bluuebunny/crossref_metadata_2025_split huggingface dataset:
Virus specificity and nucleoporin requirements for MX2 activity are affected by GTPase function and capsid-CypA interactions
Authors: Layish Bailey , Goli Ram , Flick Haley , Huang Szu-Wei , Zhang Robert Z. , Kvaratskhelia Mamuka , Kane Melissa 
Published: November 2023

AbstractHuman myxovirus resistance 2 (MX2/MXB) is an interferon-induced GTPase that inhibits human immunodeficiency virus-1 (HIV-1) infection by preventing nuclear import of the viral preintegration complex. The HIV-1 capsid (CA) is the major viral determinant for sensitivity to MX2, and complex interactions between MX2, CA, nucleoporins (Nups), cyclophilin A (CypA), and other cellular proteins influence the outcome of viral infection. To explore the interactions between MX2, the viral CA, and CypA, we utilized a CRISPR-Cas9/AAV approach to generate CypA knock-out cell lines as well as cells that express CypA from its endogenous locus, but with specific point mutations that would abrogate CA binding but should not affect enzymatic activity or cellular function. We found that infection of CypA knock-out and point mutant cell lines with wild-type HIV-1 and CA mutants recapitulated the phenotypes observed upon cyclosporine A (CsA) addition, indicating that effects of CsA treatment are the direct result of blocking CA-CypA interactions and are therefore independent from potential interactions between CypA and MX2 or other cellular proteins. Notably, abrogation of GTP hydrolysis by MX2 conferred enhanced antiviral activity when CA-CypA interactions were abolished, and this effect was not mediated by the CA-binding residues in the GTPase domain, or by phosphorylation of MX2 at position T151. We additionally found that elimination of GTPase activity also altered the Nup requirements for MX2 activity. Our data demonstrate that the antiviral activity of MX2 is affected by CypA-CA interactions in a virus-specific and GTPase activity-dependent manner. These findings further highlight the importance of the GTPase domain of MX2 in regulation of substrate specificity and interaction with nucleocytoplasmic trafficking pathways.Author SummaryHIV-1 entry into the nucleus is an essential step in viral replication that involves complex interactions between the viral capsid and multiple cellular proteins, including the proline isomerase cyclophilin A. Nuclear entry of HIV-1 and other primate lentiviruses is inhibited by the antiviral protein MX2. Here, we show that direct interactions between capsid and cyclophilin A affect the antiviral activity and specificity of MX2, and that these interactions are altered when the enzymatic activity of MX2 is eliminated. We demonstrate that abolishing enzymatic activity of MX2 also alters the requirements for nuclear pore complex components for viral restriction. Our study provides new insights into how the enzymatic function of MX2 affects inhibition of lentiviral nuclear import.
A Computational Approach for Structural and Functional Analyses of Disease-associated Mutations in the HumanCYLDGene
Authors: Roy Arpita Singha , Feroz Tasmiah , Islam Md. Kobirul , Munim Md. Adnan , Supti Dilara Akhter , Antora Nusrat Jahan , Reza Hasan Al , Gosh Supriya , Bahadur Newaz Mohammad , Alam Mohammad Rahanur , Hossain Md Shahadat 
Published: November 2023

