bluuebunny/crossref_metadata_2025 huggingface dataset:
The 3D genomics of lampbrush chromosomes highlights the role of active transcription in chromatin organization
Authors: Lagunov T. , Gridina M. , Nurislamov A. , Kulikova T. , Maslova A. , Konstantinov V. , Popov A. , Krasikova A. , Fishman V.
Published: January 2025

Lampbrush chromosomes are giant meiotic bivalents in growing oocyte nuclei that have served as a classic model system for studying chromatin organization and RNA synthesis for over a century. Despite their importance, the molecular mechanisms underlying lampbrush chromosomes formation and their distinctive chromomere-loop architecture have remained poorly understood. Here, we provide the first comprehensive genomic, cytological, and biophysical analysis of lampbrush chromosome organization by integrating single-cell Hi-C, RNA-seq, NOMe-seq, FISH mapping, and chromatin simulations. Single-nucleus Hi-C analysis revealed CTCF-independent contact domains with stable boundaries defined by transcription units in a convergent orientation. Сontact domains identified through Hi-C analysis correspond to insulated chromomeres in lampbrush chromosomes. Small transcriptionally inactive contact domains surrounded by transcription units in the diverged orientation form ‘chromatin knots’, which are often detached from the chromosome axis. Transcription loops frequently manifest as a ‘cross’ pattern with reduced contacts within chromatin domains. Integrative analysis of the whole-genome data uncovers the mechanisms underlying lampbrush chromosome structure, revealing how hypertranscription modulates chromatin stiffness and repositions SMC complexes to establish the distinctive chromomere-loop organisation. Biophysical modeling through polymer simulation reproduces key features of lampbrush chromosomes, including transcription loop formation, chromomere compaction, and insulation patterns. These findings offer a unifying framework for understanding the remarkable chromatin architecture of lampbrush chromosomes and their transcription-dependent organization.

Highlights

-

First integration of single-cell Hi-C, RNA-seq, NOMe-seq and microscopy methods uncovers molecular mechanisms underlying lampbrush chromosome architecture.

-

Hi-C reveals contact patterns corresponding to lampbrush chromomeres and transcription loops, validated through BAC-based FISH mapping.

-

Lampbrush chromosomes are segmented into contact domains formed via a CTCF-independent mechanism, with boundaries coinciding with convergently oriented gene pairs.

-

Hypertranscription shapes lampbrush chromosome through multiple mechanisms, increasing stiffness and decreasing compaction of transcribed units, generating outward pressure, pushing transcription loops away from the chromosome axis, and repositioning SMC complexes to form transcription-dependent domains with stable boundaries.

-

Polymer simulations including these mechanisms replicate key features of LBC organization, supporting the proposed model of lampbrush chromosomes formation.

Graphical Abstract
Hypoxia modulates human pulmonary arterial adventitial fibroblast phenotype through HIF-1α activation
Authors: Philip Jennifer L , Caneba Christine A , Caggiano Laura R , Prakash Nandhini , Cheng Tik-Chee , Barlow Katherine A. , Mustafa Tasneem , Tabima Diana M , Hacker Timothy A , Masters Kristyn S , Chesler Naomi C
Published: January 2025

Hypoxic pulmonary hypertension (HPH) develops in association with diseases characterized by low oxygen levels leading to pulmonary artery (PA) narrowing and death. Hypoxia has been linked to increased PA collagen and changes in PA adventitial fibroblast (PAAF) metabolism. However, the mechanisms by which hypoxia regulates PAAF function are unknown. Hypoxia-inducible factor-1α (HIF-1α) is a subunit of a transcription factor that is degraded in normoxia but stabilized in hypoxia and is involved in extracellular matrix remodeling by fibroblasts. We examined the role of hypoxia and HIF-1α in regulating PAAF function. Human PAAF (HPAAF) were cultured in normoxic and hypoxic conditions. Cells were further treated with HIF1-α inhibitor or no drug. Protein expression, mRNA expression, enzyme activity, and metabolite concentration were examined. Male C57BL6/J mice were exposed to 0 or 10 days of hypoxia after which right ventricular hemodynamics and tissue metabolism were assessed. Hypoxia led to an increase in collagen content and decrease in matrix metalloproteinase-2 (MMP2) activity. HIF-1α inhibition limited collagen accumulation and restored MMP2 activity. HPAAF demonstrated elevated lactic acid concentration and decreased ATP in hypoxia. HIF-1α inhibition blunted these effects. Mice exposed to hypoxia developed significant elevation in right ventricle systolic pressures and had decreased ATP levels in pulmonary tissue. This study investigated the mechanisms by which hypoxia drives HPAAF-mediated collagen accumulation and metabolic changes. We identify the key role of HIF-1α in regulating changes. These findings provide important insights into understanding HPAAF-mediated PA remodeling and help identify possible novel therapeutic targets.
Light-activated tetanus neurotoxin for conditional proteolysis and inducible synaptic inhibitionin vivo
Authors: Roh Heegwang , Kim Dongwook , Kim Byeongchan , Jeon Younghyeon , Kim Yeonghye , Jacko Martin , Xu Fei , Lin Chang , Um Ji Won , Ting Alice Y.
Published: January 2025

