bluuebunny/crossref_metadata_2025_split huggingface dataset:
A deep learning framework for predicting the neutralizing activity of COVID-19 therapeutics and vaccines against evolving SARS-CoV-2 variants
Authors: Matson Robert P. , Comba Isin Y. , Silvert Eli , Niesen Michiel J.M. , Murugadoss Karthik , Padwardhan Dhruti , Suratekar Rohit , Goel Elizabeth-Grace , Poelaert Brittany J. , Wan Kanny , Brimacombe Kyle R. , Venkatakrishnan AJ , Soundararajan Venky 
Published: October 2023

AbstractUnderstanding how viral variants evade neutralization is crucial for improving antibody-based treatments, especially with rapidly evolving viruses like SARS-CoV-2. Yet, conventional assays are limited in the face of rapid viral evolution, relying on a narrow set of viral isolates, and falling short in capturing the full spectrum of variants. To address this, we have developed a deep learning approach to predict changes in neutralizing antibody activity of COVID-19 therapeutics and vaccines against emerging viral variants. First, we trained a variational autoencoder (VAE) using all 67,885 unique SARS-CoV-2 spike protein sequences from the NCBI virus (up to October 31, 2022) database to encode spike protein variants into a latent space. Using this VAE and a curated dataset of 7,069in vitroassay data points from the NCATS OpenData Portal, we trained a neural network regression model to predict fold changes in neutralizing activity of 40 COVID-19 therapeutics and vaccines against spike protein sequence variants, relative to their neutralizing activity against the ancestral strain (Wuhan-Hu-1). Our model also employs Bayesian inference to quantify prediction uncertainty, providing more nuanced and informative estimates. To validate the model’s predictive capacity, we assessed its performance on a test set ofin vitroassay data collected up to eight months after the data included in the model training (N = 980). The model accurately predicted fold changes in neutralizing activity for this prospective dataset, with an R2of 0.77. Expanding our methodology to include all available data from NCBI virus and NCATS OpenData Portal up to date, we assessed predicted changes in activity for current COVID-19 monoclonal antibodies and vaccines against newly identified SARS-CoV-2 lineages. Our predictions suggest that current therapeutic and vaccine-induced antibodies will have significantly reduced activity against newer XBB descendants, notably EG.5, FL.1.5.1, and XBB.1.16. Using the model, we were able to primarily attribute the observed predicted loss in activity to the F456L spike mutation found in EG.5 and FL.1.5.1 sequences. Conversely, mRNA-bivalent vaccines are predicted to be less susceptible to the recent BA.2.86 variant compared to new XBB descendants. These findings align closely with recent research, underscoring the potential of deep learning in shaping therapeutic and vaccine strategies for emerging viral variants.
The Hao-Fountain syndrome protein USP7 regulates neuronal connectivity in the brain via a novel p53-independent ubiquitin signaling pathway
Authors: Chen Hao , Ferguson Cole J. , Mitchell Dylan C. , Titus Amanda , Paulo Joao A. , Hwang Andrew , Lin Tsen-Hsuan , Yano Hiroko , Gu Wei , Song Sheng-Kwei , Yuede Carla M. , Gygi Steven P. , Bonni Azad , Kim Albert H. 
Published: October 2023

AbstractPrecise control of protein ubiquitination is essential for brain development, and hence, disruption of ubiquitin signaling networks can lead to neurological disorders. Mutations of the deubiquitinase USP7 cause the Hao-Fountain syndrome (HAFOUS), characterized by developmental delay, intellectual disability, autism, and aggressive behavior. Here, we report that conditional deletion of USP7 in excitatory neurons in the mouse forebrain triggers diverse phenotypes including sensorimotor deficits, learning and memory impairment, and aggressive behavior, resembling clinical features of HAFOUS. USP7 deletion induces neuronal apoptosis in a manner dependent of the tumor suppressor p53. However, most behavioral abnormalities in USP7 conditional mice persist despite p53 loss. Strikingly, USP7 deletion in the brain perturbs the synaptic proteome and dendritic spine morphogenesis independently of p53. Integrated proteomics analysis reveals that the neuronal USP7 interactome is enriched for proteins implicated in neurodevelopmental disorders and specifically identifies the RNA splicing factor Ppil4 as a novel neuronal substrate of USP7. Knockdown of Ppil4 in cortical neurons impairs dendritic spine morphogenesis, phenocopying the effect of USP7 loss on dendritic spines. These findings reveal a novel USP7-Ppil4 ubiquitin signaling link that regulates neuronal connectivity in the developing brain, with implications for our understanding of the pathogenesis of HAFOUS and other neurodevelopmental disorders.
Low booster uptake in cancer patients despite health benefits
Authors: Figueiredo Jane C. , Levy Julia , Choi So Yung , Xu Alexander M. , Merin Noah M. , Hamid Omid , Lemos Tucker , Nguyen Nathalie , Nadri Maimoona , Gonzalez Alma , Mahov Simeon , Darrah Justin M. , Gong Jun , Paquette Ronald L. , Mita Alain C. , Vescio Robert A. , Salvy Sarah J. , Mehmi Inderjit , Hendifar Andrew E. , Natale Ronald , Tourtellotte Warren G. , Krishnan Ramanujan V. , Huynh Carissa A. , Sobhani Kimia , Reckamp Karen L. , Merchant Akil A. 
Published: October 2023

