bluuebunny/crossref_metadata_2025 huggingface dataset:
Interferon Dependent Immune Memory during HSV-1 Neuronal Latency Results in Increased H3K9me3 and Restriction of Reactivation by ATRX
Authors: Whitford Abigail L. , Auguste Gaelle , Francois Alison K. , Boutell Chris , Miller Clint , Dremel Sarah , Cliffe Anna. R
Published: January 2025

Herpes simplex virus-1 (HSV-1) establishes a lifelong latent infection in neurons and reactivation from this latent state is the cause of recurrent oral and ocular infections, herpes simplex keratitis, and encephalitis. Neuronal conditions during initial HSV-1 infection have a long-term impact on latency, modulating how responsive latent genomes are to reactivation and, therefore, their ability to cause disease. Type I interferon (IFNα) exposure during initial infection results in promyelocytic leukemia nuclear-body (PML-NB) formation and a more restrictive form of HSV-1 latency. Here we demonstrate that IFNα induced PML-NBs recruit histone chaperones to the viral genome and promote the deposition of the repressive heterochromatin mark, histone H3 lysine 9 tri-methylation (H3K9me3), and its reader, ATRX (alpha-thalassemia/mental retardation, X-linked). This work reveals the mechanism by which immune signaling during initial infection induces an epigenetic memory on HSV-1 genomes that is maintained during latency and inhibits reactivation. ATRX is highly abundant in neurons and is essential for maintaining cellular heterochromatin during neuronal stress. Here we find that ATRX prevents transcription, and subsequent reactivation, from H3K9me3-bound latent genomes by remaining associated with viral chromatin following stress-induced phosphorylation of histone H3. This indicates that H3K9me3-associated viral genomes are refractory to reactivation when read by ATRX. This work demonstrates that ATRX acts as a neuronal restriction factor against HSV-1 reactivation, elucidating a new potential target for inhibiting HSV-1 reactivation and subsequent human disease.
KV1.8 (Kcna10) potassium channels enhance fast, linear signaling in vestibular hair cells and facilitate vestibulomotor reflexes and balance
Authors: Martin Hannah R. , Verdone Brandie Morris , López-Ramírez Omar , Green Merrill , Silvian Dana , Scott Emily , Cullen Kathleen E. , Eatock Ruth Anne
Published: January 2025

Vestibular hair cells (HCs) faithfully and rapidly detect head motions and gravity, driving motor reflexes that stabilize balance and gaze during locomotion. With the transition from water to land, the amniote vestibular inner ear added type I HCs, which differ from amniote type II HCs and anamniote HCs by their large calyx afferent synapse, non-quantal afferent transmission, and a large, low-voltage-activated K+conductance (gK,L). We recently showed that both gK,Land the major type II K+conductances (A-type and delayed rectifier) require KV1.8 (Kcna10) subunits. Here we compared KV1.8-null (Kcna10−/−) and control animals to see how KV1.8 affects function as measured by receptor potentials and nonquantal postsynaptic potentials evoked by direct hair bundle motions, and by vestibulomotor behaviors. Recordings were taken from extrastriolar zones of the utricle. In both HC types, KV1.8 affected receptor potentials by reducing response time and gain, increasing dampening, and expanding the frequency bandwidth toward high frequencies. Effects are most prominent in type I HCs: lowpass corner frequencies of receptor potentials inKcna10−/−HCs of both types were ∼20 Hz,vs. ∼400 Hz in control type I and ∼70 Hz in control type II. We recorded nonquantal postsynaptic potentials from extrastriolar calyces, and found that the synaptic transfer function had lower gain and greater phase lag inKcna10−/−mice. In behavioral tests,Kcna10−/−mice had vestibular-ocular reflexes with different response dynamics at low frequencies, impaired performance on a narrow balance beam, abnormal body posture and abnormal head motions in water and on land, and also rarely assumed bipedal stances. These vestibulomotor deficits inKcna10−/−mice likely reflect the changes noted in HCs, where KV1.8 expression is concentrated; that is, slower signaling of high-frequency head motions byKcna10−/−HCs fails to fully stabilize body and head position during locomotion. Thus, gK,L(KV1.8) contributes to fast signal transmission in the amniote vestibular inner ear and supports improved performance on challenging vestibulomotor tasks.

Graphical Abstract
DeepSynBa: Actionable Drug Combination Prediction with Complete Dose-Response Profiles
Authors: Kuru Halil Ibrahim , Zhang Haoting , Rattray Magnus , Ek Carl Henrik , Cicek A. Ercument , Tastan Oznur , Milo Marta
Published: January 2025

Motivation

Many cancer monotherapies demonstrate limited clinical efficacy, making combination therapies a relevant treatment strategy. The extensive number of potential drug combinations and context-specific response profiles complicates the prediction of drug combination responses. Existing computational models are typically trained to predict a single aggregated synergy score, which summarises drug responses across different dosage combinations, such as Bliss or Loewe scores. This oversimplification of the drug-response surface leads to high prediction uncertainty and limited actionability because these models fail to differentiate between potency and efficacy.