The light chain of tetanus neurotoxin (TeNT) is a 52 kD metalloprotease that potently inhibits synaptic transmission by cleaving the endogenous vesicle fusion protein VAMP2. To mitigate the toxicity of TeNT and harness it as a conditional tool for neuroscience, we engineered Light-Activated TeNT (LATeNT) via insertion of the light-sensitive LOV domain into an allosteric site. LATeNT was optimized by directed evolution and shown to have undetectable activity in the dark mammalian brain. Following 30 seconds of weak blue light exposure, however, LATeNT potently inhibited synaptic transmission in multiple brain regions. The effect could be reversed over 24 hours. We used LATeNT to discover an interneuron population in hippocampus that controls anxiety-like behaviors in mouse, and to control the secretion of endogenous insulin from pancreatic beta cells. Synthetic circuits incorporating LATeNT converted drug, Ca2+, or receptor activation into transgene expression or reporter protein secretion. Due to its large dynamic range, rapid kinetics, and highly specific mechanism of action, LATeNT should be a robust tool for conditional proteolysis and spatiotemporal control of synaptic transmissionin vivo.
Clonal relationships between Tph and Tfh cells in patients with SLE and in murine lupus
Authors: Sasaki Takanori , Sowerby John , Xiao Yinan , Wang Runci , Marks Kathryne E. , Horisberger Alice , Gao Yidan , Lee Pui Y. , Qu Yujie , Sze Marc A. , Alves Stephen E. , Levesque Marc C. , Fujio Keishi , Costenbader Karen H. , Rao Deepak A.
Published: January 2025

Pathologic T cell-B cell interactions drive disease in systemic lupus erythematosus (SLE). The T cells that activate B cell responses include T peripheral helper (Tph) and T follicular helper (Tfh) cells, yet the developmental and clonal relationships between these B cell-helper T cell populations are unclear. Here we use T cell receptor (TCR) profiling to demonstrate clonal overlap between Tph and Tfh cells in the circulation of patients with SLE. Expanded Tph and Tfh cell clones persist over the course of 1 year in patients with a new diagnosis of SLE, and clones are observed to shift both from Tfh to Tph cells and from Tph to Tfh cells over time. High resolution analysis of cells sorted as Tph cells (CXCR5-PD-1hi) and Tfh cells (CXCR5+PD-1hi) from SLE patients revealed considerable heterogeneity among cells sorted as Tph cells and highlighted a specific cluster of cells that expressed transcriptomic features of activated B cell-helper T cells. This cell population, marked by expression ofTOXandCXCL13,was found in both sorted Tph and Tfh cells, and was clonally linked in these two populations. Analysis of B cell-helper T cells in murine pristane-induced lupus demonstrated similar populations of Tph and Tfh cells in both lung and spleen with strong clonal overlap. T cell-specific loss of Bcl6 prevented accumulation of Tfh cells and reduced accumulation of Tph cells in pristane-treated mice, indicating a role for Bcl6 in the survival and expansion of both populations. Together, these observations demonstrate a shared developmental path among pathologically expanded Tph and Tfh cells in lupus. The persistence of expanded Tph and Tfh cells clones over time may impose barriers to induction of stable tolerance by immunosuppressive medications or by B cell depletion.
Cognitive Performance in Relation to Systemic and Brain Iron at Perimenopause
Authors: Barnett Amy L. , Wenger Michael J. , Miles Pamela , Wu Dee , Isingizwe Zitha Redempta , Benbrook Doris M. , Yuan Han
Published: January 2025

Background

The literature on the relationships among blood iron levels, cognitive performance, and brain iron levels specific to women at the menopausal transition is ambiguous at best. The need to better to understand these potential relationships in women for whom monthly blood loss (and thus iron loss) is ceasing is highlighted by the fact that iron accumulates in brain tissue over time and that accumulation is thought to be a factor in the development of neurodegenerative disease.

Methods

Non-anemic women who were either low in iron or had normal iron levels for their age and race/ethnicity provided blood samples, underwent MRI scans to estimate brain iron levels, and performed a set of cognitive tasks with concurrent EEG. Results: Cognitive performance as well as brain dynamics were positively related to iron levels, including measures associated with oxygen transport. There were no relationships between any of the blood measures of iron and brain iron.

