bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison candidate Tick-borne encephalitis virus vaccines based on mRNA, adenovirus serotype 25 and chimera of YFV vaccine strain
Authors: Kuznetsova Nadezhda A. , Gushchin Vladimir A. , Marchuk Elizaveta V. , Siniavin Andrei E. , Kleymenov Denis A. , Nikiforova Maria , Zubkova Olga V. , Popova Olga , Vavilova Irina V. , Ozharovskaia Tatiana A. , Mazunina Elena P. , Bykonia Evgeniia N. , Bogdanov Egor Y. , Zolotar Anastasia N. , Shidlovskaya Elena V. , Usachev Evgeny V. , Usacheva Olga V. , Shatalov Alexey G. , Zlobin Vladimir I. , Logunov Denis Y. , Gintsburg Alexander L.
Published: January 2025

Background

Despite the availability of several licensed inactivated vaccines, the development of new vaccines against the Tick-borne encephalitis virus (TBEV) remains an important task, especially in countries endemic to this pathogen. The risk of infection with TBEV increases every year because of increase in the number of ticks, the emergence of tick carriers into new territories, and active human activity in areas of TBEV natural foci. Annual reports of vaccination failures have prompted us to search for approaches to creating a new vaccine.

Objectives

In our study, we used the same PrM and E antigens to produce three vaccine candidates against tick-borne encephalitis (TBE): 1) a live attenuated YFV 17DD-UN vaccine strain, 2) recombinant adenovirus (rAd) vectors, and 3) mRNA encapsulated in lipid nanoparticles (LNP).

Methods

We generated and assessed the immunogenicity and protective efficacy of three candidate TBEV vaccines based on mRNA, simian adenovirus type 25, and a chimera of the YFV 17DD-UN attenuated strain.

Results

Analysis of the virus-neutralizing titers in the blood sera of immunized mice revealed a statistically significant difference among the three candidate vaccines. The immunogenicity and protective efficacy of the candidate mRNA-LNP vaccine were found to be higher than those of the other two vaccines.

Conclusions

Based on the results of our study, it can be concluded that the mRNA-based platform is more promising for the creation of a vaccine against TBEV.
ADAR1 Regulates Lipid Remodeling through MDM2 to Dictate Ferroptosis Sensitivity
Authors: Kung Che-Pei , Terzich Nick D. , Ilagen Ma Xenia G. , Prinsen Michael J. , Kaushal Madhurima , Kladney Raleigh D. , Weber Jade H. , Mabry Alex R. , Torres Luisangely Soto , Bramel Emily R. , Freeman Eric C. , Sabloak Thwisha , Cottrell Kyle A. , Ryu Sua , Weber William M. , Maggi Leonard , Shriver Leah P. , Patti Gary J. , Weber Jason D.
Published: January 2025

Triple-negative breast cancer (TNBC), lacking expression of estrogen, progesterone, and HER2 receptors, is aggressive and lacks targeted treatment options. An RNA editing enzyme, adenosine deaminase acting on RNA 1 (ADAR1), has been shown to play important roles in TNBC tumorigenesis. We posit that ADAR1 functions as a homeostatic factor protecting TNBC from internal and external pressure, including metabolic stress. We tested the hypothesis that the iron- dependent cell death pathway, ferroptosis, is a ADAR1-protected metabolic vulnerability in TNBC by showing that ADAR1 knockdown sensitizes TNBC cells to GPX4 inhibitors. By performing single-reaction monitoring-based liquid chromatography coupled to mass spectrometry (LC-MS) to measure intracellular lipid contents, we showed that ADAR1 loss increased the abundance of polyunsaturated fatty acid phospholipids (PUFA-PL), of which peroxidation is the primary driver of ferroptosis. Transcriptomic analyses led to the discovery of the proto-oncogene MDM2 contributing to the lipid remodeling in TNBC upon ADAR1 loss. A phenotypic drug screen using a ferroptosis-focused library was performed to identify FDA- approved cobimetinib as a drug-repurposing candidate to synergize with ADAR1 loss to suppress TNBC tumorigenesis. By demonstrating that ADAR1 regulates the metabolic fitness of TNBC through desensitizing ferroptosis, we aim to leverage this metabolic vulnerability to inform basic, pre-clinical, and clinical studies to develop novel therapeutic strategies for TNBC.
Solution conformational differences between conventional and CENP-A nucleosomes are accentuated by reversible deformation under high pressure
Authors: Gupta Kushol , Sekulić Nikolina , Allu Praveen Kumar , Sapp Nicklas , Huang Qingqiu , Sarachan Kathryn , Christensen Mikkel , Lund Reidar , Krueger Susan , Curtis Joseph E. , Gillilan Richard E. , Van Duyne Gregory D. , Black Ben E.
Published: January 2025