Results

We introduce DeepSynBa, an actionable model that predicts the complete dose-response matrix of drug pairs instead of relying on an aggregated synergy score. This is achieved by predicting parameters describing the response surface as an intermediate layer in the model. We evaluated DeepSynBa on the NCI-ALMANAC dataset, which comprises nearly 300,000 drug pair–cell line combinations. DeepSynBa outperforms the state-of-the-art methods in the dose-response matrix prediction task across multiple evaluation scenarios, including testing on novel drug combinations, cell lines, and drugs, across nine different tissue types. We also show that DeepSynBa yields reliable synergy score predictions. More importantly, DeepSynBa can predict drug combination responses across different dosages for untested combinations. The intermediate dose-response parameter layer allows for separating efficacy from potency, which informs the selection of dosage ranges that optimise efficacy while limiting off-target toxicity in experimental screens. The predictive capability and the downstream actionability make DeepSynBa a powerful tool for advancing drug combination research beyond the limitations of the current approaches.

Availability

The code and the dataset for DeepSynBa are available athttps://github.com/hikuru/DeepSynBa.

Contact

marta.milo@astrazeneca.comorotastan@sabanciuniv.edu
Mitochondrial dysfunction underlies monocyte immune deficiency in patients with severe alcohol-related hepatitis
Authors: Middleton Paul K. , Aramayo Ricardo J. , Montoya Alex , Shliaha Pavel V. , Pope Simon , Fets Louise , Vergis Nikhil , Thursz Mark R. , Cochemé Helena M.
Published: January 2025

Severe alcohol-related hepatitis (sAH) is a life-threatening form of alcohol-related liver disease (ARLD) associated with a significant short-term mortality. Opportunistic infections due to impaired immune function are a major cause of patient mortality. Mitochondrial dysfunction within the liver is a well-recognised feature of ARLD and sAH. However, whether these hepatic mitochondrial defects extend to the immune system of sAH patients, underlying their immune dysfunction, remains unclear. Here, we demonstrate that sAH monocytes exhibit an increased content of inefficient, dysfunctional mitochondria. These changes were underpinned by abnormal mitochondrial cristae ultrastructure, which were associated with depletion of cristae structural proteins and alterations in cardiolipin profiles. Overall, our study uncovers novel structural and functional mitochondrial defects, which likely contribute to impaired monocyte immune function in sAH.
Capturing Nematic Order on Tissue Surfaces of Arbitrary Geometry
Authors: Eckert Julia , Andrews Toby G. R. , Pollard Joseph , Priya Rashmi , Yap Alpha S. , Morris Richard G.
Published: January 2025

A leading paradigm for understanding the large-scale behavior of tissues is via generalizations of liquid crystal physics; much like liquid crystals, tissues combine fluid-like, viscoelastic behaviors with local orientational order, such as nematic symmetry. Whilst aspects of quantitative agreement have been achieved for flat monolayers, the most striking features of tissue morphogenesis — such as symmetry breaking, folding and invagination — concern surfaces with complex curved geometries. As yet, however, characterizing such complex behaviors in three dimensions has been frustrated due to the absence of proper image analysis methods; current state-of-the-art methods almost exclusively rely on two-dimensional (2D) intensity projections of multiple image planes, which superimpose data and lose geometric information that can be crucial. Here, we describe an analysis pipeline that properly captures the nematic order of tissue surfaces of arbitrary geometry, which we demonstrate in the context ofin vitromulticellular aggregates, andin vivozebrafish hearts. For the former, we correlate the number of topological defects with the aggregate’s surface area and verify theoretical predictions, whilst for the latter, we link biological properties to physical concepts (Laplace pressure) through spatio-temporal correlations of the heart geometry with fluorescence signals of intracellular proteins. Our analysis enables access to the ‘hidden’ third dimension of conventional image acquisition via stacked 2D planes and highlights how such characterizations can deliver meaningful physical insight.
Females use multiple cues to assess competition for egg-laying decisions
Authors: Sharma Manvi , Ramesh Ashwini , Nagaraj Nisha , Isvaran Kavita
Published: January 2025

Animals deploy a wide suite of behavioural responses to reduce fitness costs related to competition. One common strategy is spatial avoidance of resource patches associated with high competition and this involves a need to accurately assess the level of competition associated with patches. Although well-studied in the context of predation risk (alarm cues vs kairomones), we lack in our understanding of how inputs from multiple types of cues are used for assessing the level of conspecific competition. We tested howAedes aegyptifemales select sites for oviposition when they encounter multiple types of cues from varying densities of conspecifics. We hypothesised that females perceive conspecific young within these sites as potential competition for their offspring, and tailor their response to the type and level of competition. Through binary choice trials, we assessed female oviposition behaviour in response to a gradient in two types of conspecific cues – egg and larvae. Our results indicate that female response was sensitive to the type of cue. Females showed attraction towards pools with low densities of both egg and larval conspecifics indicating conspecific cueing and the strength of response was stronger towards egg cues. However, this attraction response disappeared at high densities of conspecifics (both egg and larvae) suggesting that the resulting trade-off between benefits from conspecific cueing and costs of competition likely shapes oviposition site selection responses. The broad nature of the oviposition response was similar toward both egg and larval cues, but there were fine level differences in responses towards egg and larvae that depended on the conspecific density level. Our study shows that animals are under selection to use multiple cues to assess conspecific competition to minimise the costs of competition.
The sodium channel SCN2A regulates cortical excitatory and inhibitory neurogenesis
Authors: Uy Jarryll A. , Dargaei Zahra , Geahchan Sarah , Botler Laura , Pan Yi , Brown Chad O. , Howe Jennifer L. , Scherer Stephen W. , Bains Jaideep S. , Singh Karun K.
Published: January 2025

