bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct Patterns of SARS-CoV-2 BA.2.87.1 and JN.1 Variants in Immune Evasion, Antigenicity and Cell-Cell Fusion
Authors: Li Pei , Liu Yajie , Faraone Julia , Hsu Cheng Chih , Chamblee Michelle , Zheng Yi-Min , Carlin Claire , Bednash Joseph S. , Horowitz Jeffrey C. , Mallampalli Rama K. , Saif Linda J. , Oltz Eugene M. , Jones Daniel , Li Jianrong , Gumina Richard J. , Liu Shan-Lu 
Published: March 2024

ABSTRACTThe rapid evolution of SARS-CoV-2 variants presents a constant challenge to the global vaccination effort. In this study, we conducted a comprehensive investigation into two newly emerged variants, BA.2.87.1 and JN.1, focusing on their neutralization resistance, infectivity, antigenicity, cell-cell fusion, and spike processing. Neutralizing antibody (nAb) titers were assessed in diverse cohorts, including individuals who received a bivalent mRNA vaccine booster, patients infected during the BA.2.86/JN.1-wave, and hamsters vaccinated with XBB.1.5-monovalent vaccine. We found that BA.2.87.1 shows much less nAb escape from WT-BA.4/5 bivalent mRNA vaccination and JN.1-wave breakthrough infection sera compared to JN.1 and XBB.1.5. Interestingly. BA.2.87.1 is more resistant to neutralization by XBB.15-monovalent-vaccinated hamster sera than BA.2.86/JN.1 and XBB.1.5, but efficiently neutralized by a class III monoclonal antibody S309, which largely fails to neutralize BA.2.86/JN.1. Importantly, BA.2.87.1 exhibits higher levels of infectivity, cell-cell fusion activity, and furin cleavage efficiency than BA.2.86/JN.1. Antigenically, we found that BA.2.87.1 is closer to the ancestral BA.2 compared to other recently emerged Omicron subvariants including BA.2.86/JN.1 and XBB.1.5. Altogether, these results highlight immune escape properties as well as biology of new variants and underscore the importance of continuous surveillance and informed decision-making in the development of effective vaccines.
Phosphorylation of PLPPR3 membrane proteins as signaling integrator at neuronal synapses
Authors: Kroon Cristina , Bareesel Shannon , Kirchner Marieluise , Gimber Niclas , Ranti Dimitra , Brosig Annika , Textoris-Taube Kathrin , Zolnik Timothy A. , Mertins Philipp , Schmoranzer Jan , Leondaritis George , Eickholt Britta J. 
Published: March 2024

AbstractPhospholipid-phosphatase related protein 3 (PLPPR3, previously known as Plasticity Related Gene 2 or PRG2) belongs to a family of transmembrane proteins, highly expressed in neuronal development, which regulate critical growth processes in neurons. Prior work established crucial functions of PLPPR3 in axon guidance, filopodia formation and axon branching. However, little is known regarding the signaling events regulating PLPPR3 function. We identify here 26 high-confidence phosphorylation sites in the intracellular domain of PLPPR3 using mass spectrometry. Biochemical characterization established one of these – S351 – as abona fidephosphorylation site of PKA. Experiments in neuronal cell lines suggest that phosphorylation of S351 does not regulate filopodia formation. Instead, it regulates binding to BASP1, a signaling molecule previously implicated in axonal growth and regeneration. Interestingly, both PLPPR3 intracellular domain and BASP1 enrich in presynapses in primary neurons. We propose that the presynaptic PLPPR3-BASP1 complex may function as novel signaling integrator at neuronal synapses.
Insights into Cellular Evolution: Temporal Deep Learning Models and Analysis for Cell Image Classification
Authors: Zhao Xinran , de Perez Alexander Ruys , Dimitrova Elena S. , Kemp Melissa , Anderson Paul E. 
Published: March 2024

I.AbstractUnderstanding the temporal evolution of cells poses a significant challenge in developmental biology. This study embarks on a comparative analysis of various machine-learning techniques to classify sequences of cell colony images, thereby aiming to capture dynamic transitions of cellular states. Utilizing transfer learning with advanced classification networks, we achieved high accuracy in single-timestamp image categorization. We introduce temporal models—LSTM, R-Transformer, and ViViT—to explore the effectiveness of integrating temporal features in classification, comparing their performance against non-temporal models. This research benchmarks various machine learning approaches in understanding cellular dynamics, setting a foundation for future studies to enhance our understanding of cellular developments with computational methods, contributing significantly to biological research advancements.
Reduced Filaggrin expression induces dysregulated intracellular signalling in atopic eczema
Authors: Hughes AJ , Coppock L , Tachie-Menson T , Thomas BR , Dewan P , Doykov I , Mills K , O’Toole EA , O’Shaughnessy RFL 
Published: March 2024

