bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural insights into the RNA binding inhibitors of the C-terminal domain of the SARS-CoV-2 nucleocapsid
Authors: Dhaka Preeti , Mahto Jai Krishna , Singh Ankur , Kumar Pravindra , Tomar Shailly 
Published: October 2024

AbstractThe SARS-CoV-2 nucleocapsid (N) protein is an essential structural element of the virion, playing a crucial role in enclosing the viral genome into a ribonucleoprotein (RNP) assembly, as well as viral replication and transmission. The C-terminal domain of the N-protein (N-CTD) is essential for encapsidation, contributing to the stabilization of the RNP complex. In a previous study, three inhibitors (ceftriaxone, cefuroxime, and ampicillin) were screened for their potential to disrupt the RNA packaging process by targeting the N-protein. However, the binding efficacy, mechanism of RNA binding inhibition, and molecular insights of binding with N-CTD remain unclear. In this study, we evaluated the binding efficacy of these inhibitors using isothermal titration calorimetry (ITC), revealing the affinity of ceftriaxone (18 ± 1.3 μM), cefuroxime (55 ± 4.2 μM), and ampicillin (28 ± 1.2 μM) with the N-CTD. Further inhibition assay and fluorescence polarisation assay demonstrated RNA binding inhibition, with IC50ranging from 10.4 to 12.4 μM and KDvalues between 24 and 32 μM for the inhibitors. Additionally, we also determined the inhibitor-bound complex crystal structures of N-CTD-Ceftriaxone (2.0 Å) and N-CTD-Ampicillin (2.2 Å), along with the structure of apo N-CTD (1.4 Å). These crystal structures revealed previously unobserved interaction sites involving residues K261, K266, R293, Q294, and W301 at the oligomerization interface and the predicted RNA-binding region of N-CTD. These findings provide valuable molecular insights into the inhibition of N-CTD, highlighting its potential as an underexplored but promising target for the development of novel antiviral agents against coronaviruses.HighlightsThe inhibitors ceftriaxone, cefuroxime, and ampicillin-demonstrated high-affinity binding to the C-terminal domain (N-CTD) of the SARS-CoV-2 nucleocapsid (N) protein, effectively disrupting the formation of the N-CTD-RNA complex.Complex crystal structures of N-CTD with ceftriaxone and ampicillin revealed previously unobserved distinct binding sites.Structures reveal how the selected inhibitors disrupt the oligomerization of N-CTD and hinder the RNA packaging process of the virus.
Mapping AAV capsid sequences to functions through function-guidedin silicoevolution
Authors: Zheng Hanyu , Guo Binjie , Mo Aisheng , Wei Hongyan , Wu Yile , Lin Xurong , Jiang Haohan , Li Hengguang , Zhang Yunshuo , Song Zhuoyuan , Ni Xuebin , Huang Yan , Gu Xiaosong , Yu Bin , Cheng Ningtao , Wang Xuhua 
Published: October 2024

SummaryArtificial intelligence (AI) has been suggested to facilitate time- and cost-effective functional engineering of adeno-associated virus (AAV) capsid sequences. Nevertheless, an AI-empowered approach to identify AAV capsid sequence-to-multifunction relationships remains elusive. To overcome this challenge, we propose a machine-intelligent design method to map an AAV capsid sequence to multiple functions, thereby enabling directin silicoengineering of AAV capsids. To fuse multiple functions into a single capsid sequence, a heuristic algorithm coupled with contrastive learning and reinforcement learning, named function-guided evolution (FE), was introduced to steer further evolution of the high-performing capsid sequences generated by a naïve language model toward functions. We then illustrated the evolutionary mechanism of the FE approach for function-guided generation of capsid sequences. Further optimization steers the evolution toward desired functions within a function-guided landscape. Despite the constraint of datasets of only 129 entries, we successfully constructed a model to map AAV capsid sequences to multiple functions of improved viability coupled with central nervous system (CNS) tropism.In vivoexperiments confirmed that two of the top eight engineered variants exhibited enhanced viability and remarkable CNS tropism. This interpretable machine-intelligent design method represents a pioneering effort enabling directin silicoengineering of AAV capsids for effective gene delivery.Graph AbstractIn BriefThis study introduces ALICE, a novel machine-intelligent design method that enables directin silicoengineering of adeno-associated virus (AAV) capsids with multiple functions.In vivoexperiments have validated the enhanced viability and central nervous system tropism of the variants engineered through ALICE.HighlightsALICE represents a pioneering machine-intelligent design method for directin silicoengineering of AAV capsids with multiple functions.Utilizing a limited dataset of 129 entries, ALICE successfully maps AAV capsid sequences to multiple functions.We elucidated the evolutionary mechanism of capsid sequences toward desired functions within the ALICE system.We revealed that the AAV variants engineered by ALICE exhibit increased viability and about 372-fold increased central nervous system tropism.
Immersion in nature attenuates the development of mechanical secondary hyperalgesia: a role for insulo-thalamic effective connectivity
Authors: Medina Sonia , Hughes Sam 
Published: October 2024