Voltage-gated sodium channels regulate neuronal excitability and fast synaptic transmission in the postnatal and adult brain. The geneSCN2A, encoding the sodium channel Nav1.2, regulates synaptic development and variants inSCN2Aare associated with autism spectrum disorders (ASD). The expression pattern ofSCN2Abegins during fetal cortical development, prior to the onset of synaptic transmission, but it is unknown whether SCN2A regulates early cortical development through mechanisms independent of synaptic transmission. Here we reveal that isogenic and ASD patient-derived human forebrain organoids modelling a loss of SCN2A function display impaired excitatory and inhibitory neurogenesis, leading to a developmental imbalance. Unexpectedly, we find precocious generation of cortical inhibitory neurons is driven by elevated sonic hedgehog (SHH) signaling and is reversible through pharmacological inhibition. Functionally, these developmental phenotypes arise due to sodium channel dysfunction and lead to abnormal neuronal network activity. Our results identify a new mechanisim for cortical excitatory and inhibitory neurogenesis involvingSCN2A, and reveal that early neurogenesis deficits precedes postnatal neural circuit dysfunction in SCN2A-associated disorders.
Sensory discrimination of chemical and temperature stimuli in the acoelSymsagittifera roscoffensis
Authors: Komarov Nikita , Aeschbacher Christopher , Sauterel Laurent , Zuercher Evan , Bailly Xavier , Martinez Pedro , Sprecher Simon G.
Published: January 2025

Environmental cues provide critical sensory information for the survival of animals. Understanding how distinct sensory cues elicit or modulate certain behaviour thus provides insights into the neuronal adaptations to rapid and continuous changes in the surrounding world. Intertidal ecosystems are a particularly exposed to environmental fluctuations. Due to changing exposure to seawater, animals are subjected to continuous fluctuations of temperature or salinity during the course of day-night and tidal cycles. Animals in the intertidal environment show physiological and behavioural adaptations to these changes. When the acoelSymsagittifera roscoffensisis exposed to daylight during the tidal cycle, these animals are found at the surface of sandy beaches, which enhance the exposure of their photosynthetic algal (Tetraselmis convolutae) symbionts to light. Moreover,S. roscoffensisshows a strong positive phototactic displacement as well as both positive and negative geotaxis, both being evolved behavioural adaptations to enhance light-exposure for its photosymbiont. Currently little is known about other sensory systems and their functions inS. roscoffensis. In this study, we probe sensory capabilities ofS. roscoffensisfocusing on chemical and temperature cues. Our findings support thatS. roscoffensisshows avoidance behaviours to increased temperature and high salinity, preferring cooler environments with lower salinity.
Climatic niche conservatism in non-native plants depends on introduction history and biogeographic context
Authors: Rönnfeldt Anna , Holle Valén , Schifferle Katrin , Gallien Laure , Knight Tiffany , Weigelt Patrick , Craven Dylan , Cabral Juliano Sarmento , Zurell Damaris
Published: January 2025

Many tools informing preventive invasion management build on the assumption that introduced species will conserve their climatic niches outside their native ranges. Previous research testing the validity of this assumption found contradictory results regarding niche conservatism vs. niche switching for non-native species. An open question is in how far these contradictions reflect context dependency, yet only few studies compared the niche dynamics of species introduced to multiple regions. Here, we used an ordination-based approach to quantify the climatic niche changes (stability, unfilling, expansion) of 316 plant species introduced to eight different regions across the world, including the Pacific region with extreme isolation between island groups. We then performed multiple phylogenetic regressions to assess how the regional context and species’ characteristics affect niche dynamics. Niche conservatism varied across regions, even within species. While niche expansion into previously unoccupied climates was generally low, niche unfilling varied strongly between regions. Generally, region-specific introduction history and species’ biogeographic attributes were more important for explaining niche changes than ecological traits. Niche expansion was consistently higher for species with small native range sizes, and niche stability increased. In contrast, niche unfilling decreased with time since introduction which could suggest that the lack of niche conservatism observed in many regions might be transient and potentially related to dispersal limitations. Overall, our results shed light on the context dependency of climatic niche changes when species are introduced to new regions, highlighting that the species and region-specific context should be accounted for when assessing the potential for niche changes.

Significance Statement

As non-native species are introduced to new regions by humans, they may occupy the same climatic conditions as in their native ranges, leave parts of their native niche unfilled or expanding into previously unoccupied conditions. Knowing to which extent these niche dynamics generally occur is essential for understanding and managing biological invasions. Here, we evaluate regional differences in the climatic niche dynamics of non-native plants that were introduced to multiple regions across the world. We found marked variation across regions, influenced by factors such as the time that has passed since species were introduced, or biogeographic attributes of both the native and non-native ranges. These findings indicate that a lack of apparent niche changes is likely a temporary phenomenon.
Evolutionary potential of theEscherichia coliantimutator ΔnudJis reduced via altered mutational spectrum
Authors: Green R , Richards H , Ozbilek D , Tyrrell F , Barton V , Lovell SC , Gifford DR , Lagator M , McBain AJ , Krašovec R , Knight CG
Published: January 2025