AbstractAtopic eczema (AE) is the most common inflammatory dermatosis, affecting up to 20% of children. Loss of function mutations in the Filaggrin (FLG) gene are the most strongly implicated genetic risk factor for AE, but little is known about the signalling pathways altered in response to loss ofFLG.To explore the downstream effects of loss of FLG on the cellular environment, we combined RNAseq analysis of siRNA knockdown of normal human keratinocytes and analysis of tape strip (TS) samples from AE patients who were clinically phenotyped and genotyped forFLGmutation status.RNA-seq analysis revealed an increase in BMP signalling following FLG KD, which we validatedin vivousing TS samples and biopsies. Recombinant BMP2 or BMP6 increased FLG and suprabasal keratin expression in vitro. Phosphoproteomic analysis identified 237 significantly differentially phosphorylated proteins following FLG KD. Kinase enrichment analysis identified downregulation of ERK1/2 and AKT1 signalling which was confirmed in AE biopsies. cFOS was downregulated following FLG KD and correlated with FLG expression in repository datasets. cFOS was downregulated following BMP6 treatment, implying that cFOS may be an important link between FLG and BMP signalling. Finally, proteomic analysis of TS samples identified altered desmosomal expression and phosphorylation following either loss of FLG or increased BMP signalling. Therefore, we have identified a SMAD1/Filaggrin/AKT axis as a potential therapeutic avenue in AE.
Epidemiological inference at the threshold of data availability: an influenza A(H1N2)v spillover event in the United Kingdom
Authors: Fozard John A. , Thomson Emma C. , Illingworth Christopher J. R. 
Published: March 2024

AbstractViruses which infect animals regularly spill over into the human population, but individual events may lead to anything from a single case to a novel pandemic. Rapidly gaining an understanding of a spillover event is critical to calibrating a public health response. We here propose a novel method, using likelihood free rejection sampling to evaluate the properties of an outbreak of swine-origin influenza A(H1N2)v in the United Kingdom, detected in November 2023. From the limited data available we generate historical estimates of the probability that the outbreak had died out in the days following the detection of the first case. Our method suggests that the outbreak could have been said to be over with 95% certainty between 19 and 29 days after the first case was detected, depending upon the probability of a case being detected. We further estimate the number of undetected cases conditional upon the outbreak still being live, the epidemiological parameter R0, and the date on which the spillover event itself occurred. Our method requires minimal data to be effective. While our calculations were performed after the event, the real-time application of our method has potential value for public health responses to cases of emerging viral infection.
Phenylphenalenones and Linear Diarylheptanoid Derivatives are Biosynthesized via Parallel Routes inMusella lasiocarpa, the Chinese Dwarf Banana
Authors: Lyu Hui , Ernst Lukas , Nakamura Yoko , Okamura Yu , Köllner Tobias G. , Luck Katrin , Liu Benye , Chen Yu , Beerhues Ludger , Gershenzon Jonathan , Paetz Christian 
Published: March 2024

AbstractPhenylphenalenones (PPs) are complex polycyclic natural products that play an important role in the chemical defense system of banana and plantain (Musaceae). Although suggestions for how plants synthesize the PP scaffold were first proposed more than 50 years ago, no biosynthetic information is yet available at the enzyme level. Here, we use transcriptomic data from seeds ofMusella lasiocarpa, the Chinese dwarf banana, to identify five biosynthetic genes involved in the formation of dihydrocurcuminoids. Characterization of the substrate specificities of the enzymes reveals two distinct dihydrocurcuminoid pathways leading to the two types of major aromatic seed metabolites, the PPs and the linear diarylheptanoid derivatives. Furthermore, through multiple rounds of feeding potential intermediates toM. lasiocarparoot protein extract, followed by high-resolution mass spectrometry profiling, product isolation, and NMR-based elucidation, we demonstrate the stepwise conversion of a dihydrocurcumin-type precursor to the PP 4’-hydroxylachnanthocarpone. In contrast to the commonly hypothesized Diels–Alder cyclization mechanism, we propose an unexpected two-step cyclization route to the PP scaffold.
Polyglutamylation of microtubules drives neuronal remodeling
Authors: Gavoci Antoneta , Zhiti Anxhela , Rusková Michaela , Magiera Maria M. , Wang Mengzhe , Ziegler Karin A. , Hausrat Torben Johann , Engelhardt Stefan , Kneussel Matthias , Balastik Martin , Janke Carsten , Misgeld Thomas , Brill Monika S. 
Published: March 2024