Solution-based interrogation of the physical nature of nucleosomes has its roots in X-ray and neutron scattering experiments, including those that provided the initial observation that DNA wraps around core histones. In this study, we performed a comprehensive small-angle scattering study to compare canonical nucleosomes with variant centromeric nucleosomes harboring the histone variant, CENP-A. We used nucleosome core particles (NCPs) assembled on an artificial positioning sequence (Widom 601) and compared these to those assembled on a natural α-satellite DNA cloned from human centromeres. We establish the native solution properties of octameric H3 and CENP-A NCPs using analytical ultracentrifugation (AUC), small-angle X-ray scattering (SAXS), and contrast variation small-angle neutron scattering (CV-SANS). Using high-pressure SAXS (HP-SAXS), we discovered that both histone identity and DNA sequence have an impact on the stability of octameric nucleosomes in solution under high pressure (300 MPa), with evidence of reversible unwrapping in these experimental conditions. Both canonical nucleosomes harboring conventional histone H3 and their centromeric counterparts harboring CENP-A have a substantial increase in their radius of gyration, but this increase is much less prominent for centromeric nucleosomes. More broadly for chromosome-related research, we note that as HP-SAXS methodologies expand in their utility, we anticipate this will provide a powerful solution-based approach to study nucleosomes and higher-order chromatin complexes.
Identification of a divergent botulinum neurotoxin like gene cluster inFurfurilactobacillus
Authors: Wei Xin , Lee Pyung-Gang , Dong Min , Doxey Andrew C.
Published: January 2025

Botulinum neurotoxins (BoNTs) are among the most potent biological toxins and are traditionally associated withClostridiumspecies. However, recent discoveries have identified BoNT-like proteins in diverse bacterial genera, revealing an expanding family of neurotoxins with unique evolutionary and functional traits. In this study, we report the identification of a novel BoNT-like gene cluster inFurfurilactobacillussp. OKN36, encoding a toxin we tentatively designate as “Furfuritoxin”. Sequence and structural analyses indicate that Furfuritoxin shares key domains with clostridial neurotoxins, including a light chain zinc metalloprotease domain and heavy chain translocase and binding domains, while exhibiting significant sequence divergence. Phylogenetic analysis places Furfuritoxin within a divergent lineage alongside previously reported BoNT/Wo, suggesting a shared ancestral relationship. Gene neighborhood analysis reveals features shared with other BoNT gene clusters including ORFX-related genes and conjugation-associated elements, indicating horizontal gene transfer may have facilitated its distribution. This study adds to the growing family of BoNT-like toxins, providing insights into their evolution and diversity.
Monitoring fungicide resistance frequencies – a case study of barley net blotch
Authors: Knight N. L. , Adhikari K. C. , Mair W. J. , Dodhia K. , Zulak K. G. , Lopez-Ruiz F. J.
Published: January 2025

Decreased sensitivity to fungicides impacts the effectiveness of fungicide applications for managing plant disease. Knowledge of the frequency of decreased sensitivity in field populations is critical for evaluating risks for disease control. This study has applied a droplet digital PCR detection approach to assess pathogen populations and quantify the frequencies of alleles associated with decreased sensitivity to either demethylation inhibitor or succinate dehydrogenase inhibitor fungicides inPyrenophora terescausing net blotch on barley in Western Australia.Pyrenophora teresf.maculatawas the most frequent form of the pathogen in the sampled region. Frequencies of decreased fungicide sensitivity alleles varied, being as great as 92% for the PtTi insertion in the CYP51A promoter, 88% for C-S75 and 28% for L489-2. Impacts of cultivar selection and weed hosts on the presence and survival of decreased fungicide sensitivity were observed. Determining the dynamics of alleles within different field populations ofP. teresprovides an important perspective on the impact of fungicides, the fitness associated with decreased fungicide sensitivity alleles and the susceptibility of barley cultivars.
Assessing Generative Diffusion Models for Enhanced Sampling of Folded and Disordered Protein States Across Scales and in All-atom Resolution
Authors: Bera Palash , Mondal Jagannath
Published: January 2025

Molecular dynamics (MD) simulations are indispensable for studying the dynamic behavior of biomolecules, yet they are often constrained by timescale challenges that limit sampling efficiency. Generative machine learning (ML) models have recently emerged as promising tools to address these limitations. In this study, we revisit the potential of the Denoising Diffusion Probabilistic Model (DDPM) as an approach for enhancing the sampling and for generation of atomistically accurate conformational ensembles of biomolecules of diverse size, ranging from small folded proteins to large intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs). By training DDPM independently on MD simulation data of torsion angle and all-atom coordinates, we demonstrate their ability to effectively explore conformational space, including sparsely sampled regions, and to generate novel conformations. The performance of DDPM is evaluated on a diverse set of systems, including the Trp-cage mini-protein, the folded protein BPTI, the IDPα-Synuclein, and the IDR Ash1. Our results reveal that DDPM-generated ensembles accurately reproduce key structural features such as secondary structure, radius of gyration, and contact maps, while also capturing the inherent conformational heterogeneity of IDPs. These findings highlight the potential of DDPM to enhance the efficiency and accuracy of biomolecular simulations, offering a scalable framework for gaining deeper insights into protein structure and dynamics.
Recovering ecological interactions by mining non-target data from whole genome re-sequencing projects
Authors: Jones Mirkka , Rastas Pasi , Chacón-Duque J. Camilo , DiLeo Michelle F. , Nair Abhilash , Oostra Vicencio , Saastamoinen Marjo , Duplouy Anne
Published: January 2025