SummaryPatients with cancer are at increased risk of death from COVID-19 and have reduced immune responses to SARS-CoV2 vaccines, necessitating regular boosters. We performed comprehensive chart reviews, surveys of patients attitudes, serology for SARS-CoV-2 antibodies and T-cell receptor (TCR) β sequencing for cellular responses on a cohort of 982 cancer patients receiving active cancer therapy accrued between November-3-2020 and Mar-31-2023. We found that 92·3% of patients received the primer vaccine, 70·8% received one monovalent booster, but only 30·1% received a bivalent booster. Booster uptake was lower under age 50, and among African American or Hispanic patients. Nearly all patients seroconverted after 2+ booster vaccinations (>99%) and improved cellular responses, demonstrating that repeated boosters could overcome poor response to vaccination. Receipt of booster vaccinations was associated with a lower risk of all-cause mortality (HR=0·61, P=0·024). Booster uptake in high-risk cancer patients remains low and strategies to encourage booster uptake are needed.HighlightsCOVID-19 booster vaccinations increase antibody levels and maintain T-cell responses against SARS-CoV-2 in patients receiving various anti-cancer therapiesBooster vaccinations reduced all-cause mortality in patientsA significant proportion of patients remain unboosted and strategies are needed to encourage patients to be up-to-date with vaccinations
A natural cyclic peptide valinomycin enhances plant innate immunity
Authors: Yoo Nayeon , Kang Ji Eun , Kim Da-Ran , Lee Huiwon , Ko Dohee , Kwak Youn-Sig , Chung Eui-Hwan 
Published: October 2023

SUMMARYVarious natural compounds as alternative agents for the chemical management of plant diseases have long been proposed. Valinomycin, aStreptomyces-derived cyclic peptide, acts as an antifungal agent against several plant pathogenic fungi, includingBotrytis cinerea. Here, we report the novel function of valinomycin, plant immune-boosting. Valinomycin potentiates pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) inArabidopsis, leading to enhanced resistance against bacterial speck disease locally and systemically. Moreover, this plant immune-boosting activity of valinomycin is associated with plant hormonal signaling. Thus, we propose that valinomycin harbors potential as a biocontrol agent suppressing complex pathogen infections, such as bacteria and fungi.
Decoding spatial organization maps and context-specific landscapes of breast cancer and its microenvironment via high-resolution spatial transcriptomic analysis
Authors: Seo Eun Seop , Lee Boram , Hwang Inwoo , Kim Ji-Yeon , Park Kyeongmee , Park Woong-Yang 
Published: October 2023

AbstractSingle-cell RNA transcriptomics has revealed the intricate heterogeneity of both tumors and their microenvironment. However, a notable limitation is its inability to retain spatial context, a crucial aspect of understanding cell identity and function. In this study, we employed imaging-based single-cell spatial transcriptomics to elucidate the tumor and immunological landscapes of two breast cancer samples. By resolving over 400 000 cells per slide, we demonstrated that transcriptional differences lead to structural disparities within and between tumors. Additionally, we observed that the composition of the tumor microenvironment varies depending on its spatial location. Notably, we detected immune cell gradients transitioning from the tumor periphery to its core regions and from tertiary lymphoid structure to immune inflamed regions, in alignment with the specific function of each cell type. This finding facilitated a more precise classification of the tumor immune microenvironment. This study provides a comprehensive dataset for breast cancer researchers and underscores the significance of spatial context in understanding the multifaceted heterogeneity of cancer and its environment.
Structure of PSI-LHCI fromCyanidium caldariumprovides evolutionary insights into conservation and diversity of red-lineage LHCs
Authors: Kato Koji , Hamaguchi Tasuku , Kumazawa Minoru , Nakajima Yoshiki , Ifuku Kentaro , Hirooka Shunsuke , Hirose Yuu , Miyagishima Shin-ya , Suzuki Takehiro , Kawakami Keisuke , Dohmae Naoshi , Yonekura Koji , Shen Jian-Ren , Nagao Ryo 
Published: October 2023

