bluuebunny/crossref_metadata_2025 huggingface dataset:
IL-1β Signalling Modulates T Follicular Helper and Regulatory Cells in Human Lymphoid Tissues
Authors: Vaineau Romain , Jeger-Madiot Raphaël , Ali-Moussa Samir , Prudhomme Laura , Debarnot Hippolyte , Coatnoan Nicolas , Dubois Johanna , Binvignat Marie , Vantomme Hélène , Gouritin Bruno , Fourcade Gwladys , Engeroff Paul , Belbézier Aude , Luscan Romain , Denoyelle Françoise , Lorenzon Roberta , Ribet Claire , Rosenzwajg Michelle , Bellier Bertrand , Klatzmann David , Tchitchek Nicolas , Graff-Dubois Stéphanie
Published: October 2024

Background

Dysregulation of the T follicular helper (Tfh) and T follicular regulatory (Tfr) homeostasis in the germinal center (GC) can result in antibody-mediated autoimmunity. While interleukin-1β (IL-1β) has been shown to be an important modulator of the GC response in animal models via the expression of IL-1 agonist (IL-1R1) and antagonist (IL-1R2) receptors on follicular T cells, such regulation has not yet been studied in humans.

Methods

We investigated Tfh and Tfr phenotypes in human secondary lymphoid organs — namely tonsils, spleens, and mesenteric lymph nodes — using flow cytometry, single-cell transcriptomics, andin vitrocell culture. We also benchmarked our findings with a cohort of patients with autoimmune and inflammatory diseases.

Results

We found that Tfh and Tfr cells exhibit organ-specific phenotypes related to their activation status and IL-1 receptor expression. An excess of IL-1R1 over IL-1R2 was linked to the emergence of a unique activated Tfr subset that combines features of both Treg and GC-Tfh cells. Single-cell transcriptomics andin vitrostudies showed that IL-1β signaling through IL-1R1 promotes follicular T-cell activation. Inhibiting IL-1β resulted in upregulation of IL-1R1 expression, showing a fine-tuned regulation. In autoimmune patients, high IL-1β and circulating Tfr levels correlated with higher autoantibody levels, linking inflammation, IL-1β signaling, and the Tfr/Tfh balance.

Conclusions

Our study underscores the pivotal role of IL-1β in follicular T-cell activation, contributing to pathological antibody production in humans. Targeting IL-1β signaling in Tfh and Tfr cells could offer new treatment strategies for antibody-mediated autoimmune diseases.
Comparative analysis of Endoxifen, Tamoxifen and Fulvestrant: A Bioinformatics Approach to Uncover Mechanisms of Action in Breast Cancer
Authors: Remmel H. Lawrence , Hammer Sandra S. , Singh Harjinder , Shneyderman Anastasia , Veviorskiy Alexander , Alawi Khadija M. , Korzinkin Mikhail , Zhavoronkov Alex , Quay Steven C.
Published: October 2024

Breast cancer remains a significant health challenge, with estrogen receptor positive (ER+) subtypes being particularly prevalent forms of breast cancer. Current anti-estrogen therapies, such as tamoxifen and fulvestrant, have limitations, including partial agonist activity and resistance development, which evidence the need for more potent alternatives. Endoxifen, a metabolite of tamoxifen, has emerged as a promising breast cancer therapeutic candidate due to its superior anti-estrogenic effects and side effect profile. The omics signatures for endoxifen, tamoxifen and fulvestrant, obtained from publicly available datasets, were aggregated and harmonized by means of the PandaOmics platform, a commercially available target-discovery platform using multiple AI engines including generative pretrained transformers. Pathway enrichment analyses provided insight into these agents’ mechanisms of action (MOA) in breast cancer. The analyses revealed unexpected variances in several key pathways from expected interactions via estrogen-dependent and independent effects. All three drugs downregulated estrogen signaling and cell cycle-related pathways, such as E2F targets, G2-M checkpoints, Myc targets, and mitotic spindle, and stimulated apoptosis. Fulvestrant and tamoxifen activated pro-inflammatory and immune pathways and perturbed epithelial-mesenchymal transition (EMT). Endoxifen perturbed the PI3K/Akt/mTORC1 pathway, pursuant to distinct molecular mechanisms compared to its parent compound, tamoxifen, and fulvestrant. In summary, advanced AI-driven methodologies demonstrate the capacity to analyze multi-omics data in a comparative way to advance the understanding of endocrine therapy mechanisms in breast cancer. This insight into the distinct effects of endoxifen, tamoxifen, and fulvestrant may aid in selecting the most effective therapies for specific indications and in identifying drug-specific biomarkers.
Does sex matter in neurons’ response to hypoxic stress?
Authors: Voogd Eva J.H.F. , Levers Marloes R. , Hofmeijer Jeannette , Frega Monica , van Putten Michel J.A.M.
Published: October 2024

Background

Stroke exhibits significant sex differences in incidence, response to treatment and outcome. Preclinical studies suggest that hormones, particularly estrogens, are key to differential sensitivity, as female neurons demonstrate enhanced resilience compared to males in both in vivo and in vitro models. This study investigates whether these sex-specific differences in neuronal vulnerability extend to the ischemic penumbra and explores the effects of estrogens under such conditions.