The study of parasitic species can shed light on aspects of their host’s ecology. Such interactions are however often unknown or understudied due to the difficulty to detect and/or quantify many infections. Whole-genome sequencing and re-sequencing data have been generated at an increasing rate and reduced costs over the last two decades. Projects based on whole organisms, like whole insect specimens, provide genomic material for the target taxon, but may also include sequencing reads from associated microbes and other parasites. Here, we screened for the presence of non-host reads in a collection of whole-genome (re-) sequence projects from the Glanville fritillary butterfly,Melitaea cinxia,a model organism in research on the ecology and evolution of species in spatially structured and fragmented landscapes. We identified infections with different bacteria and eukaryotic parasites, which are shared between populations and underly both previously known and new biotic interactions for this butterfly species. The bacterial symbiontWolbachia, usually common in insects, was found at relatively low prevalence, whileSpiroplasmawas ubiquitous across samples from several European populations of the butterfly. Additionally, we confirmed expected rates of larval parasitism by at least two parasitoid wasps. Such results provide proof of principle that key ecological interactions can be uncovered efficiently from existing data, an important first step to characterising the role host-associated organisms play in shaping the ecology and evolutionary history of their host species.
Quantification of spliced and unspliced transcripts by velocyto is inaccurate for 5’-sequencing data
Authors: Klingler Doreen , Schleicher Jan T. , Claassen Manfred
Published: January 2025

RNA velocity allows for the prediction of future states of individual cells based on their current transcriptional activity. The technique depends on the separate quantification of spliced and unspliced transcripts in single-cell RNA-sequencing data, first introduced by velocyto in 2018. Since its introduction, significant advances have been made in the field, including new protocols by 10x Genomics that enable sequencing from the 5’-end of mRNA molecules instead of the 3’-end. Despite these advances, velocyto has not been updated since its release but is still commonly used with these new protocols. In this study, we demonstrate that velocyto cannot accurately detect the reversed direction of transcripts, leading to incorrect count assignments. By comparing velocyto to alevin-fry, a quantification method compatible with 5’-sequencing data, we show that this limitation can result in substantial deviations in inferred velocities and differing interpretations. Therefore, we do not recommend the use of velocyto with 5’-sequencing data.
Shifting ecological niches ofPrunusspecies under climate change
Authors: Vanalli Chiara , Gatto Marino , Casagrandi Renato , Bevacqua Daniele
Published: January 2025

Climate change is strongly impacting agriculture, reducing crop production and shifting the geographic distribution of suitable areas for crop cultivation. To safeguard future global yield and feed a growing world population, the migration of crop production areas to new suitable sites represents a way to adapt to a changing climate. Here, we aim to identify the ecological niche ofPrunusspecies, namely peach, plum, almond, apricot and sweet cherry, and examine their expected future shifts under climate change. For eachPrunusspecies, we selected from the literature processed-based phenological models for dormancy break, blooming and fruit ripening, whose fulfillment determines whether an area is suitable for crop cultivation. Historically, the ecological niche ofPrunusspecies spans mid-low European latitudes, while higher latitudes fail satisfying the forcing requirements for blooming and fruit ripening. In future, this constraint is expected to become less restrictive with a northwards expansion of the suitable areas. However, this will be contrasted by a contraction of the niche at low latitudes due to dormancy break failures. While bridging established mechanistic knowledge on the climatic effects of plant phenological traits with citizen science observations, our work brings new insights into how fruit crops will respond to global warming.
Multiscale Rugosity Assessment of Coral Reefs Using Underwater Photogrammetry
Authors: Barrera Falcon Erick , Rioja-Nieto Rodolfo , Hernández Landa Roberto Carlos
Published: January 2025

Understanding the structural complexity of coral reefs is essential for assessing their condition, biodiversity, and resilience. Traditional methods commonly use a rugosity index, based on the chain method, that overlooks the underlaying structure of coral reefs. However, digital underwater photogrammetry allows to build models of coral structures which can then be used to decompose reef topography across multiple layers. This study introduces a wavelet-based method for the multiscale analysis of reef rugosity, considering reef’s surface and underlying characteristics. Data were collected from six reefs within the Cozumel Reefs National Marine Park (CRNP) at depths ranging from 6 to 14 m. High-resolution Digital Elevation Models (DEMs) and orthomosaics were constructed using digital underwater photogrammetry (UWP). The elevation profiles extracted from the DEMs were analyzed using a Maximum Overlap Discrete Wavelet Transform (MODWT), with a Daubechies mother wavelet to decompose the reef topography into local rugosity (related to live coral coverage) and underlying rugosity (related to the historical context of the formation of the reef matrix). The wavelet-based method effectively decomposed the DEMs into components representing rugosity at different scales, with the reconstructed DEMs being statistically equivalent to the data source (p> 0.05). Underlying reef characteristics contributed the most to the rugosity estimates. Significant differences in rugosity were observed between reefs (p< 0.05), where interpretations differed based on the contribution of surface and underlying characteristics. For the CRNP, Agariciid and branching corals are the primary drivers of surface rugosity (p<0.05), rather than the mound & boulder, and meandroid corals. Our results highlight that traditional methods to estimate rugosity can underestimate the importance of local rugosity in maintaining rugosity over time.
Harnessing landscape genomics to evaluate genomic vulnerability and future climate resilience in an East Asia perennial
Authors: Feng Li , Wang Cong-Ying , Zhou Li-Pan , Wang Yi-Han , Wang Jing , Wang Zheng-Yuan , Zhou Tao , Wang Xu-Mei
Published: January 2025