AbstractLight-harvesting complexes (LHCs) are diversified among photosynthetic organisms, and their structural variety in photosystem I-LHC (PSI-LHCI) supercomplexes has been shown. However, structural and evolutionary correlations of red-lineage LHCs are unknown. Here we determined a 1.92-Å resolution cryo-electron microscopic structure of a PSI-LHCI supercomplex isolated from the red algaCyanidium caldariumRK-1 (NIES-2137) which is an important taxon in the Cyanidiophyceae, and subsequently investigated these correlations through structural comparisons and phylogenetic analysis. The PSI-LHCI structure shows five LHCI subunits together with a PSI-monomer core. The five LHCIs are composed of two Lhcr1s, two Lhcr2s, and one Lhcr3. Phylogenetic analysis of LHCs bound to PSI in red-lineage algae showed clear orthology of LHCs betweenC. caldariumandCyanidioschyzon merolae, whereas no orthologous relationships were found betweenC. caldariumLhcr1–3 and LHCs in other red-lineage PSI-LHCI structures. These findings provide evolutionary insights into conservation and diversity of red-lineage LHCs associated with PSI.
3-O-methyltolcapone and Its Lipophilic Analogues are Potent Inhibitors of Transthyretin Amyloidogenesis with High Permeability and Low Toxicity
Authors: Poonsiri Thanalai , dell’Accantera Davide , Loconte Valentina , Casnati Alessandro , Cervoni Laura , Arcovito Alessandro , Benini Stefano , Ferrari Alberto , Cipolloni Marco , Cacioni Elisa , Franco Francesca De , Giacchè Nicola , Rinaldo Serena , Folli Claudia , Sansone Francesco , Berni Rodolfo , Cianci Michele 
Published: October 2023

ABSTRACTTransthyretin (TTR) is an amyloidogenic homotetramer involved in the transport of thyroxine in blood and cerebrospinal fluid. To date, more than 130 TTR point mutations are known to destabilise the TTR tetramer, leading to its extracellular pathological aggregation accumulating in several organs, such as heart, peripheral and autonomic nerves, and leptomeninges. Tolcapone is an FDA-approved drug for Parkinson’s disease that has been repurposed as a TTR stabiliser. We characterised 3-O-methyltolcapone and two newly synthesized lipophilic analogues, which are expected to be protected from the metabolic glucuronidation which is responsible of the lability of tolcapone in the organism. Immunoblotting assays indicated the high degree of TTR stabilisation, coupled with binding selectivity towards TTR in diluted plasma of 3-O-methyltolcapone and its lipophilic analogues. Furthermore,in-vitrotoxicity data showed their several-fold improved neuronal and hepatic safety compared to tolcapone. Calorimetric and structural data showed that both T4 binding sites of TTR are occupied by 3-O-methyltolcapone and its lipophilic analogs, consistent with an effective TTR tetramer stabilisation. Moreover,in-vitropermeability studies showed that the three compounds can effectively cross the blood-brain barrier, which is a prerequisite for the inhibition of TTR amyloidogenesis in the cerebrospinal fluid. Our data demonstrate the relevance of 3-O-methyltolcapone and its lipophilic analogs as potent inhibitors of TTR amyloidogenesis.
NRC immune receptor networks show diversified hierarchical genetic architecture across plant lineages
Authors: Goh Foong-Jing , Huang Ching-Yi , Derevnina Lida , Wu Chih-Hang 
Published: October 2023