AbstractNature-based social prescribing has been shown to improve physical and mental health and is increasingly used to manage chronic pain using immersive virtual reality (VR). However, the mechanisms of nature-based analgesia during immersive VR experiences remain unclear. In this study, we used experimentally induced sensitisation within central nociceptive pathways using high frequency stimulation (HFS) over the right forearm in 30 healthy participants and tracked the development of secondary hyperalgesia across three conditions: immersive VR nature, non-immersive 2D nature video, and no intervention. Immersive nature VR significantly reduced the development and spread of hyperalgesia, with sustained analgesic effects correlating with perceived presence. Bayesian modelling of neuroimaging endpoints collected separately revealed nature VR induced analgesic effects correlated with insulo-thalamic effective connectivity. We propose that the analgesic effects of nature are likely mediated via top-down endogenous analgesic systems which could be working to reduce the development and spread of heterotopic plasticity in the spinal cord.
Cortical alpha rhythms interpolate occluded motion from natural scene context
Authors: Yeh Lu-Chun , Bardelang Max , Kaiser Daniel 
Published: October 2024

AbstractTracking objects as they dynamically move in and out of sight is critical for parsing our ever-changing real-world surroundings. Here, we explored how the interpolation of occluded object motion in natural scenes is mediated by top-down information flows expressed in cortical alpha rhythms. We recorded EEG while participants viewed videos of a person walking across a scene. We then used multivariate decoding on alpha-band responses to decode the direction of movement across the scene. In trials where the person was temporarily occluded, alpha dynamics interpolated the person’s predicted movement. Critically, they did so in a context-dependent manner: When the scene context required the person to stop in front of an obstacle, alpha dynamics tracked the termination of motion during occlusion. As these effects were obtained with an orthogonal task at fixation, we conclude that alpha rhythms automatically interpolate occluded motion in a context-dependent way.
WITHDRAWN: Effect of inactivated conditioned media from DENV-2-infected endothelial cells on epithelial cell healing: live cell imaging analysis
Authors: Hincapie Victoria , Cardona-Gomez Juan Carlos , Gallego-Gomez Juan Carlos , Villarreal-Julio Rafael Guillermo , Blandon Jonny , Ordonez Brayan E. , Perez Gabriel A. , Cuartas-Lopez Alexandra Milena 
Published: October 2024

Withdrawal StatementThe authors have withdrawn their manuscript because Several authors have expressed strong opposition to publishing in preprint, as they believe there are still important details, key experiments, and additional tests needed to complete the research. The authors argue that the study is not yet ready for publication as the investigation is still ongoing. Furthermore, some authors state that they did not grant their approval for preprint publication and therefore do not authorize its release at this stage. For these reasons, we kindly ask that our requests be respected. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.Thank you very much for your understanding and cooperation.
Human tonsil organoids reveal innate pathways modulating humoral and cellular responses to ChAdOx1
Authors: Pudjohartono Maria Fransiska , Powell Kate , Barnes Eleanor , Klenerman Paul , Provine Nicholas M 
Published: October 2024