AbstractDevelopmental remodeling shapes neural circuits via activity-dependent pruning of synapses and axons. The cytoskeleton is critical for this process, as microtubule loss via enzymatic severing is an early step of pruning across many circuits and species. However, how microtubule-severing enzymes, such as spastin, are activated in specific neuronal compartments remains unknown. Here, we reveal that polyglutamylation, a posttranslational tubulin modification that is enriched in neurons, plays an instructive role in developmental remodeling by tagging microtubules for severing. Motor neuron-specific gene deletion of enzymes that add or remove tubulin polyglutamylation—TTLL glutamylases vs. CCP deglutamylases—accelerates or delays neuromuscular synapse remodeling in a neurotransmission-dependent manner. This mechanism is not specific to peripheral synapses but also operates in central circuits, e.g., the hippocampus. Thus, tubulin polyglutamylation acts as an activity-dependent rheostat of remodeling and shapes neuronal morphology and connectivity.
A cellular assay to determine the fusion capacity of MFN2 variants linked to Charcot-Marie-Tooth type 2A
Authors: Barsa Chloe , Perrin Julian , David Claudine , Mourier Arnaud , Rojo Manuel 
Published: March 2024

AbstractCharcot-Marie-Tooth Disease (CMT) is an inherited peripheral neuropathy with two main forms: demyelinating CMT1 and axonal CMT2. The most frequent subtype of CMT2 (CMT2A) is linked to mutations ofMFN2, encoding a membrane-anchored GTP-binding protein essential for mitochondrial outer membrane fusion. The use of Next-Generation Sequencing for genetic analysis has led to the identification of increasing numbers ofMFN2variants, but a majority of them remain variants of unknown significance, depriving patients of a clear diagnosis. In this work, we establish a cellular assay allowing to assess the impact ofMFN2variants linked to CMT2A on the fusion capacity of MFN2. The analysis of 12MFN2variants revealed that five abolish fusion, one induces an important reduction and six retain a fusion capacity similar to that of wild-type MFN2. Their analysis with computational variant effect predictors demonstrated a remarkable correlation of our results with predictions based on protein sequence analysis. This work develops novel tools to determine the functional impact of known and novelMFN2variants and identifies computational tools allowing to predict their possible consequences and pathogenicity.
FlhE functions as a chaperone to prevent formation of periplasmic flagella in Gram-negative bacteria
Authors: Halte Manuel , Andrianova Ekaterina P. , Goosmann Christian , Chevance Fabienne F.V. , Hughes Kelly T. , Zhulin Igor B. , Erhardt Marc 
Published: March 2024

AbstractThe bacterial flagellum is an organelle utilized by many Gram-negative bacteria to facilitate motility. The flagellum is composed of a several µm long, extracellular filament that is connected to a cytoplasmic rotor-stator complex via a periplasmic rod. Composed of ∼20 structural proteins, ranging from a few subunits to several thousand building blocks, the flagellum is a paradigm of a complex macromolecular structure that utilizes a highly regulated assembly process. This process is governed by multiple checkpoints that ensure an ordered gene expression pattern coupled to the assembly of the various flagellar building blocks in order to produce a functional flagellum. Using epifluorescence, super-resolution STED and transmission electron microscopy, we discovered that inSalmonella, the absence of one periplasmic protein, FlhE, prevents proper flagellar morphogenesis and results in the formation of periplasmic flagella. The periplasmic flagella disrupt cell wall synthesis, leading to a loss of the standard cell morphology resulting in cell lysis. We propose a model where FlhE functions as a periplasmic chaperone to control assembly of the periplasmic rod to prevent formation of periplasmic flagella. Our results highlight that bacteria evolved sophisticated regulatory mechanisms to control proper flagellar assembly and minor deviations from this highly regulated process can cause dramatic physiological consequences.
Monkeys have rhythm
Authors: Rajendran Vani G. , Marquez Juan Pablo , Prado Luis , Merchant Hugo 
Published: March 2024