Conclusions

Higher iron status was associated with better cognitive performance in a sample of women who were neither iron deficient nor anemic, without there being any indication that higher levels of systemic iron were related to higher levels of brain. Consequently, addressing low iron levels at the menopausal transition may be a candidate approach for alleviating the “brain fog” commonly experienced at menopause.
Multi-resolution vision transformer model for skin cancer subtype classification using histopathology slides
Authors: Chaurasia Abadh K , Toohey Patrick W , Harris Helen C , Hewitt Alex W
Published: January 2025

Introduction

Digital pathology has significantly advanced cancer diagnosis by enabling high-resolution visualisation and assessment of tissue specimens. However, the manual analysis of these images remains labour-intensive and susceptible to human error, resulting in inconsistencies in diagnosis and treatment decisions. Herein, we developed and externally validated a multi-resolution model for classifying subtypes of skin cancer from whole slide images ( WSIs).

Methods

We constructed a dataset comprising approximately 1.13 million histological patches (dividing the WSIs into non-overlapping tiles) from the Non-Melanoma Skin Cancer Segmentation (NMSCS) and Heidelberg datasets. All the patches were normalised using the Macenko method before training a self-supervised vision transformer-based model to classify the most common subtypes of skin cancer: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), intraepidermal carcinoma (IEC), Melanoma, Naevi, and Non-cancerous. Our multi-resolution model was designed to classify melanoma and non-melanoma skin cancer subtypes, incorporating multi-resolution data at 10x, 20x, 40x, and 400x magnifications. The model was externally validated on 5,147 slides from 4,066 patients for non-melanoma cancer subtypes. The model’s performance was evaluated using classification metrics, and the quadratic weighted Cohen’s Kappa (k) score was used to measure the agreement between the model’s predictions and the actual labels with a 95% confidence interval (CI).

Results

Our multi-resolution model demonstrated strong classification performance across six classes, achieving an overallkscore of 0.859 (95% CI: 0.851, 0.866) and 0.898 (95% CI: 0.892, 0.904) on the validation and testing sets, respectively, reflecting robust performance across diverse skin cancer subtypes. The multi-resolution model for non-melanoma skin cancer exhibited superior performance, achieving an overallkscore of 0.919 (95% CI: 0.914, 0.924) on the validation set. On the testing set, thekscore ranged from 0.996 to 0.889 with magnifications of 10x, 20x, 40x, and 400x. The attention maps highlighted clinically relevant features for cancerous tissue at different magnifications. Additionally, the model obtained akscore of 0.791 (95% CI: 0.774, 0.808) on the external data at the slide level, indicating substantial agreement between the model’s prediction and the actual label of WSIs.

Conclusion

Our multi-resolution model has the potential to assist anatomical pathologists in automatically detecting, highlighting, and classifying subtypes of melanoma and non-melanoma skin cancer subtypes directly from WSIs. This capability could ultimately improve patient outcomes and more effective clinical decision-making in digital pathology. For non-melanoma cancer, our model could be deployed in regions with limited access to experienced dermatopathologists and a high incidence of the disease, particularly in low-resource settings.
Does Music Support Cognitive Control and Affective Responses During Acute Exercise? An Exploratory Systematic Review and Meta-analysis
Authors: Danso Andrew , Vigl Julia , Koehler Friederike , Knittle Keegan , Bamford Joshua S. , Nijhuis Patti , Haapala Eero A. , Wong Ming Yu Claudia , Wright Shannon E. , Baltazar Margarida , Serres Nora , Hansen Niels Chr. , Schiavio Andrea , Saarikallio Suvi , Luck Geoff
Published: January 2025

Cognitive control, defined as the allocation of mental resources required for goal-directed behaviour, is crucial for exercise participation as it is involved in regulating negative cognitive and affective responses caused by the demands of exercise. Research on both music and acute exercise separately show engagement of cognitive control processes and affective responses, with low-to-moderate exercise intensities reliably influencing cognitive and affective outcomes (e.g., core affect). However, the combined effects of music and acute exercise on cognitive control and affective outcomes remain underexplored. Accordingly, this review and meta-analysis explores how music influences cognitive control and affective outcomes during acute exercise. 10 studies met the inclusion criteria, with nine providing data for effect size calculations across 21 intervention arms. Meta-analyses revealed significant effects of music on attention allocation (g = 1.05, 95% CI [0.03, 2.07]; p = 0.04), inhibitory control (g = 1.87, 95% CI [0.37, 3.37]; p = 0.01), and core affect (g = 0.86, 95% CI [0.24, 1.48]; p < 0.01). Exercise intensity significantly moderated outcomes (p = 0.036), suggesting that higher intensities diminish the effectiveness of music in elevating cognitive control and affective outcomes during acute exercise. Findings were limited by high heterogeneity (I2 > 97%) across study protocols and outcome measures. Due to the aforementioned heterogeneity, the findings of this review must be interpreted cautiously.
Asymmetric limits on timely interventions from noisy epidemic data
Authors: Parag Kris V. , Lambert Ben , Donnelly Christl A. , Beregi Sandor
Published: January 2025