In this era of rapid climate change, understanding the adaptive potential of organisms is imperative for buffering biodiversity loss. Genomic forecasting provides invaluable insights into population vulnerability and adaptive potential under diverse climatic conditions, thereby facilitating management interventions, bolstering population resilience, and shaping germplasm conservation strategies tailored to specific species. Here we integrated population genomics and landscape genomics approaches, leveraging single-nucleotide polymorphisms obtained through whole-genome resequencing of 43 Rheum palmatum complex populations, to pinpoint adaptive variation and its significance in the context of future climates, delineate seed zones, and establish guidelines for ex situ germplasm conservation to capture the majority of existing adaptive diversity. Our analysis unveiled that the species complex comprised two distinct genetic clusters, exhibiting differential climate adaptation and genomic vulnerabilities across its distribution range. We also determined that the species range could be subdivided into three distinct seed zones, with varying sample requirements per seed zone corresponding to differed conservation efforts. Overall, our findings provide a genome-wide perspective on climate adaptation and valuable insights into germplasm conservation strategies aimed at enhancing population resilience in future climates, serving as a blueprint for restoration plans of other vulnerable species.
Longitudinal Trajectories of Cognition and Neural Metrics as Predictors of Persistent Distressing Psychotic-Like Experiences Across Middle Childhood and Early Adolescence
Authors: Karcher Nicole R. , Dong Fanghong , Johnson Emma C. , Paul Sarah E. , Kilciksiz Can Misel , Oh Hans , Schiffman Jason , Agrawal Arpana , Bogdan Ryan , Jackson Joshua J. , Barch Deanna M.
Published: January 2025

Objectives

Psychotic-like experiences (PLEs) may arise from genetic and environmental risk leading to worsening cognitive and neural metrics over time, which in turn lead to worsening PLEs. Persistence and distress are factors that distinguish more clinically significant PLEs. Analyses used three waves of unique longitudinal Adolescent Brain Cognitive Development Study data (ages 9-13) to test whether changes in cognition and structural neural metrics attenuate associations between genetic and environmental risk with persistent distressing PLEs.

Methods

Multigroup univariate latent growth models examined three waves of cognitive metrics and global structural neural metrics separately for three PLE groups: persistent distressing PLEs (n=356), transient distressing PLEs (n=408), and low-level PLEs (n=7901). Models then examined whether changes in cognitive and structural neural metrics over time attenuated associations between genetic liability (i.e., schizophrenia polygenic risk scores/family history) or environmental risk scores (e.g., poverty) and PLE groups.

Results

Persistent distressing PLEs showed greater decreases (i.e., more negative slopes) of cognition and neural metrics over time compared to those in low-level PLE groups. Associations between environmental risk and persistent distressing PLEs were attenuated when accounting for lowered scores over time on cognitive (e.g., picture vocabulary) and to a lesser extent neural (e.g., cortical thickness, volume) metrics.

Conclusions

Analyses provide novel evidence for extant theories that worsening cognition and global structural metrics may partially account for associations between environmental risk with persistent distressing PLEs.
The evolutionary dynamics of organellar pan-genomes in Arabidopsis thaliana
Authors: Zou Yi , Zhu Weidong , Hou Yingke , Sloan Dan B , Wu Zhiqiang
Published: January 2025

In plants, comparative analyses of organellar genomes often depend on draft assemblies, with large-scale investigations into the complex structural rearrangements of mitochondrial genomes remaining scarce. Here, we conducted a comprehensive analysis of the dominant conformations and dynamic heteroplasmic variants of organellar genomes in the model plant Arabidopsis thaliana, utilizing high-quality long-read assemblies validated at read-level resolution from 149 samples. We found that mitochondrial and plastid genomes share common types of structural and small-scale variants driven by similar DNA sequence features. However, rearrangements mediated by repetitive sequences in mitochondrial genomes evolved so rapidly that they often became decoupled from other types of variants. Rare complex events involving elongation and fusion were also observed, contributing to the unalignable regions commonly found at the interspecies level. Additionally, we demonstrated that disrupting and rescuing organellar DNA maintenance could drive the rapid evolution of dominant mitochondrial genome conformations. Our study provides an unprecedentedly detailed view of the dynamics of organellar genomes at pan-genome scale in A. thaliana, paving the way to unlock the full potential of organellar genetic resources.
The Mathematics of Serocatalytic Models with applications to public health data
Authors: Kamau Everlyn , Chen Junjie , Bajaj Sumali , Torres Nicolás , Creswell Richard , Pavlich-Mariscal Jaime A. , Donnelly Christl , Cucunubá Zulma , Lambert Ben
Published: January 2025