AbstractTumor suppressor Cylindromatosis protein (CYLD) regulates NF- κB and JNK signaling pathway by cleaving K63 linked poly-ubiquitin chain from its substrate molecules and thus preventing the progression of tumorigenesis and metastasis of the cancer cells. Mutations in CYLD can cause aberrant structure and abnormal functionality leading to tumor formation. In this study, we utilized several computational tools such as PANTHER, PROVEAN, PREDICT- SNP, POLYPHEN 2, PHD SNP, PON P2, and SIFT to find out deleterious nsSNPs. We also highlighted the damaging impact of those deleterious nsSNPs on the structure and function of the CYLD utilizing Consurf, I-Mutant, SDM, Phyre2, HOPE, Swiss PDB Viewer, and Mutation 3D. We shortlisted 18 high-risk nsSNPs from a total of 446 nsSNPs recorded in the NCBI database. Based on the conservation profile, stability status, and structural impact analysis we finalized 13nsSNPs. Molecular docking analysis and molecular dynamic simulation concluded the study with the findings of two significant nsSNPs (R830K, H827R) which have a remarkable impact on binding affinity, RMSD, RMSF, Radius of gyration, and hydrogen bond formation during CYLD-ubiquitin interaction. The principal component analysis compared native and two mutants R830K, H827R of CYLD that signifies structural and energy profile fluctuations during molecular dynamic (MD) simulation. Finally, the Protein-protein interaction network showed CYLD interacts with 20 proteins involved in several biological pathways that mutations can impair. Considering all these in silico analyses, our study recommended conducting large-scale association studies of nsSNPs of CYLD with cancer as well as designing precise medications against diseases associated with these polymorphisms.
Virtual Tissue Expression Analysis
Authors: Simeth Jakob , Hüttl Paul , Schön Marian , Nozari Zahra , Huttner Michael , Schmidt Tobias , Altenbuchinger Michael , Spang Rainer 
Published: November 2023

ABSTRACTMotivationBulk RNA expression data is widely accessible, whereas single-cell data is relatively scarce in comparison. However, single-cell data offers profound insights into the cellular composition of tissues and cell-type-specific gene regulation, both of which remain hidden in bulk expression analysis.ResultsHere, we present tissueResolver an algorithm designed to extract single-cell type information from bulk data, enabling us to attribute expression changes to individual cell types. The outcome is a virtual tissue that can be analyzed in a manner similar to single-cell RNA-seq data. When validated on simulated data tissueResolver outperforms competing methods. Additionally, our study demonstrates that tissueResolver reveals previously overlooked celltype specific regulatory distinctions between the activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subtypes of diffuse large B-cell lymphomas (DLBCL).Availability and ImplementationR package available athttps://github.com/spang-lab/tissueResolver. Code for reproducing the results of this paper is available athttps://github.com/spang-lab/tissueResolver-docs.Contactjakob.simeth@klinik.uni-regensburg.de
Molybdate delays sulphide formation in the sediment and transfer to the bulk liquid in a model shrimp pond
Authors: Torun Funda , Hostins Barbara , De Schryver Peter , Boon Nico , De Vrieze Jo 
Published: November 2023

AbstractShrimp are commonly cultured in earthen aquaculture ponds where organic-rich uneaten feed and faeces accumulate on and in the sediment to form anaerobic zones. Since the pond water is rich in sulphate, these anaerobic conditions eventually lead to the production of sulphide. Sulphides are toxic and even lethal to the shrimp that live on the pond sediment, but physicochemical and microbial reactions that occur during the accumulation of organic waste and the subsequent formation of sulphide in shrimp pond sediments remain unclear. Molybdate treatment is a promising strategy to inhibit sulphate reduction, thus, preventing sulphide accumulation. We used an experimental shrimp pond model to simulate the organic waste accumulation and sulphide formation during the final 61 days of a full shrimp growth cycle. Sodium molybdate (5 and 25 mg/L Na2MoO4.2H2O) was applied as a preventive strategy to control sulphide production before oxygen depletion. Molybdate addition partially mitigated H2S production in the sediment, and delayed its transfer to the bulk liquid by pushing the higher sulphide concentration zone towards deeper sediment layers. Molybdate treatment at 25 mg/L significantly impacted the overall microbial community composition and treated samples (5 and 25 mg/L molybdate) had about 50% higher relative abundance of sulphate reducing bacteria than the control (no molybdate) treatment. In conclusion, molybdate has the potential to work as mitigation strategy against sulphide accumulation in the sediment during shrimp growth by directly steering the microbial community in a shrimp pond system.
Scalable De Novo Classification of Antibiotic Resistance of Mycobacterium Tuberculosis
Authors: Serajian Mohammadali , Marini Simone , Alanko Jarno N. , Noyes Noelle R. , Prosperi Mattia , Boucher Christina 
Published: November 2023