Methods

Primary cortical neuronal networks were generated from male and female new-born Wistar rats and cultured on micro-electrode arrays or glass coverslips. Male and female networks were subjected to hypoxic conditions, followed by a recovery phase, with or without exogenous estrogen treatment. Electrophysiological activity, including spikes and bursts, was monitored and analyzed. Apoptosis was assessed through immunocytochemistry, focusing on caspase-dependent and apoptosis inducing factor (AIF)-dependent pathways.

Results

Under hypoxic conditions, male and female neuronal networks exhibited a similar decrease in firing and network burst rates, with an associated increase in network burst durations. Estrogen treatment altered these dynamics, leading to increased network burst rates and decreased network burst duration for both sexes. During recovery, no significant differences were observed between estrogen-treated and untreated networks. Immunocyto-chemistry revealed that estrogen significantly influenced caspase-dependent apoptosis, and to a lesser extent AIF-dependent apoptosis.

Conclusions

In our model of the ischemic penumbra, sex-dependent differences in neuronal responses to hypoxic injury are primarily driven by estrogen, rather than intrinsic neuronal characteristics. Although our electrophysiological data demonstrated that estrogen influenced network activity, it did not offer long-term neuroprotection after hypoxia.
Short-term caloric restriction or resveratrol supplementation alters large-scale brain network connectivity in male and female rats
Authors: van Rooij Judith R.A. , van den Berg Monica , Vasilkosvka Tamara , Van Audekerke Johan , Kosten Lauren , Bertoglio Daniele , Adhikari Mohit H , Verhoye Marleen
Published: October 2024

Introduction: Dietary interventions such as caloric restriction (CR) exert positive effects on brain health. Unfortunately, poor compliance hinders the success of this approach. A proposed alternative is resveratrol (Rsv), a CR–mimetic known to promote brain health. Direct comparison between the effects of Rsv and CR on brain health is lacking, with limited knowledge on their sex-specific effects. Therefore, we aimed to compare and unravel the sex-specific impact of these dietary interventions on spontaneous brain activity. Methods: Here, we used resting-state fMRI to investigate functional connectivity (FC) changes in five prominent resting-state brain networks (RSNs) in healthy four month old male and female F344 rats supplemented to either 40% CR or daily Rsv supplementation (10 mg/kg, oral) for the duration of one month. Results: Our results demonstrated a decreased body weight (BW) in CR rats, as well as an increase in body weight in male Rsv supplemented rats, compared to female Rsv supplemented rats, whereas this difference between sexes was not observed in the control or CR groups. Furthermore, we found that both CR or Rsv supplementation induce a female-specific decrease of FC between the subcortical network and hippocampal network, and between the subcortical network and lateral cortical network. Moreover, Rsv supplementation lowered FC within the hippocampal network and between the hippocampal and the default mode like network, the lateral cortical network and the sensory network – an effect not observed for the CR rats. Finally, we observed an overall lower FC in male rats compared to females, irrespective of dietary intervention, within the subcortical network and between the subcortical, the sensory and default mode like network. Discussion: Our findings reveal that both CR and Rsv induce a similar female–specific decrease of FC in RSNs associated with memory and emotion, all the while CR and Rsv induce dissimilar changes in body weight and other within– and between RSN FC measures. Altogether, this study provides insight into the effects and comparability of short-term CR and Rsv supplementation on brain connectivity within and between RSNs in both male and female F344 rats, providing a FC reference for future research of dietary effects.
Structure of the virulence-associatedNeisseria meningitidisfilamentous bacteriophage MDAΦ
Authors: Böhning Jan , Graham Miles , Coureuil Mathieu , Tarafder Abul K. , Meyer Julie , Nassif Xavier , Bille Emmanuelle , Bharat Tanmay A. M.
Published: October 2024

Neisseria meningitidisis a human commensal bacterium that can opportunistically invade the bloodstream and cross the blood-brain barrier, where it can cause septicaemia and meningitis. These diseases, if left untreated, can be lethal within hours. HyperinvasiveN. meningitidisstrains often express a genomically encoded filamentous bacteriophage called MDAΦ, which promotes colonisation of mucosal host surfaces to facilitate invasion. How this phage is organised and how it promotes biofilm formation and infection at the molecular level is unclear. Here, we present an electron cryomicroscopy structure of the MDA phage, showing that MDAΦ is a class I filamentous inovirus, with the major capsid protein arranged within the phage as a highly curved and densely packed α-helix. Comparison with other filamentous bacteriophages offers clues about inoviral genome encapsidation mechanisms, providing a framework for understanding the evolutionary diversity of inoviruses. A disordered, N-terminal segment in the major capsid protein presents hydrophobic patches on the surface of assembled phage particles, which, together with electron cryotomography data of phage bundles, furnishes a structural rationale for phage-phage interactions that were seen previously in an epithelium adhesion infection model ofN. meningitidis. Taken together, our results shed light on the structure, organisation, and higher order assembly of a biomedically relevant phage encoded in the genome of a human pathogen. Molecular insights gleaned from this study increase our understanding of phage evolution, phage-mediated bacterial adhesion and pathogenicity.
Interspecies systems biology links bacterial metabolic pathways to nematode gene expression, behavior, and survival
Authors: Athanasouli Marina , Loschko Tobias , Rödelsperger Christian
Published: October 2024