Serocatalytic models are powerful tools which can be used to infer historical infection patterns from age-structured serological surveys. These surveys are especially useful when disease surveillance is limited and have an important role to play in providing a ground truth gauge of infection burden. In this tutorial, we consider a wide range of serocatalytic models to generate epidemiological insights. With mathematical analysis, we explore the properties and intuition behind these models and include applications to real data for a range of pathogens and epidemiological scenarios. We also include practical steps and code in R and Stan for interested learners to build experience with this modelling framework. Our work highlights the usefulness of serocatalytic models and shows that accounting for the epidemiological context is crucial when using these models to understand infectious disease epidemiology.
Representation of conceptual affordances in eye movements and the entorhinal cortex
Authors: Eperon Alexander , Doeller Christian F. , Theves Stephanie , Bottini Roberto
Published: January 2025

Structural representations in the entorhinal cortex are a crucial feature of cognitive maps. However, a complete understanding of task structure often requires knowledge of the actions available at each state (analogous to the moves of different pieces on a chessboard). Moreover, action representations are key to several models of the hippocampal-entorhinal system. In this study, we tested whether the entorhinal cortex represents the actions that allow transitioning between states of a conceptual space. In particular, participants learned to transition between numerically-labelled states using different mathematical operations. Behaviourally, participants learned and generalised action information across states. Action information was also reflected in eye movements, indicating the active processing of the possible actions for a given state during the trials. Importantly, we found that neural pattern similarity in the right entorhinal cortex scaled with the similarity of action affordances across the states. This affordance representation was not explained by other properties of the task space such as link distance between the states or action magnitude. In sum, this study provides first evidence for the integration of action information into ocular and entorhinal representations of conceptual spaces, suggesting that these may not just store experiences, but provide information about how to explore knowledge.
Molecular sorting of nitrogenase catalytic cofactors
Authors: Salinero-Lanzarote Alvaro , Lian Josh , Namkoong Gil , Suess Daniel L. M. , Rubio Luis M. , Dean Dennis R. , Pérez-González Ana
Published: January 2025

The free-living diazotrophAzotobacter vinelandiiproduces three genetically distinct but functionally and mechanistically similar nitrogenase isozymes, designated as Mo-dependent, V-dependent, and Fe-only. They respectively harbor nearly identical catalytic cofactors that are distinguished by a heterometal site occupied by Mo (FeMo-cofactor), V (FeV-cofactor), or Fe (FeFe-cofactor). Completion of FeMo-cofactor and FeV-cofactor formation occurs on molecular scaffolds prior to delivery to their catalytic partners. In contrast, completion of FeFe-cofactor assembly occurs directly within its cognate catalytic partner. Because hybrid nitrogenase species that contain the incorrect cofactor type cannot reduce N2to support diazotrophic growth there must be a way to prevent misincorporation of an incorrect cofactor when different nitrogenase isozyme systems are produced at the same time. Here, we show that fidelity of the Fe-only nitrogenase is preserved by blocking the misincorporation of either FeMo-cofactor or FeV-cofactor during its maturation. This protection is accomplished by a two-domain protein, designated AnfO. It is shown that the N-terminal domain of AnfO binds to an immature form of the Fe-only nitrogenase and the C-terminal domain, tethered to the N-terminal domain by a flexible linker, has the capacity to capture FeMo- and FeV-cofactor. AnfO does not prevent the normal activation of Fe-only nitrogenase because completion of FeFe-cofactor assembly occurs within its catalytic partner and, therefore, is never available for capture by AnfO. These results support a post-translational mechanism involving the molecular sorting of structurally similar metallocofactors that involve both protein-protein interactions and metallocofactor binding while exploiting differential pathways for nitrogenase associated catalytic cofactor assembly.
USP1 acts as a chaperone for HSFA2 and plays a crucial role in thermopriming in Arabidopsis
Authors: Manickam Prabhu , Shekhawat Kirti , Fatima Anam , Alhoraibi Hanna M. , Abulfaraj Aala A. , Rayapuram Naganand , Hirt Heribert
Published: January 2025

Plants employ diverse strategies to cope with different types of heat stress. The response to short-term acute heat stress differs significantly from that to moderate heat stress followed by severe stress events. After experiencing moderate heat stress, plants exhibit a more robust response to subsequent severe stress, a phenomenon known as thermopriming or acquired thermotolerance. Thermopriming creates a memory by maintaining the heat stress (HS) memory-related genes in an alert state. In this work, we investigated the role of Arabidopsis Universal Stress Protein 1 (USP1) in plant heat stress responses. CRISPR-Cas9 generated knockoutusp1mutant lines showed no morphological changes during development and normal growth conditions. However,usp1mutant plants showed enhanced levels of apoplast hydrogen peroxide and superoxide reactive oxygen species accumulation upon heat stress. Transcriptome analyses revealed that genes related to protein folding, electron transport, and oxidative phosphorylation are strongly upregulated inusp1mutant plants. USP1 is essential for acquired thermotolerance, asusp1mutants are compromised in heat stress memory but show normal responses to acute heat stress similar tohsfa2mutants. Biochemical assays showed that USP1 functions as a molecular chaperone, protecting the transcription factor HSFA2 from heat-induced denaturation. Moreover,usp1mutant plants show decreased transcript levels of heat stress response genes and reduced H3K4me3 enrichment at memory gene loci. These data show that USP1 plays an important role as a chaperone of HSFA2 in mediating plant heat stress memory.
Small molecule-controlled gene expression: Design of drug-like high affinity small molecule modulators of a custom-made riboswitch
Authors: Hedwig Vera , Spöring Maike , Aspnes Gary , Gottschling Dirk , Klein Holger , Klugmann Matthias , Kreuz Sebastian , Ries Benjamin , Schnapp Gisela , Scharsich Sandra , Hartig Jörg S. , Hucke Oliver
Published: January 2025