Deciding on when to initiate or relax an intervention in response to an emerging infectious disease is both difficult and important. Uncertainties from noise in epidemiological surveillance data must be hedged against the potentially unknown and variable costs of false alarms and delayed actions. Here we clarify and quantify how case under-reporting and latencies in case ascertainment, which are predominant surveillance noise sources, can restrict the timeliness of decision-making. Decisions are modelled as binary choices between responding or not that are informed by reported case curves or transmissibility estimates from those curves. Optimal responses are triggered by thresholds on case numbers or estimate confidence levels, with thresholds set by the costs of the various choices. We show that, for growing epidemics, both noise sources induce additive delays on hitting any case-based thresholds and multiplicative reductions in our confidence in estimated reproduction numbers or growth rates. However, for declining epidemics, these noise sources have counteracting effects on case data and limited cumulative impact on transmissibility estimates. We find this asymmetry persists even if more sophisticated feedback control algorithms that consider the longer-term effects of interventions are employed. Standard surveillance data therefore provide substantially weaker support for deciding when to initiate a control action or intervention than for determining when to relax it. This information bottleneck during epidemic growth may justify proactive intervention choices.
Excessive monitoring for Hydroxychloroquine retinal toxicity in a trial to delay clinical type 1 diabetes created burden without benefit
Authors: Lord Sandra M , Libman Ingrid M , Buckner Jane H , Dansingani Kunal K , Nischal Ken K , Bingley Polly J , Speake Cate , You Lu , Greenbaum Carla J
Published: January 2025

Background/Aims

Type 1 Diabetes TrialNet (TrialNet) conducted a placebo randomized trial in children and adults with pre-clinical type 1 diabetes (T1D) to test whether hydroxychloroquine (HCQ) could delay or prevent progression to clinical T1D. Study regulators required more frequent monitoring for retinal toxicity than is recommended by clinical guidelines and we evaluated the impact of this monitoring.

Methods

We obtained the outcome of all eye exams from TrialNet and focused on exams that were recommended for follow up outside the protocol or for repeat testing within the trial.

Results

No HCQ related retinal toxicity was found, but increased frequency of monitoring led to additional testing due to incomplete exams or technical difficulties, and incidental findings prompted the need for follow up outside the study.

Conclusion

Our analysis suggests that increased frequency of retinal monitoring provided no benefit, created additional burdens, and that future trials testing HCQ in a pre-clinical T1D population could safely follow standard clinical guidelines for retinal surveillance.
Sparse Polygenic Risk Score Inference with the Spike-and-Slab LASSO
Authors: Song Junyi , Zabad Shadi , Yang Archer , Li Yue
Published: January 2025

Large-scale biobanks, with comprehensive phenotypic and genomic data across hundreds of thousands of samples, provide amble opportunities to elucidate the genetics of complex traits and diseases. Consequently, there is a growing demand for robust and scalable methods for disease risk prediction from genotype data. Performing inference in this setting is challenging due to the high-dimensionality of genomic data, especially when coupled with relatively smaller sample sizes. Popular Polygenic Risk Score (PRS) inference methods address this challenge by adopting sparse Bayesian priors or penalized regression techniques, such as the Least Absolute Shrinkage and Selection Operator (LASSO). However, the former class of methods are not as scalable and do not produce exact sparsity, while the latter may over-shrink large coefficients. In this study, we presentSSLPRS, a novel PRS method based on the Spike-and-Slab LASSO (SSL) prior, which offers a theoretical bridge between the two frameworks. We extend previous work to derive a coordinate-ascent inference algorithm for theSSLPRSmodel that operates on GWAS summary statistics. The software implementation, which uses state-of-the-art techniques to scale PRS inference to millions of genetic variants, has an average runtime of three minutes. To illustrate the statistical properties of the new model, we conducted experiments on nine quantitative phenotypes in the UK Biobank, which showed thatSSLPRSis competitive with state-of-the-art methods in terms of prediction accuracy. The method also produces highly sparse effect size estimates without excessive shrinkage and, on average, selects 5% fewer variants than theLASSO.
Hydrological Connectivity Enhances Fish Biodiversity in Amazonian Mining Ponds: Insights from eDNA and Traditional Sampling
Authors: Timana-Mendoza Camila , Reyes-Calderón Alonso , Venail Patrick , Britzke Ricardo , Santa-Maria Monica C. , Araújo-Flores Julio M. , Silman Miles , Fernandez Luis E.
Published: January 2025