All animals live in tight association with complex microbial communities, yet studying the effects of individual bacteria remains challenging. Here, we exploit the system of the bacterial feeding nematodePristionchus pacificus, where specific interactions can be studied in isolation. We sequenced the genomes of 84Pristionchus-associated bacteria to investigate how differences in bacterial metabolic potential affect nematode traits. Specifically, we identified the Paerucumarin biosynthesis pathway as a strong candidate for nematode survival. Hypothesizing that bacterial production of coumarin derivatives contributed to increased lethality, we demonstrated nematicidal effects of two related compounds using supplementation assays. To explore metabolic interactions at a broader scale, we generated nematode transcriptomes for 38 bacterial diets and constructed a coexpression network that revealed distinct developmental and environmental signatures. Interspecies association studies resulted in a bipartite network with more than 2,800 interactions which may assist future studies to identify metabolites affecting various biological processes.
The Composition of the Bacterial Community in Raw Milk from Holstein Dairy Cattle Correlated with the Occurrence ofKlebsiella pneumoniaeClinical Mastitis Infections
Authors: O’Brien Bridget , Jung Dongyun , Park Soyoun , Kurban Daryna , Cai Zhangbin , Nguyen Ngoc Sang , Li Zhiwei , Dufour Simon , Ronholm Jennifer
Published: October 2024

Klebsiella pneumoniaeis a common, opportunistic bacterial pathogen that can cause severe clinical mastitis in dairy cattle. Optimizing the bovine udder microbiome to resist mastitis pathogens is a growing area of research; however, previous work has not examined which members of the mammary microbiome may have antagonistic interactions withK. pneumoniae. In this study, we collected quarter-level milk samples from Holstein dairy cows in Québec, Canada every two weeks for 14 months and analyzed differences in the milk microbiome between samples that were collected from healthy quarters, quarters that developed subclinical mastitis, and quarters that experiencedK. pneumoniaeclinical mastitis (KP-CM) (n= 512 milk samples). The occurrence of subclinical mastitis did not cause significant differences in the alpha-diversity of the milk microbiome, nor did subclinical mastitis alter the interactions between taxa in the microbiome. However, the occurrence of KP-CM caused reductions in Shannon diversity in raw milk relative to healthy milk and altered the interactions between taxa. Specifically,K. pneumoniaeshowed negative interactions with the genusAerococcus.The negative interactions betweenAerococcusspp. andK. pneumoniaein the context of the bovine milk microbiome should be analyzed further.
ChIPbinner: An R package for analyzing broad histone marks binned in uniform windows from ChIP-Seq or CUT&RUN/TAG data
Authors: Padilla R. , Bareke E. , Hu B. , Majewski J.
Published: October 2024

Background

The decreasing costs of sequencing, along with the growing understanding of epigenetic mechanisms driving diseases, have led to the increased application of chromatin immunoprecipitation (ChIP-Seq), Cleavage Under Targets & Release Using Nuclease (CUT&RUN) and Cleavage Under Targets and Tagmentation (CUT&TAG) sequencing – which are designed to map DNA or chromatin-binding proteins to their genome targets – in biomedical research. Existing software tools, namely peak-callers, are available for analyzing data from these technologies, although they often struggle with diffuse and broad signals, such as those associated with broad histone post-translational modifications (PTMs).

Results

To address this limitation, we present ChIPbinner, an open-source R package tailored for reference-agnostic analysis of broad PTMs. Instead of relying on pre-identified enriched regions from peak-callers, ChIPbinner divides (bins) the genome into uniform windows. Thus, users are provided with an unbiased method to explore genome-wide differences between two samples using scatterplots, principal component analysis (PCA), and correlation plots. It also facilitates the identification and characterization of differential clusters of bins, allowing users to focus on specific genomic regions significantly affected by treatments or mutations. We demonstrated the effectiveness of this tool through a case study assessing H3K36me2 depletion following NSD1 knockout in head and neck squamous cell carcinoma, highlighting the advantages of ChIPbinner in detecting broad histone mark changes over existing software.

Conclusions

Binned analysis provides a more holistic view of the genomic landscape, allowing researchers to uncover broader patterns and correlations that may be missed when solely focusing on individual peaks. ChIPbinner offers researchers a convenient tool to perform binned analysis. It improves on previously published software by providing a clustering approach that is independent of each bin’s differential enrichment status, while also offering additional features for downstream analysis of these differentially enriched bins.
Understanding genetic diversity and phylogeography of Common Teal and its phylogenetic relationship with other water bird species in the wetlands of Kashmir Himalayas
Authors: Ahmad Khursheed , Bisht Divyanshi , Joshi Bheem Dutt , Goyal Surender P. , Nigam Parag , Khan Khurshid Alam , Haq Iqram ul , Javid Mohsin
Published: October 2024

Understanding the genetic diversity and phylogeography of migratory species is critical for biodiversity conservation and the effective management of wetland ecosystems. The Kashmir Himalayas, an integral part of the Central Asian Flyway, host several key wetlands that provide critical wintering grounds for a variety of migratory birds.

This study focuses on assessing the genetic characteristics and phylogenetic relationships of the Common Teal (Anas crecca) in comparison to other species within the families Anatidae and Rallidae. We analysed 149 blood samples, including 71 fromA. creccaand 78 from other species in the two families, collected from wetlands in the Kashmir region. Using four mitochondrial markers—cytochrome oxidase subunit I (COI), cytochrome b (Cyt b), 16S rRNA, and the control region—we evaluated the genetic diversity and lineage connectivity of these species.