The rate of spontaneous mutation is a key factor in determining the capacity of a population to adapt to a novel environment, for example a bacterial population exposed to antibiotics. Genetic and environmental factors controlling the mutation rate commonly also cause shifts in the relative rates of different mutational classes, i.e. the spectrum of spontaneous mutations. When the mutational spectrum is altered, the relatively enriched and depleted mutations may differ in their fitness effects. Here we aim to explore how a reduced mutation rate and altered mutational spectrum can contribute to adaptation inEscherichia coli. We measure mutation rates across a set of Nudix hydrolase deletants, finding multiple strains with an antimutator phenotype. We focus on the antimutator ΔnudJwhich can cause a 6-fold mutation rate reduction relative to the wildtype with an altered mutational spectrum. Not only doesnudJdeletion reduce the probability of antibiotic resistance arising but, in the case of rifampicin, the accessible resistance mutations under this altered mutation spectrum have greater fitness costs. While this effect is, so far, specific to this drug, it opens up the possibility of reducing the likelihood of resistance mutations establishing through simultaneous modification of mutation rate and spectrum. The identification and characterisation of antimutator alleles such as ΔnudJprovides potential targets for ‘antievolution drugs’ which could be applied during antibiotic treatment to inhibit NudJ activity. Such an approach could suppress spontaneous resistance evolution both through fewer resistance mutations and by limiting access to the fittest mutations.
multiHIVE: Hierarchical Multimodal Deep Generative Model for Single-cell Multiomics Integration
Authors: Nanduri Anirudh , Pavan Musale Krushna , Pandey Kushagra , Zafar Hamim
Published: January 2025

Motivation

Recently developed single-cell multiomics technologies are enhancing our understanding of cellular heterogeneity by providing multiple views of a biological system. CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) is one such multiomics assay, with the ability to connect cell states to functions by simultaneously profiling RNA and surface proteins from the same cell. However, the distinct technical characteristics of these data modalities pose significant challenges to their integration into a cohesive representation of cellular identity.

Results

Here we present multiHIVE, a hierarchical multimodal deep generative model for inferring cellular embeddings by integrating CITE-seq data modalities. multiHIVE employs hierarchically stacked latent variables as well as modality-specific latent variables to capture shared and private information from the modalities respectively, facilitating integration, denoising and imputation tasks. Extensive benchmarking using gold-standard real and simulated datasets demonstrates multiHIVE’s superiority in integrating CITE-seq datasets. Moreover, multiHIVE outperformed the state-of-the-art methods in imputing missing protein measurements and integration of CITE-seq dataset with unimodal dataset. Using a thymocyte development dataset, we showed that multiHIVE’s cellular embeddings can lead to improved trajectory inference and gene trend identification. Finally, using datasets across development and disease, we demonstrated that factorization of multiHIVE-inferred denoised expression into gene expression programs aids in identifying biological processes at multiple levels of cellular hierarchy.

Availability and Implementation

multiHIVE is implemented in Python and is publicly available athttps://github.com/Zafar-Lab/multiHIVE.
Visualizing sub-organellar lipid distribution using correlative light and electron microscopy
Authors: Lennartz H. Mathilda , Khan Suman , Böhlig Kristin , Leng Weihua , Elsner Falk , Scher Nadav , Wilsch-Bräuninger Michaela , Avinoam Ori , Nadler André
Published: January 2025

Lipids and proteins compartmentalize biological membranes into nanoscale domains which are crucial for signaling, intracellular trafficking and many other cellular processes. Studying nanodomain function requires the ability to measure protein and lipid localization at the nanoscale. Current methods for visualizing lipid localization do not meet this requirement. Here, we introduce a correlative light and electron microscopy workflow to image lipids (Lipid-CLEM), combining near-native lipid probes and on-section labeling by click chemistry. This approach enables the quantification of relative lipid densities in membrane nanodomains. We find differential partitioning of sphingomyelin into intraluminal vesicles, recycling tubules, and the boundary membrane of the early endosome, representing a degree of nanoscale organization previously observed only for proteins. We anticipate that our Lipid-CLEM workflow will greatly facilitate the mechanistic analysis of lipid functions in cell biology, allowing for the simultaneous investigation of proteins and lipids during membrane nanodomain assembly and function.
A cell-matrix interaction regulates the undifferentiated state and self-renewal capacity of avian primordial germ cells
Authors: Ichikawa Kennosuke , Motoe Yuzuha , Watanabe Tenkai , Ezaki Ryo , Matsuzaki Mei , Horiuchi Hiroyuki , McGrew Michael J.
Published: January 2025

Primordial germ cells (PGCs) are lineage restricted precursor cells of sperm and eggs. Whilst avian PGCs from chicken can be cultured and modified to produce genome-edited chickens, the long-term culture of PGCs from other bird species has not been achieved. Here, we explored the effects of a cell-matrix interaction on the in vitro propagation of chicken PGCs. Blocking integrin signaling severely reduced the self-renewal of the PGC, indicating that a PGC-matrix interaction is an essential process for self-renewal. We investigated the properties of somatic cell differentiated PGCs and expression analyses suggested that the PGCs undergo a partial epithelial-to-mesenchymal transition caused by excess PGC-matrix interactions. Finally, we conducted a long-term culture of chicken PGCs with matrix components, resulting in significant induction of their somatic conversion. These results suggested that a high level of PGC-matrix interaction can cause somatic conversion, whilst a moderate level is essential for their proliferation. Overall, we identified a molecular aspect of self-renewal and maintaining undifferentiated states of avian PGCs.
Enzymes can activate and mobilize the cytoplasmic environment across scales
Authors: Dindo Mirco , Metson Jakob , Ren Weitong , Chatzittofi Michalis , Yagi Kiyoshi , Sugita Yuji , Golestanian Ramin , Laurino Paola
Published: January 2025