The expansion of artisanal and small-scale gold mining (ASGM) in the Madre de Dios region of the Peruvian Amazon has transformed primary forests into a novel wetland complex of thousands of abandoned mining ponds. Despite their ecological relevance, post-mining recovery of these systems remains understudied, particularly regarding fish biodiversity and recolonization. In this study, we evaluate fish community richness and composition in mining ponds of different dimensions, years post abandonment, and degree of pulse flood connectivity using traditional collection-based methods and environmental DNA (eDNA) with the 12S and COI markers. We compared these two methods of biodiversity inventory and contrasted results from ASGM waterbodies with those obtained from nearby pristine oxbow lakes. Overall, we registered more fish richness at all sites using eDNA vs traditional methods, especially with the 12S marker. We identified 14 and 13 unique genera using traditional methods and eDNA, respectively, with 40 genera detected by both approaches, evidencing their complementarity. Notably, we found that the degree of pulse flooding connectivity was the main predictor of species richness among the abandoned mining ponds (p-value < 0.05). We registered 11 to 22, 23 to 71, and 56 morphospecies in non-flooded mining ponds, pulse flooded mining ponds and nearby oxbow lakes, respectively. Furthermore, the fish community composition of mining ponds most influenced by pulse flooding were similar to that of pristine lakes. Our findings highlight the role of hydrological connectivity in ecological recovery within mining-impacted wetlands. Future restoration efforts should enhance aquatic connectivity to accelerate recovery in post-mining environments.
The genusBoecheraas a model for apomixis research
Authors: Mandakova Terezie
Published: January 2025

The genusBoechera, a prominent member of the tribe Boechereae within the family Brassicaceae, has emerged as an exceptional model for apomixis research, owing to its unique evolutionary, reproductive, and genomic characteristics. With over 480 genetically distinct taxa and a distribution spanning North America, Greenland, and parts of Asia,Boecheraexemplifies remarkable ecological and genetic diversity. A hallmark of the genus is its high frequency of gametophytic apomixis, including diplospory and apospory, which, combined with hybridization, drive genetic innovation and environmental adaptability. Moreover,Boecherais notable for its diploid expression of apomixis, independent of polyploidy, providing an unparalleled system for dissecting asexual reproduction. Genomic adaptations, such as heterochromatic supernumerary chromosomes, further highlight its evolutionary complexity. Recent advances, including the discovery of critical regulatory genes likeAPOLLOandUPGRADE2, have deepened our understanding of the genetic basis of apomixis. These insights positionBoecheraas a cornerstone for elucidating apomictic pathways and leveraging these mechanisms for crop improvement. The genus not only enhances our understanding of apomixis but also offers transformative potential for agriculture.
Histone Variant H2A.Z Cooperates with EBNA1 to Maintain Epstein-Barr Virus Latent Epigenome
Authors: Castro-Muñoz Josue Leonardo , Maestri Davide , Yoon Leena , Karisetty Bhanu Chandra , Tempera Italo , Lieberman Paul
Published: January 2025

Chromatin structure plays a central role in the regulation of Epstein-Barr Virus (EBV) latency. The histone variant H2A.Z.1 has been implicated in chromatin structures associated with initiation of transcription and DNA replication. Here, we investigate the functional role of H2AZ.1 in the regulation of EBV chromatin, gene expression and copy number during latent infection. We found that H2A.Z.1 is highly enriched with EBNA1 binding sites atoriPand Qp, and to a lesser extent with transcriptionally active CTCF binding sites on the EBV genomes in both Mutu I Burkitt lymphoma (BL) and SNU719 EBV-associated gastric carcinoma (EBVaGC) cell lines. RNA-interference depletion of H2A.Z.1 resulted in the reactivation of viral lytic genes (ZTA and EAD) and increases viral DNA copy numbers in both MutuI and SNU719 cells. H2A.Z depletion also led to a decrease in EBNA1 binding tooriPandQp, on the viral episome as well as on oriP plasmids independently of other viral genes and genomes. H2A.Z.1 depletion also reduced peaks of H3K27ac and H4K20me3 at regulatory elements in the EBV genome. In the cellular genome, H2A.Z.1 colocalized with only a subset of EBNA1 binding sites and H2A.Z.1 depletion altered transcription of genes associated withmyc targetsandmTORC1 signaling. Taken together, these findings indicate that H2A.Z.1 cooperates with EBNA1 to regulate chromatin structures important for epigenetic programming of the latent episome.