Our findings reveal that the mitochondrial DNA haplotypes ofA. creccain the Kashmir Himalayas are shared with European populations, indicating strong maternal gene flow and connectivity between distant populations. A minimum spanning haplotype network analysis showed minimal nucleotide differences among haplotypes, particularly in the Cyt b and control regions, suggesting low genetic differentiation and a high degree of similarity among individuals. Notably, we identified at least four distinct maternal lineages ofA. creccain the Kashmir wetlands, reflecting diverse migratory sources.

Our results also highlight that DNA barcoding using COI exhibited both high and low species resolution, with significant intraspecific variation, making it a valuable tool for further phylogeographic studies. The observed genetic diversity and haplotype sharing with distant populations underscore the ecological importance of Kashmir’s wetlands as crucial habitats for migratory species. Our study emphasizes the need for targeted conservation and management strategies to preserve these vital ecosystems and the biodiversity they support.
A membrane-targeted photoswitch restores physiological ON/OFF responses to light in the degenerate retina
Authors: Ziraldo Gaia , Cupini Sara , Sesti Valentina , Delfino Emanuela , Lanzani Guglielmo , Bertarelli Chiara , Benfenati Fabio , Di Marco Stefano
Published: October 2024

The lack of effective therapies for visual restoration inRetinitis pigmentosaand macular degeneration has led to the development of new strategies such as optogenetics and retinal prostheses. However, visual restoration is poor due to the massive light-evoked activation of retinal neurons, regardless of the segregation of visual information in ON and OFF channels, essential for contrast sensitivity and spatial resolution. Here, we show that Ziapin2, a membrane photoswitch which modulates neuronal capacitance and excitability in a light-dependent manner, is capable of reinstating, in two distinct genetic models of photoreceptor degeneration, brisk and sluggish ON, OFF, and ON-OFF responses in retinal ganglion cells evoked by full-field stimuli, with reactivation of their excitatory and inhibitory conductances. Intravitreally injected Ziapin2 in fully blind rd10 mice restored light-driven behavior and optomotor reflexes. The results indicate that Ziapin2 is a promising molecule for reinstating physiological visual responses in the late stages of retinal degeneration.
Nanotextured steel surface exhibits antifungal activity
Authors: Tripathi Anuja , Champion Julie A.
Published: October 2024

Fungal adhesion to stainless steel, an alloy commonly used in food and beverage sectors, public and healthcare settings, and numerous medical devices, can give rise to serious infections, ultimately leading to morbidity, mortality, and significant healthcare expenses. In this study, we demonstrate that nanotextured stainless steel (nSS) fabricated using an electrochemical technique is an antibiotic-free biocidal surface againstCandida AlbicansandFusarium Oxysporumwith 98% and 97% reduction, respectively. The nanoprotrusion features on nSS can have both physical contact with cell membranes and chemical impact on cells through production of reactive species, this material should not contribute to drug resistant fungus as antibiotics can. As nSS is also antibacterial and compatible with mammalian cells, demonstration of antifungal activity gives nSS the potential to be used to create effective, scalable, and sustainable solutions to broadly and responsibly prevent fungal and other microbial infections caused by surface contamination.

Abstract Figure
De-novoGenome Assembly of the Edwardsiid AnthozoanEdwardsia elegans
Authors: Rutlekowski Auston , Modepalli Vengamanaidu , Ketchum Remi , Moran Yehu , Reitzel Adam
Published: October 2024

Cnidarians (sea anemones, corals, hydroids, and jellyfish) are a key outgroup for comparisons with bilaterial animals to trace the evolution of genomic complexity and diversity within the animal kingdom, as they separated from most other animals 100s of millions of years ago. Cnidarians have extensive diversity, yet the paucity of genomic resources limits our ability to compare genomic variation between cnidarian clades and species. Here we report the genome forEdwardsia elegans, a sea anemone in the most specious genus of the family Edwardsiidae, a phylogenetically important family of sea anemones that contains the model anemoneNematostella vectensis. TheE. elegansgenome is 396 Mb and predicted to encode approximately 49,000 proteins. We annotated large conservation of macrosynteny betweenE. elegansand other Edwardsiidae anemones as well as conservation of both microRNAs and ultra conserved noncoding elements previously reported in other cnidarians species. We also highlight microsyntenic variation of clustered developmental genes and ancient gene clusters that vary between species of sea anemones, despite previous research showing conservation between cnidarians and bilaterians. Overall, our analysis of theE. elegansgenome highlights the importance of using multiple species to represent a taxonomic group for genomic comparisons, where genomic variation can be missed for large and diverse clades.
High Throughput Morphological Screening Identifies Chemically Defined Media for Mesenchymal Stromal Cells that Enhances Proliferation and Supports Maintenance of Immunomodulatory Function
Authors: Spoerer Thomas M. , Larey Andrew M. , Asigri Winifred , Daga Kanupriya R. , Marklein Ross A.
Published: October 2024