AbstractWe develop a robust machine learning classifier using both linear and nonlinear models (i.e., LASSO logistic regression (LR) and random forests (RF)) to predict the phenotypic resistance ofMycobacterium tuberculosis(MTB) for a broad range of antibiotic drugs. We use data from the CRyPTIC consortium to train our classifier, which consists of whole genome sequencing and antibiotic susceptibility testing (AST) phenotypic data for 13 different antibiotics. To train our model, we assemble the sequence data into genomic contigs, identify all unique 31-mers in the set of contigs, and build a feature matrixM, whereM[i, j] is equal to the number of times thei-th 31-mer occurs in thej-th genome. Due to the size of this feature matrix (over 350 million unique 31-mers), we build and use a sparse matrix representation. Our method, which we refer to as MTB++, leverages compact data structures and iterative methods to allow for the screening of all the 31-mers in the development of both LASSO LR and RF. MTB++ is able to achieve high discrimination (F-1 greater than 80%) for the first-line antibiotics. Moreover, MTB++ had the highest F-1 score in all but three classes and was the most comprehensive since it had a F-1 score greater than 75% in all but four (rare) antibiotic drugs. We use our feature selection to contextualize the 31-mers that are used for the prediction of phenotypic resistance, leading to some insights about sequence similarity to genes in MEGARes. Lastly, we give an estimate of the amount of data that is needed in order to provide accurate predictions.
The Role of Electron Spin, Chirality, and Charge Dynamics in Promoting the Persistence of Nascent Nucleic Acid-Peptide Complexes
Authors: Vyas Pratik , Santra Kakali , Preeyanka Naupada , Gupta Anu , Weil-Ktorza Orit , Zhu Qirong , Metanis Norman , Fransson Jonas , Longo Liam M. , Naaman Ron 
Published: November 2023

AbstractPrimitive nucleic acids and peptides likely collaborated during the earliest stages of biochemistry. What forces drove their interactions, and how did these forces shape the properties of primitive complexes? We investigated the association of two model primordial polypeptides with DNA. Coupling the peptides to a ferromagnetic substrate results in a dependence of the association rate and the extent of DNA binding on the orientation of magnetic moment of the substrate. The DNA binding could be nearly abolished by inverting the orientation of the magnetic field, despite the two polymers having complementary net charges. Inverting the chirality of either the entire peptide or just the connecting cysteine residue inverted the effect of the magnetic moment orientation. These results are attributed to the chiral-induced spin selectivity (CISS) effect, in which molecular chirality and electron spin interact to alter the electric polarizability of the protein. The observation of CISS effects governing simple protein-DNA complexes, suggests that this phenomenon was plausibly operative and potentially significant for primitive biomolecules. A key consequence of the CISS effect is to increase the kinetic stability of primitive protein-nucleic acid complexes. Taken together, our results show how emergent phenomena due to chirality and spin enhance bio-association.
Viral infection disrupts intestinal homeostasis via Sting-dependent NF-kB signaling
Authors: Nigg Jared C. , Blanc Hervé , Frangeul Lionel , Mongelli Vanesa , Godron Xavier , Bardin Allison J. , Saleh Maria-Carla 
Published: November 2023

