bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractA 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 summaryAdar 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

SUMMARYAside 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

AbstractMotivationSARS-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.ResultsIn 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.Availabilityhttps://cab.spbu.ru/software/wastewaterspades/Contacta.korobeynikov@spbu.ruSupplementary informationSupplementary 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

AbstractBackgroundt-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 methodThe 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.ResultsThe 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 methodsCompared 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.ConclusionsThe 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

ABSTRACTNontuberculous 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

AbstractCompared 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

ABSTRACTThe 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

AbstractStrong 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 summaryStrong 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

SUMMARYEukaryotic 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

AbstractAdaptation 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

AbstractThe 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.ImportanceCurrent 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

ABSTRACTBacteria 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.