SummarySynchronizing movements to music is one of the hallmarks of human culture whose evolutionary and neurobiological origins remain unknown. The ability to synchronize movements requires 1) detecting a steady rhythmic pulse, or beat, out of a stream of complex sounds, 2) projecting this rhythmic pattern forward in time to predict future input, and 3) timing motor commands in anticipation of predicted future beats. Here, we demonstrate that the macaque is capable of synchronizing taps to a subjective beat in real music, and even spontaneously chooses to do so over alternative strategies. This contradicts the influential “vocal learning hypothesis” that musical beat synchronization is only possible in species with complex vocalizations such as humans and some songbirds. We propose an alternative view of musical beat perception and synchronization ability as a continuum onto which a wider range of species can be mapped depending on their ability to perform and coordinate the general abilities listed above through association with reward.
Modulation of GABAAreceptor trafficking by WWC2 reveals class-specific mechanisms of synapse regulation by WWC family proteins
Authors: Dunham Thomas L. , Wilkerson Julia R. , Johnson Richard C. , Huganir Richard L. , Volk Lenora J. 
Published: March 2024

SUMMARYWWC2 (WW and C2 domain-containing protein) is implicated in several neurological disorders, however its function in the brain has yet to be determined. Here, we demonstrate that WWC2 interacts with inhibitory but not excitatory postsynaptic scaffolds, consistent with prior proteomic identification of WWC2 as a putative component of the inhibitory postsynaptic density. Using mice lacking WWC2 expression in excitatory forebrain neurons, we show that WWC2 suppresses GABAAR incorporation into the plasma membrane and regulates HAP1 and GRIP1, which form a complex promoting GABAAR recycling to the membrane. Inhibitory synaptic transmission is dysregulated in CA1 pyramidal cells lacking WWC2. Furthermore, unlike the WWC2 homolog KIBRA (WWC1), a key regulator of AMPA receptor trafficking at excitatory synapses, deletion of WWC2 does not affect synaptic AMPAR expression. In contrast, loss of KIBRA does not affect GABAAR membrane expression. These data reveal unique, synapse class-selective functions for WWC proteins as regulators of ionotropic neurotransmitter receptors and provide insight into mechanisms regulating GABAAR membrane expression.
Microtubule poleward flux as a target for modifying chromosome segregation errors
Authors: Risteski Patrik , Martinčić Jelena , Tintor Erna , Jagrić Mihaela , Tolić Iva M. 
Published: March 2024

AbstractCancer cells often display errors in chromosome segregation, some of which result from improper chromosome alignment at the spindle midplane. Chromosome alignment is facilitated by different rates of microtubule poleward flux between sister kinetochore fibers. However, the role of the poleward flux in supporting mitotic fidelity remains unknown. Here, we introduce the hypothesis that the finely tuned poleward flux safeguards against lagging chromosomes and micronuclei at mitotic exit by promoting chromosome alignment in metaphase. We used human untransformed RPE-1 cells depleted of KIF18A/kinesin-8 as a system with reduced mitotic fidelity, which we rescued by three mechanistically independent treatments, comprising low-dose taxol or co-depletion of the spindle proteins HAUS8 or NuMA. The rescue of mitotic errors was due to shortening of the excessively long overlaps of antiparallel microtubules, serving as a platform for motor proteins that drive the flux, which in turn slowed down the overly fast flux and improved chromosome alignment. In contrast to the prevailing view, the rescue was not accompanied by reduction of overall microtubules growth rates. Speckle microscopy revealed that the improved chromosome alignment in the rescue treatments was associated with slower growth and flux of kinetochore microtubules. In a similar manner, a low-dose taxol treatment rescued mitotic errors in a high-grade serous ovarian carcinoma cell line OVKATE. Collectively, our results highlight the potential of targeting microtubule poleward flux to modify chromosome instability and provide insight into the mechanism through which low doses of taxol rescue mitotic errors in cancer cells.
Molecular mechanism for regulating APOBEC3G DNA editing function by the non-catalytic domain
Authors: Yang Hanjing , Pacheco Josue , Kim Kyumin , Ebrahimi Diako , Ito Fumiaki , Chen Xiaojiang S. 
Published: March 2024