Riboswitches are regulatory RNA structures that modulate gene expression in response to a small molecule. Until now, efforts to design ligand analogs were motivated by their potential antibiotic activity. However, riboswitches are ideally suited as tools for gene therapy, enabling precise control of gene ex-pression without the need of potentially immunogenic regulatory proteins. Developing synthetic RNA switches starting from natural riboswitches will require engineering both, the ligand and the RNA sequence in order to achieve full orthogonality i.e., sensitivity to the designed small molecule modulator, but not to the natural ligand. We present the structure-based design of a drug-like small molecule ligand of the thiamine pyrophosphate (TPP) aptamer, BI-5232. BI-5232 is structurally highly diverse from the natural ligand TPP but rivals its binding affinity (KD= 1.0 nM). Importantly, in our design the pyrophosphate of TPP was replaced by an uncharged heterocycle that interacts with the PP helix in an unprecedented way, as revealed by Molecular Dynamics simulations. Subsequently, we altered the aptamer sequence to drastically reduce its affinity to TPP while retaining binding properties for our designed ligand. Based on the developed orthogonal small molecule/RNA aptamer interaction we finally constructed orthogonal ribozyme-based ON- and OFF-switches of gene expression in human cell lines. Such systems are valuable additions to the synthetic toolbox for conditionally controlling gene expression with potential applications in next-generation gene therapies.
Guess Who? Identifying individuals from their brain natural frequency fingerprints
Authors: Arana Lydia , Herrera-Morueco Juan José , Santonja Javier , Capilla Almudena
Published: January 2025

Neural oscillations are critical for brain function and cognition. Thus, identifying the typical or natural oscillatory frequencies of the brain is an important first step for understanding its functional architecture. Recently, a data-driven algorithm has been developed for mapping the brain’s natural frequencies throughout the whole cortex, free of anatomical and frequency-band constraints. However, an important limitation of this methodology is that it yields robust results only at the group level. Here, we aimed to adapt this algorithm to improve the quality of the single-subject maps of natural frequencies obtained from magnetoencephalography (MEG) recordings. To achieve this goal, we incorporated two modifications to the original method: (1) increasing the number of individual power spectra to be assigned to each k-means cluster, and (2) smoothing across neighboring voxels. To assess the quality of the single-subject maps, we relied on the fingerprinting technique. Our results show a high degree of accuracy in individual identification, both within a single recording session and across separate sessions. Furthermore, we were able to identify individuals by their natural frequency fingerprints, even with a gap of over four years between sessions. This demonstrates the robustness of the single-subject mapping of natural frequencies and opens new opportunities for identification of pathological variations in intrinsic oscillatory activity in individual subjects.
Small molecule-mediated targeted protein degradation of voltage-gated sodium channels involved in pain
Authors: Chamessian Alexander , Payne Maria , Gordon Isabelle , Zhou Mingzhou , Gereau Robert
Published: January 2025

The voltage-gated sodium channels (VGSC) NaV1.8 and NaV1.7 (NaVs) have emerged as promising and high-value targets for the development of novel, non-addictive analgesics to combat the chronic pain epidemic. In recent years, many small molecule inhibitors against these channels have been developed. The recent successful clinical trial of VX-548, a NaV1.8-selective inhibitor, has spurred much interest in expanding the arsenal of subtype-selective voltage-gated sodium channel therapeutics. Toward that end, we sought to determine whether NaVs are amenable to targeted protein degradation with small molecule degraders, namely proteolysis-targeting chimeras (PROTACs) and molecular glues. Here, we report that degron-tagged NaVs are potently and rapidly degraded by small molecule degraders harnessing the E3 ubiquitin ligases cereblon (CRBN) and Von Hippel Lindau (VHL). Using LC/MS analysis, we demonstrate that PROTAC-mediated proximity between NaV1.8 and CRBN results in ubiquitination on the 2ndintracellular loop, pointing toward a potential mechanism of action and demonstrating the ability of CRBN to recognize a VGSC as a neosubstrate. Our foundational findings are an important first step toward realizing the immense potential of NaV-targeting degrader analgesics to combat chronic pain.
Derived motor neurons transplantation promotes nerve regeneration in a rodent model of a chronically denervated nerve through delayed adoption of a chronic denervation phenotype
Authors: Cashman Cashman R. , Mi Ruifa , Hoke Ahmet
Published: January 2025