ABSTRACTThe COVID-19 pandemic response demonstrated the effectiveness of adenovirus vector vaccines in inducing protective cellular and antibody responses. However, we still lack mechanistic understanding of the factors regulating immunity induced by this platform, especially innate pathways. We utilized a human tonsil organoid model to study the regulation of adaptive responses to ChAdOx1 nCoV-19.Innate activation and cytokine release occurred within 24 hours and T and B cell activation and antigen-specific antibody secretion occurred during the ensuing 14-day culture. Among the immune cell populations, plasmacytoid dendritic cells (pDCs) exhibited the highest ChAdOx1 transduction levels. pDC-derived IFN-α was critical for humoral responses, but production of antigen in pDCs was dispensable. Furthermore, IL-6 enhanced humoral responses in both IFN-α-dependent and independent manners, indicating intricate signaling interplay. IFN-α and IL-6 also regulated the function of vaccine-activated CD4+T cells, including TFH. These data provide key insights into innate pathways regulating ChAdOx1-induced immunity and highlights the promise of this model for vaccine platform mechanistic studies.SUMMARYDespite the success of adenovirus vector vaccines, we still lack understanding of the mechanisms regulating immunity induced by this platform. This study utilized human tonsil organoids to provide key insights into innate pathways regulating ChAdOx1-induced humoral and cellular immunity.
Using known births to account for delayed marking in population estimation of North Atlantic right whales
Authors: Linden Daniel W. 
Published: October 2024

AbstractPopulation estimation using capture-recapture modeling typically requires that individuals are identifiable by unique marks. North Atlantic right whales (Eubalaena glacialis) can be identified by natural callosity patterns on their heads that are established nearly a year after birth, which has facilitated population monitoring using extensive aerial surveys. A well-maintained catalog of individual sightings has been used to annually estimate population size with a Jolly-Seber (J-S) model using a Bayesian state-space framework. Given that young animals cannot enter the catalog before an established callosity pattern, the terminal year population estimate never includes new calves despite breeding area surveys that provide a nearly complete census of births. Here, I illustrate a simple modification to the J-S likelihood whereby the number of expected entrants is a function of known births and a parameter representing initial offspring mortality. A simulation study was used as a proof of concept and indicated increased accuracy and precision of population estimates. The birth-integrated J-S model had more accurate terminal-year estimates of right whale population size that remained consistent during subsequent model fitting to additional years of sightings data. While the bias corrections were fairly small (5%) given low per capita calving rates, the demonstrated improvement in accuracy will be helpful to the conservation and management processes for this endangered species. Integrated modeling approaches make better use of available data and can improve inferences on population dynamics.
The ambiguity of “hybrid swarm”: inconsistent definitions and applications in existing research
Authors: Campbell Jillian N. , Mandeville Elizabeth G. , Lewis Nathan C. , Meuser Amanda V. 
Published: October 2024

1AbstractHybridization is common in wild taxa and often increases in frequency following anthropogenic disturbance to an environment. Next-generation sequencing techniques make genomic analysis of a large number of individuals feasible, vastly improving the analysis for and promoting a greater frequency of studies on hybridization. However, terminology surrounding hybridization can be inconsistent; in particular, the term “hybrid swarm” has been used extensively in the literature but lacks a consistent definition. In this paper, we conducted a comprehensive review of the literature that uses the term “hybrid swarm” in reference to hybridization between taxa and challenged putative definitions of the term. We found that the term “hybrid swarm” is used in a variety of contexts, including some contradictory to other literature, and that there is little consensus on what constitutes a hybrid swarm in terms of hybrid outcomes, frequency relative to disturbances, or duration of existence. We dissuade researchers from use of the term “hybrid swarm” and instead suggest more specific and clear terminology to describe aspects of hybridization. Consequently, we hope that this paper promotes consensus surrounding hybridization terminology and improves the quality of future research on hybridization.
The Curated Cancer Cell Atlas: comprehensive characterisation of tumours at single-cell resolution
Authors: Tyler Michael , Gavish Avishai , Barbolin Chaya , Tschernichovsky Roi , Hoefflin Rouven , Mints Michael , Puram Sidharth V. , Tirosh Itay 
Published: October 2024