While mesenchymal stromal cell (MSC) therapies show promise for treating several indications due to their regenerative and immunomodulatory capacity, clinical translation has yet to be achieved due to a lack of robust, scalable manufacturing practices. Expansion using undefined fetal bovine serum (FBS) or human platelet lysate contributes to MSC functional heterogeneity and limits control of product quality. The need for tunable and consistent media has thus encouraged development of chemically defined media (CDM). However, CDM development strategies are rarely comprehensive nor considerate of a medium’s impact on MSC therapeutic function. Standard practice often neglects high-level interactions of media components, such as growth factors, that are critical to MSC growth and function. Given that MSC morphology has been shown to predict their immunomodulatory function, we employed a high throughput screening (HTS) approach to elucidate effects of growth factor compositions on MSC phenotype and proliferation in a custom CDM. This approach led to the discovery and refinement of several formulations that enhanced MSC proliferation and demonstrated wide ranging impacts on MSC immunomodulation. Overall, this work reflects how our novel HTS approach serves as a generalizable tool for the comprehensive improvement of MSC manufacturing processes.
Optimal Control of Spiking Neural Networks
Authors: Costa Tiago , Castiñeiras de Saa Juan R. , Renart Alfonso
Published: October 2024

Control theory provides a natural language to describe multi-areal interactions and flexible cognitive tasks such as covert attention or brain-machine interface (BMI) experiments, which require finding adequate inputs to a local circuit in order to steer its dynamics in a context-dependent manner. In optimal control, the target dynamics should maximize a notion of long-term value along trajectories, possibly subject to control costs. Because this problem is, in general, not tractable, current approaches to the control of networks mostly consider simplified settings (e.g., variations of the Linear-Quadratic Regulator). Here, we present a mathematical framework for optimal control of recurrent networks of stochastic spiking neurons with low-rank connectivity. An essential ingredient is a control-cost that penalizes deviations from the default dynamics of the network (specified by its recurrent connections), which motivates the controller to use the default dynamics as much as possible. We derive a Bellman Equation that specifies a Value function over the low-dimensional network state (LDS), and a corresponding optimal control input. The optimal control law takes the form of a feedback controller that provides external excitatory (inhibitory) synaptic input to neurons in the recurrent network if their spiking activity tends to move the LDS towards regions of higher (lower) Value. We use our theory to study the problem of steering the state of the network towards particular terminal regions which can lie either in or out of regions in the LDS with slow dynamics, in analogy to standard BMI experiments. Our results provide the foundation of a novel approach with broad applicability that unifies bottom-up and top-down perspectives on neural computation.
A 3D Image Segmentation Study of U-Net on CT Images of the Human Aorta with Morphologically Diverse Anatomy
Authors: Chen Jiasong , Qian Linchen , Wang Pengce , Sun Christina , Qin Tongran , Kalyanasundaram Asanish , Zafar Mohammad , Elefteriades John , Sun Wei , Liang Liang
Published: October 2024

For the machine learning -assisted diagnosis of cardiac diseases, such as thoracic aortic aneurysm, the geometries of the heart and blood vessels need to be reconstructed from medical images, which is usually done by image segmentation followed by meshing. In this study, we applied U-Net (2D and 3D versions), a deep neural network with a U-shaped architecture, to segment human aorta from CT images. From our experiments, we have the following observations: (1) 2D U-Net, which segments each of the 2D slices of a 3D CT image independently, produced erroneous fragments (e.g., missing part of the aorta) and boundaries (i.e., aortic walls) in 3D; (2) 3D U-Net, which does segmentation in 3D regions of a 3D CT image, performed much better than 2D U-Net. We also observe the major weakness of the 3D U-Net: the reconstructed geometries of the aortic wall had large errors (measured by HD95) for some cases. The 3D U-Net in this study serves as a baseline for developing more advanced architectures of deep neural networks for more accurate geometry reconstruction of human aorta.
Gas1-Mediated Suppression of Hepatoblastoma Tumorigenesis
Authors: Chen Keyao , Wang Huabo , Ma Bingwei , Knapp Jessica , Henchy Colin , Lu Jie , Stevens Taylor , Ranganathan Sarangarajan , Prochownik Edward V.
Published: October 2024

Background and Aims

Hepatoblastoma (HB), the most common pediatric liver cancer, often dysregulates the Wnt/β-catenin, Hippo and NFE2L2/NRF2 pathways. Pairwise combinations of oncogenically active forms of the terminal transcription factor effectors of these pathways, namely β-catenin (B), YAP (Y) and NRF2 (N) generate HBs in mice, with the triple combination (B+Y+N) being particularly potent. Each tumor group alters the expression of thousands of B-,Y- and N-driven unique and common target genes. Identifying those most responsible for transformation is thus an important question as it might reveal new mechanistic insights and therapeutic opportunities.

Approach and Results

Transcriptional profiling of >60 murine HBs driven by the above oncogenic combinations and different B mutants and in genetic backgrounds that impair tumor growth rates but not initiation has revealed a common set of 22 “BYN genes” that are similarly deregulated in all cases. Many are associated with multiple “Cancer Hallmarks” and their expression levels often correlate with survival in human HBs, hepatocellular carcinomas and other cancers. Among the most down-regulated of these isGas1, which encodes a Glycosylphosphatidylinositol (GPI)-linked outer membrane protein. We show here that restoring Gas1 expression impairs B+Y+N-driven HB tumor growthin vivoand in HB-derived immortalized cell linesin vitroin a manner than requires membrane anchoring of the protein via its GPI moiety.