After acute injury, the peripheral nervous system regenerates more efficiently than the central nervous system, but this advantage is not maintained with chronic injuries. In large animals like humans, the slow rate of axon growth and the long distance between the central nervous system and end organ result in the adoption of a chronically denervated nerve phenotype even in the setting of acute injury: distal areas of the nerve become unable to support regenerating axons, even as the proximal aspect of the acute injury may be appropriately supportive of regeneration. We hypothesized that motor neuron transplantation into the denervated distal stump would maintain the regenerative capacity by effectively reducing the time and distance necessary for regeneration through relay formation as well as by supporting the host Schwann cells responsible for guiding regenerating axons. Using anin vitroassays, we showed the feasibility of relay formation by demonstrating ventral horn to derived-motor neuron synaptogenesis as identified by calcium imaging. Pilot studies of transplantation of embryonic stem cell-derived mouse motor neurons into chronically denervated rat nerves demonstrated improved regenerative capacity in the chronically denervated nerve following a delayed repair paradigm. While host to graft synaptogenesis was not observed, the Schwann cells in the transplanted nerve stump were maintained in a pro-regenerative state despite chronic denervation. These pilot data suggest cell transplantation can delay the adoption of a chronically denervated phenotype primarily by maintaining Schwann cells in a pro-regenerative state.
Inhibition of the angiotensin-converting enzyme N-terminal catalytic domain prevents endogenous opioid degradation in brain tissue
Authors: Hanak Filip , Swanson Jessica L. , Felczak Krzysztof , Bernstein Kenneth E. , More Swati S. , Rothwell Patrick E.
Published: January 2025

Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin peptides in the periphery, and can also regulate endogenous opioid signaling by degrading enkephalin peptides in the brain. ACE has two catalytic domains, located in the N-terminal or C-terminal region of the protein, but little is known about the roles that these two catalytic domains play in regulating endogenous opioid degradation in brain tissue. Using acute brain slice preparations from mice of both sexes, we developed methods to study degradation of Met-enkephalin-Arg-Phe (MERF) by ACE, and investigated the role of each ACE catalytic domain in MERF degradation. Using mutant mouse lines with functional inactivation of either the N-terminal domain or the C-terminal domain, we incubated acute brain slices with exogenous MERF at a saturating concentration. The degradation MERF to produce Met-enkephalin was only reduced by N-terminal domain inactivation. Additionally, application of a selective N-terminal domain inhibitor (RXP 407) reduced degradation of both exogenously applied and endogenously released MERF, without affecting degradation of endogenously released Met-enkephalin or Leu-enkephalin. Taken together, our results suggest that the ACE N-terminal domain is the primary site of MERF degradation in brain tissue, and that N-terminal domain inhibition is sufficient to reduce degradation of this specific endogenous opioid peptide. Our results have exciting implications for the development of novel pharmacotherapies that target the endogenous opioid system to treat psychiatric and neurological disorders.
Artificial intelligence and machine learning in cell-free-DNA-based diagnostics
Authors: Tsui W.H. Adrian , Ding Spencer C. , Jiang Peiyong , Lo Y.M. Dennis
Published: January 2025

The discovery of circulating fetal and tumor cell-free DNA (cfDNA) molecules in plasma has opened up tremendous opportunities in noninvasive diagnostics such as the detection of fetal chromosomal aneuploidies and cancers and in posttransplantation monitoring. The advent of high-throughput sequencing technologies makes it possible to scrutinize the characteristics of cfDNA molecules, opening up the fields of cfDNA genetics, epigenetics, transcriptomics, and fragmentomics, providing a plethora of biomarkers. Machine learning (ML) and/or artificial intelligence (AI) technologies that are known for their ability to integrate high-dimensional features have recently been applied to the field of liquid biopsy. In this review, we highlight various AI and ML approaches in cfDNA-based diagnostics. We first introduce the biology of cell-free DNA and basic concepts of ML and AI technologies. We then discuss selected examples of ML- or AI-based applications in noninvasive prenatal testing and cancer liquid biopsy. These applications include the deduction of fetal DNA fraction, plasma DNA tissue mapping, and cancer detection and localization. Finally, we offer perspectives on the future direction of using ML and AI technologies to leverage cfDNA fragmentation patterns in terms of methylomic and transcriptional investigations.
The transformative role of artificial intelligence in leadership and management development: an academic insight
Authors: Vargas Portillo Patricia
Published: January 2025

Purpose

This study examines the transformative role of Artificial Intelligence in leadership and management development, investigating how AI technologies enhance decision-making processes, talent management, and strategic planning within organizations. The research explores the integration of AI into leadership development programs while maintaining essential human elements of leadership.

Design/methodology/approach

The study employs a theoretical framework analysis focusing on adaptive learning, predictive analytics, natural language processing, and cognitive computing in leadership development. It examines implementation cases from leading organizations and analyzes current applications through case studies of successful AI integration in leadership programs.

Findings

Organizations implementing AI-driven leadership development programs demonstrate significant improvements in management effectiveness and decision-making capabilities. The research reveals that successful integration requires balancing technological innovation with human-centered leadership principles, while addressing potential biases in AI systems through regular monitoring and audits.

Practical implications

The study provides implementation strategies for organizations to integrate AI in leadership development, emphasizing the importance of robust data governance frameworks, hybrid approaches combining AI analytics with traditional mentoring, and the need for structured decision-making frameworks that merge AI-driven insights with human judgment.