Biomolecular condensates have so far been studied in terms of their structural, compositional, and functional properties. However, condensate enzymatic activity —a key aspect of cellular metabolism— remains unexplored due to the complexity of the system. In this study, using a combination of experimental, computational and theoretical techniques, we have discovered that the non-equilibrium activity which originates from catalytic reactions couples with the environment through various feedback mechanisms across five orders of magnitude of length scales. We observe that condensed enzymes catalyse more rapidly in the presence of crowding proteins and show that the increased enzymatic activity within these droplets stems from the emergence of lower-energy protein conformations induced by the highly crowded environment. Despite the crowding in the environment of the droplet, which might suggest an effective increase in its overall viscosity, we find that it becomes more agile, as evidenced by the observation of enhanced diffusion and macroscopic flow, due to the enzymatic activity. These findings shed new light on the dynamic interplay between enzymatic activity, composition and crowding in condensates, and their roles on the mobility and accessibility of various functional units in these environments, offering a novel perspective on liquidliquid phase separation in metabolically active conditions.
LncRNA SChLAP1 promotes cancer cell proliferation and invasion via its distinct structural domains and conserved regions
Authors: Oh Mihyun , Kadam Roshni Nagesh , Charania Zahra Sadruddin , Somarowthu Srinivas
Published: January 2025

Long non-coding RNAs (lncRNAs) play key roles in a range of biological processes and disease progression. Despite their functional significance and therapeutic potential, lncRNAs’ mechanisms of action remain understudied. One such lncRNA is the Second Chromosome Locus Associated with Prostate-1 (SChLAP1). SChLAP1 is overexpressed in malignant prostate cancer and is associated with unfavorable patient outcomes, such as metastasis and increased mortality. In this study, we demonstrated that SChLAP1 possesses distinct structural domains and conserved regions that may contribute to its function. We determined the secondary structure of SChLAP1 using chemical probing methods combined with mutational profiling (DMS-MaP and SHAPE-MaP). Ourin vitrosecondary structural model revealed that SChLAP1 consists of two distinct secondary-structural modules located at its 5’ and 3’ ends, both featuring regions with a high degree of structural organization. Ourin vivochemical probing identified potential protein-binding hotspots within the two modules. Overexpression of the modules led to a notable increase in cancer cell proliferation and invasion, proving their functional significance on the oncogenicity of SChLAP1. In conclusion, we discovered functionally important, independent modules with well-defined structures of SChLAP1. These results will serve as a guide to explore the detailed molecular mechanisms by which SChLAP1 promotes aggressive prostate cancer, ultimately contributing to the development of SChLAP1 as a novel therapeutic target.
Variability vs Phenotype: multimodal analysis of Dravet Syndrome Brain Organoids powered by Deep Learning
Authors: Turpin Isabel , Modrego Adriana , Martí-Sarrias Andrea , Haeb Anna-Christina , García-González Laura , Soriano Jordi , Ruiz Núria , Peñuelas-Haro Irene , Espinet Elisa , Tornero Daniel , Lao Oscar , Acosta Sandra
Published: January 2025

Brain organoids (BO) have risen as a reliable model for neurodelopmental disorders (ND), reproducing human brain development milestones. However, their significant intra- and inter-organoid variability compromises their use in advanced tasks such as drug testing. Overcoming experimental variability is crucial for models prone to variation, like unguided BO. BO modelling in Dravet Syndrome, a late-onset epileptic ND, represents a great challenge since BO variability accumulates with time, when phenotype shows in vitro. Leveraging deep learning, we developed ImPheNet, a predictive tool grounded in BO live imaging datasets. ImPheNet accurately classified phenotypes and assessed drug toxicity in BO derived from DS, revealing differences between genotypes and upon antiseizure drug exposure. These results are supported by transcriptomic and functional data, revealing an excitatory-inhibitory imbalance during the maturation of DS organoids. Altogether, our DL-predictive live imaging strategy, ImPheNet, emerges as a powerful tool enhancing BO research and advancing ND treatments.
Endurance training restores ageing-impaired lysosomal biogenesis factors in rest and response to acute exercise in rat skeletal muscle
Authors: Rajabi Hamid , Askari Benyamin , Clarke David C.
Published: January 2025