AbstractPlants developed sophisticated immune systems with nucleotide-binding domain and leucine-rich repeat-containing (NLR) proteins to repel invading pathogens. The NRC (NLR required for cell death) family includes helper NLRs that form a complex genetic network with multiple sensor NLRs to provide resistance against pathogens of solanaceous plants. However, the evolution and function of NRC networks outside solanaceous plants is currently unknown. We conducted phylogenomic and macroevolutionary analyses comparing NLRs identified from different asterids lineages and found that NRC networks expanded significantly in most lamiids but not in Ericales and campanulids. Using transient expression assays inNicotiana benthamiana, we show that NRC networks are simple in Ericales and campanulids, but are with high complexity in lamiids. Phylogenetic analyses grouped the NRC helper NLRs into three NRC0 subclades that are conserved, and several family-specific NRC subclades of lamiids that show signatures of diversifying selection. Functional analyses revealed that members of the NRC0 subclades are partially interchangeable, whereas family-specific NRC members in lamiids lack interchangeability. Our findings highlight the distinctive evolutionary patterns of the NRC networks in asterids and provide potential insights into transferring disease resistance across plant lineages.
Determining the microbial species content in tissue from Alzheimer’s and Parkinson’s Disease patients
Authors: Leitao Rodrigo , Wan Iam Ut , Fisher Matthew C. , Rhodes Johanna 
Published: October 2023

AbstractThe aetiology of Alzheimer’s disease (AD) and Parkinson’s Disease (PD) are unknown and tend to manifest at a later stage in life; even though these diseases have different pathogenic mechanisms, they are both characterized by neuroinflammation in the brain. Links between bacterial and viral infection and AD/PD has been suggested in several studies, however, few have attempted to establish a link between fungal infection and AD/PD. In this study we develop and describe a nanopore-based sequencing approach to characterise the presence or absence of fungi in both human brain tissue and cerebrospinal fluid (CSF). This approach detects fungal DNA in human brain and CSF samples even at low levels, whereas our quantitative polymerase chain reaction (qPCR) assay (FungiQuant) was unable to detect fungal DNA in the same samples. Comparison against kit-controls showed ubiquitous low-level fungal contamination that we observed in healthy human brains and CSF as well AD/PD brains and CSF. We use this technique to demonstrate the presence of fungal DNA in healthy human brains as well as AD/PD brains, withAlternaria spp.,Colletotrichum graminicola, andFilobasidium floriformeas the most prominent species. In addition, antibiotic resistantPseudomonas spp. was identified within the brain of an AD patient. Our method will be broadly applicable to investigating potential links between microbial infection and AD/PD.
Nuclear Pyruvate Dehydrogenase Complex Regulates Histone Acetylation and Transcriptional Regulation in the Ethylene Response
Authors: Shao Zhengyao , Bian Liangqiao , Ahmadi Shyon K. , Daniel Tyler J. , Belmonte Miguel A. , Burns Jackson G. , Kotla Prashanth , Bi Yang , Shen Zhouxin , Xu Shou-Ling , Wang Zhi-Yong , Briggs Steven P. , Qiao Hong 
Published: October 2023

AbstractEthylene plays its essential roles in plant development, growth, and defense responses by controlling the transcriptional reprograming, in which EIN2-C-directed regulation of histone acetylation is the first key-step for chromatin to perceive ethylene signaling. But how the nuclear acetyl coenzyme A (acetyl CoA) is produced to ensure the ethylene-mediated histone acetylation is unknown. Here we report that ethylene triggers the accumulation of the pyruvate dehydrogenase complex (PDC) in the nucleus to synthesize nuclear acetyl CoA to regulate ethylene response. PDC is identified as an EIN2-C nuclear partner, and ethylene triggers its nuclear accumulation. Mutations in PDC lead to an ethylene-hyposensitivity that results from the reduction of histone acetylation and transcription activation. Enzymatically active nuclear PDC synthesize nuclear acetyl CoA for EIN2-C-directed histone acetylation and transcription regulation. These findings uncover a mechanism by which PDC-EIN2 converges the mitochondrial enzyme mediated nuclear acetyl CoA synthesis with epigenetic and transcriptional regulation for plant hormone response.
Diatom pyrenoids are encased in a protein shell that enables efficient CO2fixation
Authors: Shimakawa Ginga , Demulder Manon , Flori Serena , Kawamoto Akihiro , Tsuji Yoshinori , Nawaly Hermanus , Tanaka Atsuko , Tohda Rei , Ota Tadayoshi , Matsui Hiroaki , Morishima Natsumi , Okubo Ryosuke , Wietrzynski Wojciech , Lamm Lorenz , Righetto Ricardo D. , Uwizeye Clarisse , Gallet Benoit , Jouneau Pierre-Henri , Gerle Christoph , Kurisu Genji , Finazzi Giovanni , Engel Benjamin D. , Matsuda Yusuke 
Published: October 2023