Social implications

The use of AI in leadership development has the potential to democratize access to learning opportunities, allowing leaders from diverse backgrounds to receive tailored training and insights. This could contribute to reducing inequalities in professional development opportunities, supporting UN Sustainable Development Goal (SDG) 10 on reducing inequalities. The use of AI in leadership development has the potential to democratize access to learning opportunities, allowing leaders from diverse backgrounds to receive tailored training and insights. This could contribute to reducing inequalities in professional development opportunities, supporting UN SDG 10 on reducing inequalities.

Originality/value

This research contributes to the emerging field of AI-augmented leadership by providing a comprehensive analysis of how organizations can effectively leverage AI technologies while maintaining authentic human connection in leadership development. It offers novel insights into the future direction of leadership development through immersive learning environments.
Impact of board gender diversity on anti-corruption disclosure: analysis in the context of the Sapin II law in France
Authors: Radhouani Roua , Ajina Aymen
Published: January 2025

Purpose

This paper aims to examine the influence of board gender diversity on corporate anti-corruption disclosure (ACD) and the role of the Sapin II Law.

Design/methodology/approach

The authors used panel data regressions on a sample of French listed firms from 2010–2020. Keywords-based content analysis is used to measure ACD. Additionally, the Difference-in-Differences (DID) model investigate whether the ACD levels with high and low female directors’ changes before and after the Sapin II Law.

Findings

There is a positive relationship between female directors and corporate ACD. This relation is particularly significant in firms who applies the Sapin II Law.

Research limitations/implications

The authors focus solely on larger French listed companies, which may not reflect small and medium-sized businesses. Due to data limitations, the authors could not include demographic factors like age, education and experience that could influence company behavior. Furthermore, self-reported data may not adequately reveal illicit practices within these companies.

Practical implications

The relationship between board gender diversity and corruption disclosure informs policymakers on reforms for female directors. The findings also aid investors and suggest that managers should view gender diversity as a governance tool to reduce corruption.

Originality/value

This paper is original in focusing on ACD and using a DID methodology to assess the impact of the Sapin II Law. It uniquely investigates threshold effects between board gender diversity and ACD and examines the French context, including the Copé-Zimmermann Law’s gender diversity mandate.
The human touch: investigating the importance of anthropomorphism in retaining episodic volunteers
Authors: Rostiani Rokhima , Indarti Nurul
Published: January 2025

Purpose

The objective of this study is to investigate how anthropomorphic perceptions of a film festival influence volunteers’ intention to continue volunteering. Specifically, it aims to understand the mediating roles of psychological proximity, psychological contract and commitment in shaping this relationship, with a focus on volunteers at film festivals in Indonesia.

Design/methodology/approach

The study employs a sequential explanatory mixed method by conducting an online survey towards volunteers and in-depth interview to selected informants. Data from 80 volunteers was analysed using partial least square structural equation modelling (PLS-SEM) to test the hypotheses. Further, in-depth interviews with 15 volunteers were also conducted and the data was analysed using content analysis to obtain deeper understanding of the phenomena.

Findings

This study found that identification provides a positive influence to volunteers’ intention to continue volunteering in a film festival. Identification is influenced by psychological proximity, which also proven to provide positive influence on psychological contract and commitment (identification and contribution). Further, this study also provides empirical evidence that psychological proximity is influenced by aspects of anthropomorphism namely moral virtue and conscious emotions.

Originality/value

This study is the first study to empirically test the anthropomorphism concept to uncover the continuance intention of film festival volunteers. Two mechanisms of anthropomorphism influence intention to continue volunteering: the indirect relationship from moral virtue to intention to continue volunteering and from conscious emotions to intention to continue volunteering.
Navigating turbulence: leadership evolution in crisis management through response–recovery frameworks
Authors: Bhat Zahid Hussain , Saba Nuzhat
Published: January 2025

Purpose

This study aims to explore the role of organisations and leaders in addressing crises, with a focus on the Coronavirus disease 2019 pandemic. It proposes a conceptual framework that integrates leadership competencies and crisis management, the response–recovery framework, explained through the five-stage cycle starting from crisis identification, crisis planning, crisis containment, crisis recovery, to redesigning crisis management.

Design/methodology/approach

This research relies on an extensive review of literature on leadership and crisis management. A structured bibliometric analysis was conducted using tools like VOSViewer and Scopus, supported by thematic synthesis, to identify key themes and trends.

Findings

This study establishes a response–recovery framework for crisis management. It identifies essential leadership roles and competencies required during various phases of crises, including crisis identification, planning, containment, recovery and redesigning management. It highlights the dynamic evolution of leadership roles and the significance of effective communication, organisational resilience and distributed leadership.

Practical implications

The proposed response–recovery framework provides actionable insights for practitioners to navigate crises effectively. It emphasises the importance of adaptable leadership styles, proactive crisis planning and fostering resilience, offering organisations a roadmap for handling future crises.

Originality/value

This study offers a unique integration of leadership and crisis management literature, presenting a novel framework aligned with the changing demands of crises. Its focus on leadership evolution across crisis stages provides valuable theoretical and practical contributions for scholars and practitioners.