection on future cobotics in hospitality
Authors: Khoa Do The , Gip Huy Quoc , Guchait Priyanko , Wang Chen-Ya
Published: December 2022

Purpose

The hospitality industry has recently witnessed explosive growth in robotization with the replacement of robots in many areas. Yet, a key consideration in this robotics wave is whether competition (i.e. robots take over all human tasks) or collaboration (i.e. humans collaborate closely with robots to perform work better) will define the future of the hospitality workspace. The purpose of this paper is to shed light on this controversial issue by taking a collaborative perspective to address the future human–robot relationship in hospitality workplace (i.e. cobotic team).

Design/methodology/approach

Drawing upon relevant theories and extant robotics literature, this paper will develop a critical reflection on the management of future cobotic team as a new phenomenon in hospitality industry.

Findings

The successful management of cobotics in hospitality lies in three interrelated key domains: feeling intelligence training for frontline employees, ethics governance for cobotics and trust building toward robot partners.

Practical implications

How to manage this cobotic team efficiently will be a focus for hospitality managers in the coming years. This paper offers several managerial insights for hospitality managers and practitioners regarding effectively managing the future collaboration between humans and robots within a dynamic work environment.

Originality/value

This study addresses cobotics as a critical yet unaddressed shift in the contemporary hospitality sector and proposes a framework highlighting three key domains for managing this cobotic team effectively. This framework also sets the direction to encourage more future empirical research exploring cobotic workforce in hospitality.
Public investment efficiency in WAEMU zone: do financing sources matter?
Authors: Bamba Moulaye , Somé Juste
Published: December 2022

Purpose

This paper aims to assess the efficiency of public investment in West African Economic and Monetary Union (WAEMU) countries at both the global and sectoral level over the 2005–2015 period.

Design/methodology/approach

This paper estimates efficiency scores using stochastic frontier analysis (SFA) models. Efficiency is divided into managerial efficiency (related to inputs management) and technological efficiency (related to production technology). A Tobit model is then used to investigate the determinants of public investment efficiency.

Findings

The findings suggest that, at the global level, WAEMU countries are less efficient than sub-Saharan African and Asian reference countries. However, the breakdown of global efficiency into managerial and technological reveals that WAEMU countries are more efficient than sub-Saharan African countries in terms of technological efficiency. Moreover, these findings are robust to nonparametric estimation. The assessment of financing sources indicates that external debt has a more positive and significant effect on public investment efficiency than internal debt does.

Originality/value

This paper is unique in that it disentangles managerial efficiency from the technological efficiency of public investment in WEAMU countries and highlights how financing sources of investment affect its efficiency. In terms of policy implications, the underlying message of the results is that the rules and conditions of domestic or regional debt in the WAEMU countries must be strengthened to ensure better monitoring and then better efficiency of these resources.