Importance

Cellular factors the restrict latent viral reactivation are of fundamental importance. We have found that the cellular histone variant H2A.Z functions in cooperation with the Epstein-Barr Virus (EBV) latency maintenance protein EBNA1 to establish a stable epigenome and restrict lytic cycle reactivation during latency. We show that H2A.Z co-occupies EBNA1 binding sites on the EBV and host genome, and that depletion of H2A.Z leads to robust reactivation of EBV from latency. H2A.Z is important for the function of EBNA1 at the origin of plasmid (oriP) replication and establishing EBV epigenetic marks. H2A.Z binds with EBNA1 at cellular binding sites and controls the expression of cellular genes in the cMyc and mTORC1 pathways that are also implicated in control of EBV latency.
Molecular evolution of silver nanoparticle resistance in a bacterial pathogen and a unique adaptation response to ionic silver
Authors: McNeilly Oliver , Mediati Daniel G. , Pittorino Matthew J. , Mann Riti , Söderström Bill , Hamidian Mehrad , Gunawan Cindy
Published: January 2025

This research explores the adaptive defense mechanisms of a nanosilver-resistant pathogen (NAgR) to protect and fight off the complex antimicrobial targeting of silver nanoparticles. The Gram-negative bacteriumAcinetobacter baumanniiupregulated expression of outer membrane proteins for cell surface defense, as well as membrane and capsule synthesis genes. Increased abundance of surface-attached biofilm colonies in NAgRwas linked to the phenotypically indicated increase in membrane integrity, with the bacterium also forming more EPS, the biopolymer matrix that protects the residing colony. In response to the known reactive oxygen species (ROS) toxicity characteristics of the nanoparticle, NAgRupregulated its oxidative stress management system, specifically involving ROS scavenger enzymes and opportunistic metal efflux pumps. Many of these evolved defense mechanisms only manifested in the resistant bacterium, while they were absent in the wild-type strain. This study also details the unique defenses of an ionic silver-adaptedA. baumanniivariant, having evolved from the same wild-type parental strain as NAgR. Despite similarities in cell surface and biofilm defense trends, the slower-to-kill tolerant strain (AgT) exclusively upregulated multidrug efflux systems and respiratory chain enzymes, thought to maintain enhanced respiration activity, a known tolerant characteristic. Identification of these stable defense mechanisms can recommend strategies for molecular targeting to overcome the adaptation phenomena.
Electrophysiological and network dynamics disruption of hippocampal CA1 neurons after NMDAr blockade by MK-801
Authors: Abad-Perez P. , Molina-Payá F. J. , Rigamonti G. , Tirado M , Cabrales G. , Montesinos Antonio Falcó , Martínez-Otero L. , Borrell V. , Sánchez-Mut J. , Redondo R. , Brotons-Mas J. R.
Published: January 2025

The N-methyl-D-aspartate receptor (NMDAr) hypofunction hypothesis suggests that excitatory-inhibitory (E-I) imbalance underlies cognitive deficits associated with neuropsychiatric disorders, such as schizophrenia (SCZ). In this study, we investigated the impact of NMDAr blockade on pyramidal neurons and interneurons in the CA1 region of the hippocampus using in vivo electrophysiological recordings during both spontaneous and exploratory behaviors. Through the administration of MK-801, an NMDAr antagonist, we assessed changes in spike train dynamics, network synchrony, and neuronal modulation by oscillatory activity, with particular emphasis on theta, gamma, and sharp-wave ripple (SWR) oscillations. We found that NMDAr blockade significantly disrupted the E-I balance, leading to altered spike train properties, reduced bursting propensity, and impaired neuronal synchronization. These changes were accompanied by decreased modulation of pyramidal neurons and interneurons by theta and gamma oscillations, as well as diminished recruitment of pyramidal neurons during SWR events. Additionally, the correlation between firing rates and movement speed was reduced, reflecting deficits in spatial coding and memory processing. Moreover, MK-801 administration disrupted place cell stability and spatial information processing. These effects likely contribute to functional disconnection between the hippocampus and other brain regions, such as the prefrontal cortex, and may underlie SCZ-associated cognitive impairments. Our findings provide valuable insights into the cellular and network-level mechanisms affected by NMDAr dysfunction, highlighting the role of oscillatory activity and spike timing in cognitive deficits. This work advances our understanding of how NMDAr hypofunction impacts hippocampal circuits and identifies potential targets for therapeutic interventions aimed at restoring cognitive function in neuropsychiatric disorders.
A recombinant hybrid provides insights into gene regulation, pathogenesis and tumorigenesis of phytopathogenic smut fungi
Authors: Werner Janina , Zuo Weiliang , Winkler Tom , Doehlemann Gunther
Published: January 2025