AbstractPyrenoids are subcompartments of algal chloroplasts that concentrate Rubisco enzymes and their CO2substrate, thereby increasing the efficiency of carbon fixation. Diatoms perform up to 20% of global CO2fixation, but their pyrenoids remain poorly characterized at a molecular level. Here, we usedin vivophoto-crosslinking to catalogue components of diatom pyrenoids and identified a pyrenoid shell (PyShell) protein, which we localized to the pyrenoid periphery of both the pennate diatom,Pheaodactylum tricornutum, and the centric diatom,Thalassiosira pseudonana.In situcryo-electron tomography (cryo-ET) revealed that the pyrenoids of both diatom species are encased in a lattice-like protein sheath. Disruption of PyShell expression inT. pseudonanaresulted in the absence of this protein sheath, altered pyrenoid morphology, and a high-CO2requiring phenotype, with impaired growth and reduced carbon fixation efficiency under standard atmospheric conditions. Pyrenoids in mutant cells were fragmented and lacked the thylakoid membranes that normally traverse the Rubisco matrix, demonstrating how the PyShell plays a guiding role in establishing pyrenoid architecture. Recombinant PyShell proteins self-assembled into helical tubes, enabling us to determine a 3.0 Å-resolution PyShell structure. We then fit thisin vitrostructure into anin situsubtomogram average of the pyrenoid’s protein sheath, yielding a putative atomic model of the PyShell within diatom cells. The structure and function of the diatom PyShell provides a new molecular view of how CO2is assimilated in the ocean, a crucial biome that is on the front lines of climate change.
Cytoplasmic Viscosity is a Potential Biomarker for Metastatic Breast Cancer Cells
Authors: Dessard Marie , Manneville Jean-Baptiste , Berret Jean-François 
Published: October 2023

AbstractCellular microrheology has shown that cancer cells with high metastatic potential are softer compared to non-tumorigenic normal cells. These findings rely on measuring the apparent Young modulus of whole cells using primarily atomic force microscopy. The present study aims to explore whether alternative mechanical parameters have discriminating features with regard to metastatic potential. Magnetic rotational spectroscopy (MRS) is employed in the examination of mammary epithelial cell lines: MCF-7 and MDA-MB-231, representing low and high metastatic potential, alongside normal-like MCF-10A cells. MRS utilizes active micron-sized magnetic wires in a rotating magnetic field to measure the viscosity and elastic modulus of the cytoplasm. All three cell lines display viscoelastic behavior, with cytoplasmic viscosities ranging from 10-70 Pa s and elastic moduli from 30-80 Pa. It is found that the tumorigenic MCF-7 and MDA-MB-231 cells are softer than the MCF-10A cells, with a twofold decrease in elastic modulus. To differentiate cells with low and high malignancy however, viscosity emerges as the more discriminating parameter, as MCF-7 exhibits a 5 times higher viscosity as compared to MDA-MB-231. These findings highlight the sensitivity of cytoplasmic viscosity to metastatic potential, suggesting its potential utility as a mechanical marker for malignant cancer cells.TOC Image
How predictability and individual alpha frequency shape memory: insights from an event-related potential investigation
Authors: Jano Sophie , Chatburn Alex , Cross Zachariah , Schlesewsky Matthias , Bornkessel-Schlesewsky Ina 
Published: October 2023

AbstractPrediction and memory are strongly intertwined, with predictions relying on memory retrieval, whilst also influencing memory encoding. However, it is unclear how predictability influences explicit memory performance, and how individual neural factors may modulate this relationship. The current study sought to investigate the effect of predictability on memory processing with an analysis of the N400 event-related potential in a context extending beyond language. Participants (N= 48, females = 33) completed a study-test paradigm where they first viewed predictable and unpredictable four-item ‘ABCD’ sequences of outdoor scene images, whilst their brain activity was recorded using electroencephalography (EEG). Subsequently, their memory for the images was tested, and N400 patterns during learning were compared with memory outcomes. Behavioural results revealed better memory for images in predictable sequences in contrast to unpredictable sequences. Memory was also strongest for predictable images in the ‘B’ position, suggesting that when processing longer sequences, the brain may prioritise the data deemed most informative. Strikingly, greater N400 amplitudes during learning were associated with enhanced memory at test for individuals with low versus high individual alpha frequencies (IAFs). In light of the relationship between the N400 and stimulus predictability, this finding may imply that predictive processing differs between individuals to influence the extent of memory encoding. Finally, exploratory analyses provided evidence for a later positivity that was predictive of subsequent memory performance. Ultimately, the results highlight the complex and interconnected relationship between predictive processing and memory, whilst shedding light on the accumulation of predictions across longer sequences.