Lysosomes, crucial for autophagy, play a pivotal role in cellular processes influenced by exercise. This study investigates the impact of ageing on lysosomal function, focusing on Transcription Factor E3 and its regulators, mTORC1 and Calcineurin, emphasizing their response and adaptation to endurance training. Twenty-five male Sprague-Dawley rats were categorised into Young (2 months), Aged sedentary and Aged sedentary single session (18 months), Aged long-term trained, and Aged trained-single session (17 months). Changes in variables were explored concerning sarcopenia by Soleus muscle fibre diameter and number measured via Eosin & Hematoxylin, phosphorylated and total TFEB protein levels via western blot, mTORC1 and Calcineurin mRNA levels via real-time PCR. Ageing happened with increased pTFE3/TFE3totalprotein (BF=579) and declined mTORC1 mRNA (BF=3.99) and muscle diameter (BF=87), signifying sarcopenia and potential contributors. Conversely, Calcineurin mRNA (BF=0.67) and muscle fibre number (BF=0.31) remained unaltered during ageing. Endurance exercise induced acute responses, reducing pTFE3/TFE3totalprotein (BF=306) and elevating mTORC1 (BF=1.57) and Calcineurin mRNA levels (BF=3.19). Three weeks of endurance training further decreased resting pTFE3/TFE3totalprotein (BF=174) while increasing Calcineurin mRNA (BF=12), and muscle fibre diameter (BF=126), with no changes in mTORC1 mRNA levels (BF=0.46) and muscle fibre number. Post-exercise, trained rats sustained decreased pTFE3/TFE3totalprotein (BF=56) and elevated mTORC1 mRNA (BF=1.16). In conclusion, this study underscores the involvement of TFE3, MTORC1, and Calcineurin in sarcopenia, proposing endurance training as an effective strategy to mitigate age-related changes and enhance muscle function in aged rats. Additionally, it suggests impairments in TFE3 possibly contribute to sarcopenia in ageing.

key point

Given the pivotal role lysosomes play in multiple homeostatic processes, investigating mTORC1, Calcineurin, and TFE3, an overlooked lysosome biogenesis factor directly involved in the metabolic effects of exercise, could help understand the metabolic state of sarcopenia and the role exercise plays in it.

Through eosin & hematoxylin, western blotting and real-time PCR, we found Aging results in Sarcopenia, reduced TFE3 activity and mTORC1 gene expression.

We saw a single bout of exercise elicit a response by increasing TFE3 protein activation, mTORC1, and Calcineurin gene expression, which is directed to improved sarcopenia.

Three weeks of exercise improved sarcopenia and was accompanied by elevated only with resting levels of TFE3 protein activation, and Calcineurin gene expression.

Endurance training was still able to licit post exercise response in TFE3 protein activation, and Calcineurin gene expression

Endurance training is a beneficial remedy for sarcopenia, and TFE3 protein is a major crucial player in inducing its effects.
Enhanced mRNA delivery using ultrasound-delivered click reactive anchors
Authors: Di Ianni Emilio , Jeon Jueun , Hu Huiyu , Quintana Jeremy M. , Lee Chanseo , Haidar Edwina Abou , Mohammadi Sedra , Zargani-Piccardi Ayrton , Mahamdeh Mohammed , Hernández Iván Coto , Ng Thomas S.C. , Breyne Koen , Lee Hakho , Breakefield Xandra O. , Miller Miles A.
Published: January 2025

Therapeutic nucleic acid delivery has many potential applications, but it remains challenging to target extrahepatic tissues in a flexible and image-guided manner. To address this issue, we report a bioorthogonal pre-targeting strategy that uses focused ultrasound to promote the delivery of mRNA-loaded lipid nanoparticles (mRNA-LNP). We synthesized amphiphilic click reactive anchors (ACRAs) consisting of a phospholipid PEG-conjugate functionalized with transcyclooctene (TCO) or its companion reactive partner methyltetrazine (mTz), yielding ACRA-TCO and ACRA-mTz. ACRA derivatives were screened for cellular activity, yielding functionalized DOPE-PEG (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N- (polyethylene glycol)) derivatives outperforming those containing saturated lipid or branched PEG. Nanobubbles encapsulating ultrasound-responsive gas precursor delivered ACRA-TCO to targeted cells and tissues using focused ultrasound, and this pre-targeting promoted the subsequent delivery of mRNA- LNP functionalized with companion ACRA-mTz. In cell cultures and in mice, ultrasound pre-targeting enhanced the accumulation of mTz-functionalized small molecule and nanoparticle compounds by 75% and 3.6-fold, respectively, and increased gene expression using mRNA-LNPin vivo. Taken together, this report presents a modular, ultrasound-enabled strategy for enhancing nucleic acid delivery in targeted tissues.
A saga of agonistic interactions in house crickets (Acheta domesticus): A direct and indirect effects perspective
Authors: Sekhar M. A. , Rothamer Brooke A. , Gillam Erin , Dochtermann Ned A.
Published: January 2025

Agonistic behaviours are widely observed across multiple taxa and are critical in shaping hierarchies, influencing resource acquisition, survival, and reproductive success. Individuals often alter their behaviour in response to the traits of others, referred to as indirect effects. Individuals also differ in their mean behavioural responses, referred to as direct effects. The combination of indirect and direct effects produce the observed social interactions. Importantly, these effects are typically measured on isolated parts of the full sequence of behaviors and traits expressed during social interactions. Here, we used house crickets,Acheta domesticus, to investigate how direct and indirect effects shape behaviors and traits across an agonistic interaction. We found that the probability of initiating aggression, but not contact, was influenced by both direct and indirect effects independent of mass. Amplitude, peak frequency, and pulse duration of stridulations occurring during agonistic interactions were influenced by direct effects but were not strongly influenced by indirect effects. These results demonstrate that the strength of indirect and direct effects vary over the course of an agonistic interaction and differentially affect the specific components of these interactions. Understanding when and how these effects are important is necessary for understanding agonistic behaviour and its evolution.
Molecular determinants of RNase MRP specificity and function
Authors: Smith Eric M. , Ly Jimmy , Haug Sofia , Cheeseman Iain M.
Published: January 2025