SUMMARYHost-microbe interactions influence intestinal stem cell (ISC) activity to modulate epithelial turnover and composition. Here we investigated the functional impacts of viral infection on intestinal homeostasis and the mechanisms by which viral infection alters ISC activity. We report that Drosophila A virus (DAV) infection disrupts intestinal homeostasis inDrosophilaby inducing sustained ISC proliferation, resulting in intestinal dysplasia, loss of gut barrier function, and reduced lifespan. We found that additional viruses common in laboratory-rearedDrosophilaalso promote ISC proliferation. The mechanism of DAV-induced ISC proliferation involves progenitor-autonomous EGFR signaling, JNK activity in enterocytes, and requires Sting-dependent NF-kB (Relish) activity. We further demonstrate that activating Sting-Relish signaling is sufficient to induce ISC proliferation, promote intestinal dysplasia, and reduce lifespan in the absence of infection. Our results reveal that viral infection can significantly disrupt intestinal physiology, highlight a novel role for Sting-Relish signaling, and support a role for viral infection in aging.Graphical Abstract
A comparison of EEG encoding models using audiovisual stimuli and their unimodal counterparts
Authors: Desai Maansi , Field Alyssa M. , Hamilton Liberty S. 
Published: November 2023

AbstractCommunication in the real world is inherently multimodal. When having a conversation, typically sighted and hearing people use both auditory and visual cues to understand one another. For example, objects may make sounds as they move in space, or we may use the movement of a person’s mouth to better understand what they are saying in a noisy environment. Still, many neuroscience experiments rely on unimodal stimuli (visual only or auditory only) to understand encoding of sensory features in the brain. The extent to which visual information may influence encoding of auditory information and vice versa in natural environments is thus unclear. Here, we addressed this question by recording scalp electroencephalography (EEG) in 11 subjects as they listened to and watched movie trailers in audiovisual (AV), visual (V) only, and audio (A) only conditions. We then fit linear encoding models that described the relationship between the brain responses and the acoustic, phonetic, and visual information in the stimuli. We also compared whether auditory and visual feature tuning was the same when stimuli were presented in the original AV format versus when visual or auditory information was removed. We found that auditory feature tuning was similar in the AV and A-only conditions, and similarly, tuning for visual information was similar when stimuli were presented with the audio present (AV) and when the audio was removed (V only). In a cross prediction analysis, we investigated whether models trained on AV data predicted responses to A or V only test data as well as using the unimodal conditions for training. Overall, prediction performance using AV training and V test sets was similar to using V training and V test sets, suggesting that the auditory information has a relatively smaller effect on EEG. In contrast, prediction performance using AV training and A only test set was slightly worse than using matching A only training and test sets. This suggests the visual information has a stronger influence on EEG, though this makes no qualitative difference in the derived feature tuning. In effect, our results show that researchers may benefit from the richness of multimodal datasets, which can then be used to answer more than one research question.
Water inside the selectivity filter of a K+ion channel: structural heterogeneity, picosecond dynamics, and hydrogen-bonding
Authors: Ryan Matthew J. , Gao Lujia , Valiyaveetil Francis I. , Kananenka Alexei A. , Zanni Martin T. 
Published: November 2023

ABSTRACTWater inside biological ion channels regulates the key properties of these proteins such as selectivity, ion conductance, and gating. In this Article we measure the picosecond spectral diffusion of amide I vibrations of an isotope labeled KcsA potassium channel using two-dimensional infrared (2D IR) spectroscopy. By combining waiting time (100 - 2000 fs) 2D IR measurements of the KcsA channel including13C18O isotope labeled Val76 and Gly77 residues with molecular dynamics simulations, we elucidated the site-specific dynamics of water and K+ions inside the selectivity filter of KcsA. We observe inhomogeneous 2D lineshapes with extremely slow spectral diffusion. Our simulations quantitatively reproduce the experiments and show that water is the only component with any appreciable dynamics, whereas K+ions and the protein are essentially static on a picosecond timescale. By analyzing simulated and experimental vibrational frequencies, we find that water in the selectivity filter can be oriented to form hydrogen bonds with adjacent, or non-adjacent carbonyl groups with the reorientation timescales being three times slower and comparable to that of water molecules in liquid, respectively. Water molecules can reside in the cavity sufficiently far from carbonyls and behave essentially like “free” gas-phase-like water with fast reorientation times. Remarkably, no interconversion between these configurations were observed on a picosecond timescale. These dynamics are in stark contrast with liquid water that remains highly dynamic even in the presence of ions at high concentrations.
Intermittent water stress favors microbial generalists that better help wheat under drought
Authors: Schmidt Ruth Lydia , Azarbad Hamed , Bainard Luke , Tremblay Julien , Yergeau Etienne 
Published: November 2023