Conclusions

Our findings implicate Gas1 as a proximal mediator of HB pathogenesis and validate the BYN gene set as one deserving of closer additional scrutiny in future studies.
Oligodendrocytes use postsynaptic proteins to coordinate myelin formation on axons of distinct neurotransmitter classes
Authors: Carey Natalie J. , Doll Caleb A. , Appel Bruce
Published: October 2024

Axon myelination can tune neuronal circuits through placement and modulation of different patterns of myelin sheaths on distinct types of axons. How myelin formation is coordinated on distinct axon classes remains largely unknown. Recent work indicates neuronal activity and vesicle release promote myelin formation, and myelin-producing oligodendrocytes express canonical postsynaptic factors that potentially facilitate oligodendrocyte-axon interaction for myelin ensheathment. Here, we examined whether the inhibitory postsynaptic scaffold protein Gephyrin (Gphn) mediates selective myelination of specific axon classes in the larval zebrafish. Consistent with this possibility, Gphn was enriched in myelin on GABAergic and glycinergic axons. Strikingly, ingphnbdeficient larvae, myelin sheaths were longer specifically on GABAergic axons, and the frequency of myelin placement shifted toward glutamatergic axons at the expense of GABAergic axons. Collectively, our results indicate that oligodendrocytes use postsynaptic machinery to coordinate myelin formation in an axon identity-dependent manner.
Theta-gamma transcranial alternating current stimulation enhances motor skill acquisition in healthy young and older adults
Authors: Gamage Nishadi N. , Liao Wei-Yeh , Hand Brodie J. , Atherton Philip J. , Piasecki Mathew , Opie George M. , Semmler John G.
Published: October 2024

Theta-gamma transcranial alternating current stimulation (TG tACS) over primary motor cortex (M1) can improve motor skill acquisition in young adults, but the effect on older adults is unknown. This study investigated the effects of TG tACS on motor skill acquisition and M1 excitability in 18 young and 18 older adults. High-definition TG tACS (6 Hz theta, 75 Hz gamma) or sham tACS was applied over right M1 for 20 minutes during a ballistic left-thumb abduction motor training task performed in two experimental sessions. Motor skill acquisition was quantified as changes in movement acceleration during and up to 60 minutes after training. Transcranial magnetic stimulation (TMS) was used to assess changes in M1 excitability with motor-evoked potentials (MEP) and short-interval intracortical inhibition (SICI) before and after training. We found that TG tACS increased motor skill acquisition compared with sham tACS in young and older adults (P< 0.001), with greater effects for young adults (P= 0.01). The improved motor performance with TG tACS lasted at least 60 minutes after training in both age groups. Motor training was accompanied by greater MEP amplitudes with TG tACS compared to sham tACS in young and older adults (P< 0.001), but SICI did not vary between tACS sessions (P= 0.40). These findings indicate that TG tACS over M1 improves motor skill acquisition and alters training-induced changes in M1 excitability in healthy young and older adults. TG tACS may therefore be beneficial to alleviate motor deficits in the ageing population.

Key Points Summary

Theta-gamma transcranial alternating current stimulation (TG tACS) can improve motor function in healthy young adults, but the effect on older adults is unknown.

We found that TG tACS improved motor skill acquisition with long-lasting effects in healthy young and older adults, but effects were stronger in young adults.

Transcranial magnetic stimulation showed that TG tACS altered the training-induced changes in motor cortex excitability, but there was no effect of TG tACS on intracortical inhibition in young or older adults.

Our data suggest that TG tACS represents a promising approach to improve motor skill acquisition throughout the lifespan, and may be beneficial in older patient populations that experience motor or cognitive deficits.
A new compression strategy to reduce the size of nanopore sequencing data
Authors: Jayasooriya Kavindu , Jenner Sasha P. , Marasinghe Pasindu , Senanayake Udith , Saadat Hassaan , Taubman David , Ragel Roshan , Gamaarachchi Hasindu , Deveson Ira W.
Published: October 2024

Nanopore sequencing is an increasingly central tool for genomics. Despite rapid advances in the field, large data volumes and computational bottlenecks continue to pose major challenges. Here we introduceex-zd, a new data compression strategy that helps address the large size of raw signal data generated during nanopore experiments.Ex-zdencompasses both a lossless compression method, which modestly outperforms all current methods for nanopore signal data compression, and a ‘lossy’ method, which can be used to achieve dramatic additional savings. The latter component works by reducing the number of bits used to encode signal data. We show that the three least significant bits in signal data generated on instruments from Oxford Nanopore Technologies (ONT) predominantly encode noise. Their removal reduces file sizes by half without impacting downstream analyses, including basecalling and detection of DNA methylation.Ex-zdcompression saves hundreds of gigabytes on a single ONT sequencing experiment, thereby increasing the scalability, portability and accessibility of nanopore sequencing.
Adaptation, not prediction, drives neuronal spiking responses in mammalian sensory cortex
Authors: Westerberg Jacob A. , Xiong Yihan S. , Nejat Hamed , Sennesh Eli , Durand Séverine , Hardcastle Ben , Cabasco Hannah , Belski Hannah , Bawany Ahad , Gillis Ryan , Loeffler Henry , Peene Carter R. , Han Warren , Nguyen Katrina , Ha Vivian , Johnson Tye , Grasso Conor , Young Ahrial , Swapp Jackie , Ouellette Ben , Caldejon Shiella , Williford Ali , Groblewski Peter A. , Olsen Shawn R. , Kiselycznyk Carly , Lecoq Jerome A. , Maier Alexander , Bastos André M.
Published: October 2024

Predictive coding (PC) hypothesizes that the brain computes internal models of predicted events and that unpredicted stimuli are signaled with prediction errors that feed forward. We tested this hypothesis using a visual oddball task. A repetitive sequence interrupted by a novel stimulus is a “local” oddball. “Global” oddballs defy predictions while repeating the local context, thereby dissociating genuine prediction errors from adaptation-related responses. We recorded neuronal spiking activity across the visual hierarchy in mice and monkeys viewing these oddballs. Local oddball responses largely followed PC: they were robust, emerged early in layers 2/3, and fed forward. Global oddball responses challenged PC: they were weak, absent in most visual areas, more robust in prefrontal cortex, emerged in non-granular layers, and did not involve inhibitory interneurons relaying predictive suppression. Contrary to PC, genuine predictive coding does not emerge early in sensory processing, and is instead exclusive to more cognitive, higher-order areas.