RNase MRP and RNase P are evolutionarily related complexes that facilitate rRNA and tRNA biogenesis, respectively. The two enzymes share nearly all protein subunits and have evolutionarily related catalytic RNAs. Notably, RNase P includes a unique subunit, Rpp21, whereas no RNase MRP-specific proteins have been found in humans, limiting molecular analyses of RNase MRP function. Here, we identify the RNase MRP-specific protein, C18orf21/RMRPP1. RMRPP1 and Rpp21 display significant structural homology, but we identify specific regions that drive interactions with their respective complexes. Additionally, we reveal that RNase MRP is required for 40S, but not 60S, ribosome biogenesis uncovering an alternative pathway for ribosome assembly. Finally, we identify Nepro as an essential rRNA processing factor that associates with the RNase MRP complex. Together, our findings elucidate the molecular determinants of RNase MRP function and underscore its critical role in ribosome biogenesis.
Prey capture learning drives critical period-specific plasticity in mouse binocular visual cortex
Authors: Bissen Diane , Cary Brian A. , Zhang Amanda , Sailor Kurt A. , Van Hooser Stephen D. , Turrigiano Gina G.
Published: January 2025

Critical periods are developmental windows of high experience-dependent plasticity essential for the correct refinement of neuronal circuitry and function. While the consequences for the visual system of sensory deprivation during the critical period have been well-characterized, far less is known about the effects of enhanced sensory experience. Here, we use prey capture learning to assess structural and functional plasticity mediating visual learning in the primary visual cortex of critical period mice. We show that prey capture learning improves temporal frequency discrimination and drives a profound remodeling of visual circuitry through an increase in excitatory connectivity and spine turnover. This global and persistent rewiring is not observed in adult hunters and is mediated by TNFα-dependent mechanisms. Our findings demonstrate that enhanced visual experience in a naturalistic paradigm during the critical period can drive structural plasticity to improve visual function, and promotes a long-lasting increase in spine dynamics that could enhance subsequent plasticity.
Involvement of orexin nerves in early stage of Alzheimer’s disease model mice and preventive effect of orexin receptor antagonists
Authors: Hada Kazuhiro , Murata Yuki , Yoshiaki Ohi , Hashimoto Sana , Watanabe Hinata , Ozeki Kayoko , Saido Takaomi C , Saito Takashi , Sasaguri Hiroki , Mizoguchi Hiroyuki , Yamada Kiyofumi , Wakiya Yoshifumi
Published: January 2025

Background

Mild cognitive impairment (MCI) is a condition between healthy cognition and dementia with a high probability of progression to Alzheimer’s disease (AD). Elevated levels of orexin (OX) have been reported in the cerebrospinal fluid of patients with MCI and AD.

Objective

To investigate the efficacy of dual OX receptor antagonists (suvorexant and lemborexant) in an early-stage AD mouse model (App-KI).

Methods

The expression of theOX receptorgene, the levels of suvorexant and lemborexant in the brain after a single oral dose, and their effects on locomotor activity were investigated in wild-type mice. In addition, the cognitive function of wild-type and App-KI mice was assessed using the Y-maze test after oral administration of suvorexant or lemborexant once a day for 60 d. After the behavioral test, amyloid-beta levels were quantified in the hippocampal CA1 region of App-KI mice.

Results

The expression of theOX receptorgene was highest in the lateral hypothalamus and was also observed in other brain regions. Drug levels peaked at 20–40 min for suvorexant and 15 min for lemborexant and declined, still detectable 24 h later. Locomotor activity was reduced after suvorexant or lemborexant administration; however, 24 h after administration, locomotor activity did not differ from the control group. In particular, the Y-maze test showed that suvorexant and lemborexant prevented cognitive impairment in App-KI mice. Furthermore, suvorexant and lemborexant suppressed amyloid-beta accumulation in the hippocampal CA1 region of App-KI mice.

Conclusion

The results suggest that suvorexant and lemborexant effectively suppress the early stages of AD.
Global risk assessment of Lyme borreliosis transmission
Authors: Cobos-Mayo Marina , Martín-Taboada Adrián , Aliaga-Samanez Alisa , Segura Marina , Olivero Jesús
Published: January 2025

We analysed the geographic risk of Lyme borreliosis taking into account the biogeography of tick vectors and carrier hosts, together with environmental and anthropogenic factors. Four pathogeographical scenarios were set in order to represent the contribution of vectors and hosts in the spatial zoonotic risk. For that propose, we built distribution models based on the occurrence of Lyme borreliosis cases in humans and ixodid vectors. BesidesIxodesspecies, we considered other ixodid ticks with potential to be vectors. These models were combined through fuzzy logic operators, according to the criteria stablished in each scenario. Finally, the transmission risk model for Lyme borreliosis which best fitted its global distribution was selected. The risk model selected considered ixodid vectors and mammal carriers as explanatory variables together with environment and anthropogenic factors.Ixodesspecies contributed to explain the geographical risk of Lyme borreliosis to larger extent than other ixodid ticks. The risk model described regions with Lyme borreliosis transmission risk where its presence is still uncertain, such as northern Africa and inland areas of western USA. Likewise, our model indicated favourable conditions for the presence of human cases in northern latitudes beyond its endemic distribution. Applying this multi-scenario methodology approach have led us to a risk model, in which the diversity of ixodid vectors and carrier hosts might modify the spatial risk without a geographical limitation.
Cellular and synaptic organization of the Octopus vertical lobe
Authors: Bidel Flavie , Meirovitch Yaron , Yang Fuming , Lichtman Jeff William , Hochner Binyamin
Published: January 2025