AbstractMicroorganisms can improve plant resistance to drought through various mechanisms such as the production of plant hormones, osmolytes, antioxidants, and exopolysaccharides. It is, however, unclear how previous exposure to water stress affects the functional capacity of the soil microbial community to help plants resist drought. We compared two soils that had either a continuous or intermittent water stress history for almost forty years. We grew wheat in these soils and subjected it to a water stress, after which we collected the rhizosphere soil and shotgun sequenced its metagenome. Wheat growing in the soil with an intermittent water stress history maintained a higher fresh biomass when subjected to water stress. Genes related to resistance to drought were more abundant in the metagenome and more prevalent, diversified, and redundant in the metagenome assembled genomes of the soil with an intermittent water stress history as compared to the soil with a continuous water stress history. We suggest that an intermittent water stress history selects for generalists that are adapted to both low and replete water contents, and that these generalists harbor a larger repertoire of genes beneficial for life under water stress.
The sleep quality- and myopia-linked PDE11A-Y727C variant impacts neural physiology by reducing catalytic activity and altering subcellular compartmentalization of the enzyme
Authors: Sbornova Irina , van der Sande Emilie , Milosavljevic Snezana , Amurrio Elvis , Burbano Steven D. , Das Prosun , Do Helen , Fisher Janet L. , Kargbo Porschderek , Patel Janvi , Porcher Latarsha , De Zeeuw Chris I. , Meester-Smoor Magda A , Winkelman Beerend H.J. , Klaver Caroline C.W. , Pocivavsek Ana , Kelly Michy P. 
Published: November 2023

ABSTRACTRecently, a Y727C variant in the dual-specific 3’,5’-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if 1) PDE11A protein is expressed in the retina or other eye segments in mouse, 2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and 3)Pde11adeletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes ofPde11aWT—but not KO mice—that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this,Pde11adeletion does not alter age-related changes in retinal or lens thickness, axial length, nor vitreous or anterior chamber depth. Further,Pde11adeletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia.
Genome of the North American wild apple speciesMalus angustifolia
Authors: Mansfeld Ben N. , Ou Shujun , Burchard Erik , Yocca Alan , Harkess Alex , Gutierrez Ben , van Nocker Steve , Tang Lisa , Gottschalk Christopher 
Published: November 2023

AbstractApple (Malus×domesticaBorkh.) production faces many challenges stemming from abiotic and biotic stresses. Abiotic stressors, such as extreme temperatures, droughts, and spring frosts, can lead to diminished yields and tree loss, while biotic stresses like fire blight and pest infestations further reduce tree health and fruit quality. To lessen the threat of these challenges, plant breeders aim to introduce resistance and resilience genes into cultivated varieties. However, high-relatedness among cultivated varieties and breeding lines, coupled with the long juvenility and generation times in apples, hinder the breeding process. The introduction of resistance traits from wild relatives is also constrained by these factors, as well as the lack of genomic resources that could assist in accelerating the introgression process. Herein, we report the assembly and annotation ofMalus angustifolia, the Southern Crabapple, one of Eastern North America’s native species. Using a combination of Pacific Biosciences High Fidelity reads, Next-generation short read sequencing, as well as chromatin conformation capture sequencing, we achieve an extremely contiguous haplotype-resolved assembly. We perform comparative haplotypic analyses to identify SNPs and large structural variants, shedding light on the genomic landscape ofM. angustifolia. Finally, we explore the phylogenetic and syntenic relationships between EurasianMalusprogenitors and the recently sequenced North American species, contributing valuable insights to the broader understanding of apple evolution and potential breeding strategies.