AbstractSingle-cell RNA-seq (scRNA-seq) has transformed the study of cancer biology. Recent years have seen a rapid expansion in the number of single-cell cancer studies, yet most of these studies profiled few tumours, such that individual datasets have limited statistical power. Combining the data and results across studies holds great promise but also involves various challenges. We recently began to address these challenges by curating a large collection of cancer scRNA-seq datasets, and leveraging it for systematic analyses of tumor heterogeneity. Here we significantly extend this repository to 124 datasets for over 40 cancer types, together comprising 2,822 samples, with improved data annotations, visualisations and exploration. Utilising this vast cohort, we systematically quantified context-dependent gene expression and proliferation patterns across cell types and cancer types. These data, annotations and analysis results are all freely available for exploration and download via the Curated Cancer Cell Atlas (3CA) website (https://www.weizmann.ac.il/sites/3CA/), a central source of data and analyses for the cancer research community that opens new avenues in cancer research.
Cefepime-Taniborbactam and Ceftibuten-Ledaborbactam Maintain Activity Against KPC Variants that Lead to Ceftazidime-Avibactam Resistance
Authors: Myers Cullen L. , Stevenson Annie , Miller Brittany , Daigle Denis M. , Uehara Tsuyoshi , Pevear Daniel C. 
Published: October 2024

AbstractKlebsiella pneumoniaecarbapenemases (KPCs) are widespread β-lactamases that are a major cause of clinical non-susceptibility of Gram-negative bacteria to carbapenems and other β-lactam antibiotics. Ceftazidime combined with the β-lactamase inhibitor avibactam (CAZ-AVI) has been effective for treating infections by KPC-producing bacteria, but emergent KPC variants confer resistance to the combination. Taniborbactam and ledaborbactam are bicyclic boronate β-lactamase inhibitors under development with cefepime and ceftibuten, respectively, to treat carbapenem-resistant bacterial infections. Here, we assessed the effects of clinically important KPC-2 and KPC-3 variants (V240G, D179Y, D179Y T243M) on the antibacterial activity of cefepime-taniborbactam (FEP-TAN) and ceftibuten-ledaborbactam (CTB-LED) and examined catalytic activity and inhibition of these variants. FEP-TAN and CTB-LED were highly active against CAZ-AVI-resistant engineeredE. colistrains expressing these variants. Purified KPC variants catalyzed more efficient CAZ hydrolysis than wild-type enzymes, and D179Y-containing KPC-3 variants additionally catalyzed more efficient FEP hydrolysis than wild-type KPC-3. All KPC variants poorly hydrolyzed CTB, and D179Y-containing variants demonstrated significantly higher affinity for CAZ than FEP or CTB. Second-order rate constants (k2/K) for inhibition of D179Y-containing KPC-2 variants were significantly reduced relative to wild-type KPC-2, with AVI most impacted.K2/Kwas less affected for D179Y-containing KPC-3 variants, and reflected robust inhibition by TAN, LED and AVI. Together, the findings illustrate a biochemical basis for greater FEP-TAN and CTB-LED antibacterial activity in KPC variant expression backgrounds relative to CAZ-AVI, whereby the boronate inhibitors have sufficient inhibitory activity, whilst FEP and CTB are poorer substrates and bind to the variant enzymes with reduced affinity compared to CAZ.
Intranasal delivery of a broadly neutralizing single domain antibody targeting ACE2 protects against SARS-CoV-2 infection
Authors: Blachier Simon , Fernández Ignacio , Conquet Laurine , Giraud Emilie , Staropoli Isabelle , Michel Vincent , Szilagyi Fruzsina , Guez Salomé , Boucharlat Alix , Chiaravalli Jeanne , Tran-Rajau Jaouen , Dufour Evelyne , Petres Stéphane , Planas Delphine , Montagutelli Xavier , Agou Fabrice , Rey Felix , Lafaye Pierre , Enninga Jost , Ayme Gabriel , Schwartz Olivier , Brelot Anne 
Published: October 2024

AbstractSARS-CoV-2 accumulates mutations over time leading to the emergence of variants, which become largely resistant to existing vaccines and spike protein-targeted antiviral treatment. Therefore, there is a need for other therapies with broad efficiency. Here, we targeted the angiotensin-converting enzyme 2 (ACE2), the major entry receptor for SARS-CoV-2. We purified three single domain heavy chain antibodies (VHHs) after immunization of an alpaca with the ectodomain of ACE2. These VHHs bound ACE2 with nanomolar affinity and specifically detected membrane-anchored ACE2. Two of them (B07 and B09) neutralized by a competitive mechanism multiple SARS-CoV-2 isolates, including Omicron variants (XBB.1.16.1; EG.5.1.3; BA.2.86.1), without impacting the proteolytic activity of the enzyme. Fusion of B07 with conventional Fc domain markedly improved its binding and neutralizing efficacy. This dimeric Fc-conjugated B07 (B07-Fc) recognized specific residues of the N-terminal helix 1 of ACE2. When administrated prophylactically and intranasally, B07-Fc induced a strong dose-dependent protection of mice expressing human ACE2 (K18-hACE2) from SARS-CoV-2 Omicron. Hamsters were weakly protected due to low binding of B07-Fc to hamster ACE2. These single domain antibodies targeting hACE2 represent potential broad-spectrum therapeutic candidates against any emerging viruses using ACE2 as a receptor. These inhalable neutralizing single domain antibodies also represent a non-invasive approach against respiratory viral infection.
Public RNA-seq data are not representative of global human diversity
Authors: Romero Irene Gallego , Rodenberg Grace , Arner Audrey M. , Li Lani , Beasley Isobel J. , Rossow Ryan , Ryan Nicholas , Wang Selina , Lea Amanda J. 
Published: October 2024