Highlights

Core principles of Predictive Coding explain local, but not global oddball brain responses

Global oddballs are sparsely encoded in visual cortex and do not engage feedforward mechanisms

Parvalbumin and somatostatin interneurons do not support sensory global oddball detection

Global oddballs are earliest, and most robustly encoded, in prefrontal brain areas

Significance

Global oddballs defy our expectations without standing out from their local context. Whether they are encoded in sensory brain areas was uncertain. Through multiarea neurophysiological recordings in mice and monkeys, Westerberg et al. show that global oddballs neuronal responses contradicts predictive coding hypotheses and emerge in higher order areas.
Pharmacological inhibition of Fms-like kinase 3 (FLT3) promotes neuronal maturation and suppresses seizure in a mouse model
Authors: Cruite Kate , Moore Madeline , Gallagher Michael D. , Coleman Emanuel M. , Yin Yuqin , Lin Shuqi , Shahbo Ellie , Lungjangwa Tenzin , Hovestadt Volker , Jaenisch Rudolf , Maguire Jamie , Tang Xin
Published: October 2024

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase predominantly expressed in blood and brain cells. While the FLT3 signaling pathway has been extensively studied in blood cell development and leukemia, its role in the brain remains largely unexplored. Through our group’s previous high-throughput drug screening work unexpectedly found that several small molecule FLT3 inhibitors (FLT3i), including KW-2449 and Sunitinib, enhance expression of the gene encoding chloride transporter KCC2 in neurons. KCC2 is crucial for brain development and function, and its dysregulation is linked to many brain diseases. These findings suggest previously unrecognized roles of FLT3 signaling in brain health and disease that have yet to be systematically studied. In this study, we utilized a functional genomics approach to investigate the transcriptomic changes induced by pharmacological inhibition of the FLT3 pathway in brain cells, including cultured primary mouse neurons, a human stem cell-derived neuronal model of Rett syndrome (RTT), and human stem cell-derived microglia cultures. Our results show that treating human or mouse neurons with FLT3i drugs significantly upregulates genes crucial for brain development while downregulating genes linked to neuroinflammation. In contrast, FLT3i treatment of human microglia, which do not express FLT3, has no effect on their gene expression, highlighting the cell type-specific roles of FLT3 signaling in the brain. To further understand how FLT3 signaling regulates the expression of neuronal maturation genes such as KCC2, we conducted a curated CRISPR screen that identified a number of transcription factors involved in FLT3i-mediated KCC2 activation in neurons. The mRNA and protein levels of several neurodevelopmental disorder (NDD) risk genes are significantly upregulated in FLT3i-treated neurons, indicating potential therapeutic applications of FLT3i in rescuing underexpression and/or haploinsufficiency of disease-associated genes. In ourin vivostudies, we evaluated the efficacy of the FLT3i drug KW-2449 in mice, demonstrating that it can effectively cross the blood-brain barrier, induce KCC2 protein expression for up to 24 hours after a single injection, and reduces seizure activity in a chemoconvulsant-induced mouse model of temporal lobe epilepsy. Collectively, our findings uncover previously unrecognized roles of neuron-specific FLT3 signaling in promoting neuronal maturation and reducing neuroinflammation. These results suggest that FLT3 kinase signaling regulates a transcriptional program vital for brain development and function, position it as a promising therapeutic target for NDD treatment.
Tissue-specific transcriptomics uncovers novel craniofacial genes underlying jaw divergence in specialist pupfishes
Authors: Palominos M. Fernanda , Muhl Vanessa , Martin Christopher H.
Published: October 2024

The regulation of gene expression is one of the key evolutionary processes driving phenotypic divergence among species. Here, we investigate the tissue-specific gene expression of a non-model adaptive radiation ofCyprinodonpupfishes, characterized by their divergent dietary niches and exceptionally fast rates of craniofacial evolution. By comparing tissue-specific gene expression in the most morphologically divergent skeletal structure, the oral jaws, with the relatively morphologically conserved caudal tail region, we identified genes that were differentially expressed exclusively in the developing jaws of each of the three trophic specialists at hatching (8 dpf) and not in any other species. We then assessed their overlap (as transcriptionally-regulated genes) with adaptive regulatory variants identified in previous genomic studies. Our analysis identifiedpycr3andatp8a1as the most promising for craniofacial evolution in the scale-eaters, both genes with no known previous craniofacial function. We functionally confirmed the craniofacial expression of these genes byin situmRNA hybridization chain reaction and demonstrated their species-specific expression in branchial and muscle tissues between sister species of this young radiation. Our work underscores the power of integrating tissue-specific transcriptomics with speciation genomics to identify novel craniofacial candidate genes controlling divergent morphogenesis in a natural ‘evolutionary mutant’ system.
BoMBR: An Annotated Bone Marrow Biopsy Dataset for Segmentation of Reticulin Fibers
Authors: Raina Panav , Dharamdasani Satyender , Chinnam Dheeraj , Sharma Praveen , Gupta Sukrit
Published: October 2024