The maize smut fungiUstilago maydisandSporisorium reilianumare closely related and have similar genomes in terms of size and synteny. WhileU. maydisinduces tumors locally at sites of infection,S. reilianumsystemically colonizes the host and causes symptoms in the inflorescences. To investigate the genetic basis of these differences, an interspecific recombinant hybrid (rUSH) with the mating type system ofS. reilianumwas generated. rUSH exhibited extensivein-plantaproliferation, showing aS. reilianum-like phenotype at all developmental stages except teliospore formation. Transcriptome profiling revealed that expression of pathogenicity-related effector gene orthologs was induced in rUSH, but not in a wild-type hybrid control. Multiple transcriptome comparisons identified 253 differentially expressed one-to-one effector orthologs with distinct regulatory patterns, including cis-, trans-, and rUSH-specific regulation. Functional analysis via CRISPR/Cas9 mutagenesis uncovered three novel virulence factors among the rUSH-specific regulated effectors. Ultimately, rUSH facilitated to identify the transcription factor UmHdp2 as key regulator ofU. maydis-induced tumorigenesis. Together, these findings highlight the utility of a recombinant, interspecific hybrid in unraveling the molecular mechanisms underlying pathogenic differences in closely related fungal pathogens.
PhorEau: a new process-based model to predict forest functioning, from tree ecophysiology to forest dynamics and biogeography
Authors: Postic Tanguy , de Coligny Francois , Chuine Isabelle , StPaul Nicolas Martin , Morin Xavier
Published: January 2025

Climate change impacts forest functioning and dynamics, yet significant uncertainties persist regarding the interactions between species composition, demographic processes, and environmental drivers. While the effects of climate change on individual plant ecophysiology are better understood, few robust tools integrate these processes dynamically, hindering accurate projections and recommendations for long-term sustainable forest management. Forest gap models strike a balance between complexity and generality and are widely used in predictive forest ecology. However, their lack of explicit representation of critical processes, such as plant phenology and water use, limits their ability to fully capture tree sensitivity to climate change, calling into question the robustness of their future predictions. Therefore, incorporating trait- and process-based representations of climate-sensitive processes within gap models is a crucial step toward generating realistic predictions of forest evolution under climate change. In this study, we coupled the ForCEEPS gap model, validated across a broad range of forest types and environmental conditions in Europe, with two process-based models: a plant phenology model (PHENOFIT) and a plant hydraulics model (SurEAU), each parameterized for the main European tree species. We then evaluated the performance of the resulting PHOREAU model across multiple processes, metrics, and time- and spatial-scales, thereby minimizing the risk of equifinality. PHOREAU demonstrated robust capabilities in predicting fine hydraulic processes at both the forest and stand scales for various species and forest types. This, combined with its enhanced ability to predict stand leaf areas from inventories, led to modest improvements in annual growth predictions compared to the original ForCEEPS model and a strong capacity to predict potential community compositions. By integrating recent advancements in plant hydraulics, phenology, and competition for light and water into a dynamic, individual-based framework, the PHOREAU model bridges the gap between trait diversity and long-term forest productivity and resilience. It offers insights into complex emergent properties and trade-offs linked to diversity effects under extreme climatic events, with significant implications for sustainable forest management strategies.
Advancing (-)-Premarineosin A as a Potent Antimalarial Therapeutic via Metabolic Engineering and Late-Stage Derivatization
Authors: McBride Christina M. , McCauley Morgan , Harris Natalia R. , Amin Sahar , Verhey-Henke Linnea , Teklemichael Awet A. , Oliphant Erin N. , Dranchak Patricia , Curtis Brian J. , Lev Katherine L. , Qu Fengrui , Snodgrass Harrison M. , Lewis Jared C. , Inglese James , Su Xin-zhuan , Pereira Filipa , Sherman David H.
Published: January 2025

Despite modern preventative and curative efforts, malaria has remained a major global health crisis. In 2023 alone, malaria was responsible for an estimated 263 million cases and 597,000 deaths. To complicate this issue, the causativePlasmodiumparasites are becoming more resistant to available therapeutics, making it difficult to treat and prevent disease progression. Hence, the discovery of new antimalarial drugs is crucial to mitigating this crisis. One promising contender is the natural product premarineosin A, an intermediate of the marineosin biosynthetic pathway that exhibits potent and selective antimalarial activity against both chloroquine-sensitive and multi-drug-resistantPlasmodiumstrains. However, its complex chemical structure and low production titers have prevented further exploration. To improve access to this promising metabolite, we identified a biosynthetic gene cluster for (-)-premarineosin A production inStreptomyces eitanensis.Metabolic engineering approaches increased production from trace levels to nearly 35 mg/L, which enabled semi-synthetic and biocatalytic derivatization of the (-)-premarineosin A scaffold. Late-stage C-H bromination of the B-ring resulted in a highly potent (EC50< 5 nM) antimalarial compound with low cytotoxicity. These findings report progress toward the sustainable access of (-)-premarineosin A and the first structure-activity relationship study for this unique scaffold in the search for improved antimalarial therapeutics.
Differential endopeptidase requirements during adaptation to changing growth conditions inVibrio cholerae
Authors: Rosch Kelly , Lei Samantha , Zheng Jennifer , Dörr Tobias
Published: January 2025