AbstractAPOBEC3G (A3G) belongs to the AID/APOBEC cytidine deaminase family and is essential for antiviral immunity. It contains two zinc-coordinated cytidine-deaminase (CD) domains. The N-terminal CD1 domain is non-catalytic but has a strong affinity for nucleic acids, whereas the C-terminal CD2 domain catalyzes C-to-U editing in single-stranded DNA. The interplay between the two domains in DNA binding and editing is not fully understood. Here, our studies on rhesus macaque A3G (rA3G) show that the DNA editing function in linear and hairpin loop DNA is greatly enhanced by AA or GA dinucleotide motifs present downstream (in the 3’-direction) but not upstream (in the 5’-direction) of the target-C editing sites. The effective distance between AA/GA and the target-C sites depends on the local DNA secondary structure. We present two co-crystal structures of rA3G bound to ssDNA containing AA and GA, revealing the contribution of the non-catalytic CD1 domain in capturing AA/GA DNA and explaining our biochemical observations. Our structural and biochemical findings elucidate the molecular mechanism underlying the cooperative function between the non-catalytic and the catalytic domains of A3G, which is critical for its antiviral role and its contribution to genome mutations in cancer.
Comparative Pore Structure and Dynamics for Bacterial Microcompartment Shell Protein Assemblies in Sheets or Shells
Authors: Raza Saad , Sarkar Daipayan , Chan Leanne Jade G. , Mae Joshua , Sutter Markus , Petzold Christopher J. , Kerfeld Cheryl A. , Ralston Corie Y. , Gupta Sayan , Vermaas Josh V. 
Published: March 2024

AbstractBacterial microcompartments (BMCs) are protein-bound organelles found in some bacteria which encapsulate enzymes for enhanced catalytic activity. These compartments spatially sequester enzymes within semi-permeable shell proteins, analogous to many membrane-bound organelles. The shell proteins assemble into multimeric tiles; hexamers, trimers, and pentamers, and these tiles self-assemble into larger assemblies with icosahedral symmetry. While icosahedral shells are the predominant formin vivo, the tiles can also form nanoscale cylinders or sheets. The individual multimeric tiles feature central pores that are key to regulating transport across the protein shell. Our primary interest is to quantify pore shape changes in response to alternative component morphologies at the nanoscale. We use molecular modeling tools to develop atomically detailed models for both planar sheets of tiles and curved structures representative of the complete shells foundin vivo. Subsequently, these models were animated using classical molecular dynamics simulations. From the resulting trajectories, we analyzed overall structural stability, water accessibility to individual residues, water residence time, and pore geometry for the hexameric and trimeric protein tiles from theHaliangium ochraceummodel BMC shell. These exhaustive analyses suggest no substantial variation in pore structure or solvent accessibility between the flat and curved shell geometries. We additionally compare our analysis to hydroxyl radical footprinting data to serve as a check against our simulation results, highlighting specific residues where water molecules are bound for a long time. Although with little variation in morphology or water interaction, we propose that the planar and capsular morphology can be used interchangeably when studying permeability through BMC pores.
Global RNA Virome in Wastewater Treatment Plants Reveals Ecological Insights and Human Health Implications
Authors: Yuan Ling , Chen Lin-xing , Yu Hanqing , Zhou Jizhong , Sun Ren , Ju Feng 
Published: March 2024

AbstractRNA viruses are widely recognized for their roles in causing human diseases and shaping Earth’s biodiversity. Wastewater treatment plants (WWTPs) are eco-friendly biotechnological systems where the roles of RNA viruses in process engineering and sanitation remain unclear. This study analyzed RNA sequencing dataset (> 3.8 Tb) from global WWTPs to examine the diversity, host associations, and auxiliary metabolic functions of RNA viruses. We identified 11,414 RNA virus operational taxonomic units (vOTUs), expanding the known diversity of RNA viruses in WWTPs by 67%. The RNA viral community in WWTPs was dominated by prokaryotic viruses, including both established RNA phage lineages and novel clades with broad ecological distributions, highlighting their underestimated diversity and broad niche breadths. Notably, a vOTU from the base-Howeltoviricetesphage clade was associated with the pathogenic bacteriumAliarcobacter cryaerophilus, suggesting potential applications in RNA phage therapy. Furthermore, the examined distribution and fate of human RNA viruses emphasized the utility of quantitative metatranscriptomics-based wastewater surveillance for public health monitoring. The discovery of auxiliary metabolic genes encoded by RNA viruses further revealed their involvement in critical host metabolic pathways such as translation and cellular respiration. These findings underscore the multifaceted roles of RNA viruses in the critical engineered systems.