Bone marrow reticulin fibrosis is associated with varied benign as well as malignant hematological conditions. The assessment of reticulin fibrosis is important in the diagnosis, prognostication and management of such disorders. The current methods for quantification of reticulin fibrosis are inefficient and prone to errors. Therefore, there is a need for automated tools for accurate and consistent quantification of reticulin. However, the lack of standardized datasets has hindered the development of such tools. In this study, we present a comprehensive dataset that comprises of 201BoneMarrowBiopsy images forReticulin (BoMBR) quantification. These images were meticulously annotated for semantic segmentation, with the focus on performing reticulin fiber quantification. This annotation was done by two trained hematopathologists who were aided by Deep Learning (DL) models and image processing techniques that generated a rough automated annotation for them to start with. This ensured precise delineation of the reticulin fibers alongside other cellular components such as bony trabeculae, fat, and cells. This is the first publicly available dataset in this domain with the aim to catalyze advancements the development of computational models for improved reticulin quantification. Further, we show that our annotated dataset can be used to train a DL model for a multi-class semantic segmentation task for robust reticulin fiber detection task (Mean Dice score: 0.92). We use these model outputs for the Marrow Fibrosis (MF) grade detection and obtained a Mean Weighted Average F1 score of 0.656 with our trained model. Our code for preprocessing the dataset is available athttps://github.com/AI-in-Medicine-IIT-Ropar/BoMBR_dataset_preprocessing.
Metagenomic Insights into the Spatio-temporal Variation of Metal and Antibiotic Resistance Genes in Lake Erie
Authors: Reddy Saahith , Kiledal E. Anders
Published: October 2024

Antibiotic resistance and metal toxicity in freshwater bodies have human health impacts and carry economic implications worldwide. The presence of metal and antibiotic resistance genes within microbial communities can be informative about both issues. The Laurentian Great Lakes contain nearly 20% of the world’s supply of freshwater; however, it is unclear how these genes are changing over time in this system. In this study, we characterized these genes in nearly two hundred metagenomes collected from multiple sites in western Lake Erie at a five-year time interval: 2014-2019. 11 metal resistance genes (MRGs) and nine antibiotic resistance genes (ARGs) were characterized and demonstrated significant changes in diversity and spatial distribution. Increased abundance was observed for genes likeaac(3)andTEM-1Bconferring resistance to aminoglycoside (gentamicin) and β-lactam antibiotics, respectively. MRGs associated with mercury, lead, and arsenic also increased in abundance over the five years. Collectively, our data point to a notable increase in both ARGs and MRGs in Lake Erie over five years, with a specific and significant increase in the abundance of genes conferring resistance to aminoglycoside and β-lactam antibiotic resistance and mercury contamination. Future integrated and systematic freshwater microbiome and public health investigations are needed to assess the potential impact on humans and environmental health from increasing microbial antibiotic and metal resistance in large freshwater reservoirs like the Great Lakes.

IMPORTANCE

Antibiotic and metal resistance genes (ARGs and MRGs) in microbial communities of the Laurentian Great Lakes have significant human and environmental health implications. However, an assessment of the Great Lakes’ microbiome for ARGs and MRGs is lacking. The abundance of 11 MRGs and 9 ARGs was characterized between 2014 and 2019 and showed significant abundance differences. Specifically, we observed an increase in genes conferring resistance to aminoglycoside (gentamicin) and β-lactam antibiotics (amongst the most commonly utilized antibiotics in humans), such asaac(3)andTEM-1B,respectively. MRGs conferring resistance to mercury, lead, and arsenic also increased in abundance, with the largest increase observed for mercury resistance genes such asMerA, MerP,andMerT. Collectively, these findings point to a concerning increased abundance of both ARGs and MRGs in Lake Erie. Further studies to assess the causes for the increase and the direct impact on human and environmental health are needed.
Interaction hierarchy among Cdv proteins drives recruitment to membrane necks
Authors: De Franceschi Nicola , Blanch-Jover Alberto , Dekker Cees
Published: October 2024

Cell division in the crenarchaea is accomplished by the Cdv system. In Sulfolobus cells, it was observed that an initial non-contractile ring of CdvA and CdvB forms at the mid location of the cell, which is followed by a second ring of CdvB1 and CdvB2 that appear to drive the constriction of the cell membrane. Here, we use anin vitroreconstituted system to explore how protein interactions among these Cdv proteins govern their recruitment to the membrane. We show that CdvA does not bind the membrane unless in complex with CdvB. We find that CdvB2 can polymerize if its self-inhibitory domain is removed, and that by itself is exhibits poor binding to the membrane. However, CdvB2 can be efficiently recruited to the membrane by both CdvB1 and CdvB. Furthermore, the CdvB1:CdvB2 co-polymer can be recruited to the membrane by CdvA:CdvB. By reconstituting these proteins in dumbbell-shaped liposomes, we show that Cdv proteins have a strong preference to localize at membrane necks of high curvature. Our findings clarify many of the mutual protein interactions of the Cdv system and their interaction with the membrane, thus helping to build a mechanistic understanding of cell division in archaeal cells.