AbstractThe field of human genetics has reached a consensus that it is important to work with diverse and globally representative participant groups. This diverse sampling is required to build a robust understanding of the genomic basis of complex traits and diseases as well as human evolution, and to ensure that all people benefit from downstream scientific discoveries. While previous work has characterized compositional biases and disparities for public genome-wide association (GWAS), microbiome, and epigenomic studies, we currently lack a comprehensive understanding of the degree of bias for transcriptomic studies. To address this gap, we analyzed the metadata for RNA-seq studies from two public databases—the Sequence Read Archive (SRA), representing 795,071 samples from 21,209 studies, and the Database of Genotypes and Phenotypes (dbGaP), representing 167,389 samples from 649 studies. We also randomly selected 620 studies from SRA for detailed, manual evaluation. We found that 3% of samples in SRA and 21% of individuals described in the literature had population descriptors (race, ethnicity, or ancestry); 28% of samples in dbGaP had paired genotype data that was used to empirically infer ancestry. In SRA, dbGaP, and the literature, race, ethnicity, and ancestry terms were frequently conflated and difficult to disambiguate. After standardizing population descriptors, we observed many clear biases: for example, among samples in SRA that were coded using US Census terms, 69.0% came from white donors, corresponding to an 1.2x overrepresentation of this group relative to the US population. Among samples in SRA coded using continental ancestry labels, 55.6% came from European ancestry donors—an 4.1x overrepresentation of this group relative to the global population. These biases were generally similar across datasets (SRA, dbGaP, literature review), and were comparable to previous reports for other ‘omics data types. However, we note that, relative to other ‘omics data subsets like GWAS, there is considerably less information, of arguably worse quality, about who is participating in RNA-seq studies. Together, these results demonstrate a critical need to improve our thoughtfulness, consistency, and effort around reporting population descriptors in RNA-seq studies, and to more generally strive for greater diversity in this important data type.
Tone at the top, corporate irresponsibility and the Enron emails
Authors: Taylor-Neu Kieran , Rahaman Abu S. , Saxton Gregory D. , Neu Dean 
Published: October 2024

PurposeThis study aims to examine whether senior Enron executive emails celebrated, or at least left a space for, corporate irresponsibility. Engaging with prior organizational-focused research, we investigate how corporate emails sent by senior executives help constitute Enron by communicating to employees senior management’s stance about important topics and social characters.Design/methodology/approachThe study analyzes the 527,356 sentences contained in 144,228 emails sent by Enron senior executives and other employees in the three-year period (1999–2001) before the company’s collapse. Sentences are used as the base-level speech unit because we are interested in identifying the tone and emotions expressed about specific topics and stakeholders. Tone is measured using Loughran and McDonald’s (2016) financial dictionary approach, and emotion is measured using Mohammad and Turney’s (2013) NRC word-emotion lexicon. Least Absolute Shrinkage and Selection Operator (LASSO) regressions are used to explore the determinants of senior management tone and emotions.FindingsThe analysis illustrates that while both senior executives and other employees utilized email to help accomplish task-related activities, they employed different evaluative tones to talk about key topics and stakeholders. Also important is what is left unsaid, with a “spiral of silence” emanating from senior management that created a space for corporate irresponsibility.Originality/valueCombining advanced computerized textual analysis with qualitative techniques, we analyze a unique dataset to explore micro details involved in using email to communicate a tone at the top. The findings illustrate how what is said or not said by senior management contributes to the constitution of an organization.