Understanding memory formation and its influence on behavior is a central challenge in neuroscience. Associative learning networks, including the mushroom body in insects, the cerebellum in mammals, and the vertical lobe (VL) in cephalopods, typically exhibit a 3-layered architecture, characterized by divergence (fan-out) followed by convergence (fan-in), facilitating sparse sensory coding (Babadi and Sompolinsky, 2014; Lin et al., 2014; Litwin-Kumar et al., 2017; Turchetti-Maia et al., 2017). Previously, using volumetric electron microscopy, we showed that the VL uniquely comprises 22 million simple amacrine (SAM) interneurons, each receiving a singular input subject to activity-dependent long-term potentiation, contrasting with typical middle-layer interneurons (Bidel, Meirovitch et al., 2023). We also demonstrated that these SAMs provide excitatory feedforward input to the output cell layer, balanced by approximately 400,000 inhibitory complex amacrines (CAM), which are morphologically diverse and integrate numerous inputs (Bidel, Meirovitch et al., 2023). Here, we leverage the same digital tissue to explore the CAMs’ morphological diversity, identifying correlations between structure, postsynaptic site density, and synaptic input proportions, which led to the classification of CAMs into distinct groups. Further analysis of the input layer in the VL revealed a meticulous structural and synaptic compartmentalization, with distinct synaptic bouton types forming three zones that integrate different inputs towards CAMs. Additionally, we identify the potential presence of a neurogenic niche in the VL, hinting at parallels with neurogenic processes in other species and warranting further investigation, particularly in the context of learning and memory. This study deepens our understanding of the VL’s cellular and synaptic architecture, revealing both shared and unique features compared to other associative networks, and highlighting the intricate interplay of structural and functional elements in memory formation.

Highlights (85 characters including space)

The VL both aligns with and deviates from standard associative network features

The VL input layer presents a unique compartmentalization by axonal bouton type

The minority inhibitory interneurons differentiate into unique functional subtypes

Mirroring the mammalian hippocampus, the VL may contain an adult neurogenic niche
Electroencephalographic responses before, during, and after upper limb paired associative stimulation
Authors: Shikauchi Yumi , Uehara Kazumasa , Okazaki Yuka O. , Kitajo Keiichi
Published: January 2025

Paired associative stimulation (PAS) is a non-invasive protocol involving repeated stimulus pairs to activate two cortical areas alternately, inducing Hebbian-like plasticity. However, its neurophysiological impacts remain unclear. To determine the changes that occur in the brain during PAS, brain activity during PAS must be measured and distinguished from the electromagnetic artifacts produced by the stimulation. Here, we present a novel dataset of electroencephalography (EEG) measurements during PAS with an inter-stimulus-interval of 25 ms (PAS25, expected to induce long-term potentiation-like changes) or 35 ms (PAS35, no expected change). This dataset includes raw data and pre-processed data with electromagnetic artefacts removed. he right ulnar nerve’s electrical stimulation preceded transcranial magnetic stimulation to the left primary motor cortex in both cases. EEG was measured before and after the PAS sessions, with only electrical or magnetic stimulation. To demonstrate the quality of the data, we summarize the stability of the stimulation site and the event-related potentials before, during, and after PAS. This dataset will enable observing brain dynamics due to the accumulation of stimulations during PAS and differences in responsiveness to stimulations before and after PAS.
Lévy Flight Patterns in the Cortical Architecture ofMacaca mulatta
Authors: Tozzi Arturo
Published: January 2025

Lévy flights (LF), a concept originating in statistical physics, describe random walks in which the step lengths follow a heavy-tailed probability distribution, often a power law. Unlike Brownian motion, where step lengths are constrained within a narrow range, LF are characterized by the coexistence of many short steps interspersed with occasional long jumps. Applying advanced computational techniques, we looked for LF-like patterns in high-resolution histological images ofMacaca mulatta(Rhesus macaque) cortical area 4 from BrainMaps.org. Step-length distributions, derived from pairwise distances between neuronal somata, exhibited heavy-tailed behavior consistent with power-law models across all samples. Maximum likelihood estimation of power-law exponents (α values: 0.87-1.08) strongly supported the heavy-tailed nature of these patterns, showing a better fit with power-law models compared to exponential or normal distributions. Connectivity analyses revealed a dual organizational structure within cortical layers: densely interconnected local clusters coexisting with sparse long-range connections. k-Nearest neighbors graphs demonstrated small-world network properties, with average clustering coefficients ranging from 0.622 to 0.630 across samples. This consistent structural organization aligns with LF principles, wherein local processing is optimized alongside global integration for efficiency and functionality. The implications extend to developmental biology, as the emergence of LF-like patterns likely reflects intrinsic self-organizing processes during embryonic and fetal development. This LF-like organization provides a natural framework for designing artificial networks that optimize performance in tasks requiring both localized specialization and global integration. Moreover, understanding the developmental origins of these patterns could guide strategies for neural repair and regeneration in stroke or neurodegenerative diseases.