The bacterial cell wall is a covalently linked meshwork of peptidoglycan (PG) that establishes cell shape and prevents osmotic lysis. This structure must be flexible enough to accommodate transenvelope protein complexes, but strong enough to withstand high intracellular pressure. In order to elongate and divide, cells must remodel the cell wall through the concerted action of PG synthesis and degradation. Endopeptidases, a class of PG degrading enzymes, facilitate cell growth by hydrolyzing PG crosslinks.Vibrio choleraeencodes several functionally redundant endopeptidases, two of which are nearly identical: ShyA and ShyC. To investigate differential roles of these enzymes, we assessed growth and morphology of ShyA and ShyC mutants. We found that ShyA, but not ShyC, is required for normal adaptation to low osmolarity medium. Cells lacking ShyA exhibited longer lag phase and aberrant morphology during adaptation, and reduced survival in the presence of a beta-lactam antibiotic. Lastly, our experiments revealed that cells lacking ShyA’s LysM domain exhibited more severe defects than cells lacking ShyA altogether, implicating the LysM domain in proper regulation of ShyA activity.
RNA promotes synapsin coacervation and modulates local translation
Authors: Rankovic Branislava , Geisterfer Zachary M , Chhabra Akshita , Jovanovic Vladimir M , Seim Ian , Hoffmann Christian , Condric Antonela , Pérez Gerard Aguilar , Freitag Kiara , Nowick Katja , Jendrach Marina , Heppner Frank , Reshetniak Sofiia , Gladfelter Amy S , Milovanovic Dragomir
Published: January 2025

Condensates are found at synapses where they support the clustering of synaptic vesicles (SVs) and neurotransmitter release. The possibility of RNA promoting the formation or function of these condensates is not known. Here, we set out to assess whether RNA affects molecular condensates in the synapse or could be regulated at these sites, focusing on synapsin-1, which is essential for synapse condensates. Usingin vitroreconstitution systems, cell lines and neurons, we show that RNA drives synapsin-1 coacervation, with some bias toward structured RNAs being more effective at promoting demixing. The importance of RNA was confirmed in living synapses, where acute disruption of native RNA induces a dispersion of SVs and synapsin. Conversely, ectopically expressed SV-like condensates have the ability to recruit RNA species and the translational machinery, which accumulates within condensate-microdomains, resulting in increased translation efficacy. Our work indicates a novel role of RNAs in modulating SV condensates, as well as translation, at the synapse.

Key Conclusions

RNA forms coacervates with synapsin-1 that readily sequester SVs.

Acute disruption of RNA affects the organization of the presynapse.

RNA secondary structure tunes the assembly of synapsin-SV condensates.

RNA competes with α-synuclein for partitioning at the condensates.

Synapsin-1/RNA condensates are hubs for local translation.
An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Ménière’s disease
Authors: Harhai Marcell , Foged Mads M. , Recazens Emeline , Lisci Miriam , Chollet Sylvain , Landoni Juan C. , Laban Nora , Manley Suliana , Lopez-Escamez Jose Antonio , Lysakowski Anna , Jourdain Alexis A.
Published: January 2025

Mitochondrial disorders (MDs) are among the most common inborn errors of metabolism and primarily arise from defects in oxidative phosphorylation (OXPHOS). Their complex mode of inheritance and diverse clinical presentations render the diagnosis of MDs challenging and, to date, most lack a cure. Here, we build on previous efforts to discover genes necessary for OXPHOS and report a highly complementary galactose-sensitized CRISPR-Cas9 “growth” screen, presenting an updated inventory now with 481 OXPHOS genes, including 157 linked to MDs. We further focus onFAM136A, a gene associated with Ménière’s disease, and show that it supports inter-membrane space protein homeostasis and OXPHOS in cell lines, mice, and patients. Our study identifies a mitochondrial basis in a familial form of Ménière’s disease (fMD), provides a comprehensive resource of OXPHOS-related genes, and sheds light on the pathways involved in mitochondrial disorders, with the potential to guide future diagnostics and treatments for MDs.

Graphical abstract

Bullet points

Genome-wide CRISPR-Cas9 growth screening complements death screening

481 genes essential for OXPHOS, including 157 mitochondrial disease genes

FAM136Asupports mitochondrial intermembrane space protein homeostasis

Depletion ofFAM136Ain Ménière’s disease models causes OXPHOS defects
Local olfactory nerve stimulation triggers patchy activation of columns across rat olfactory bulb
Authors: Jahan Israt , Kindler Lisa , Reichardt Nicolas , Suyama Hajime , Egger Veronica
Published: January 2025

Columnar organization is a hallmark of neocortical sensory areas, most prominently in primary somatosensory and visual cortex. In the olfactory bulb, the existence of a vertical columnar organization of circuits associated with glomerular input channels has been implicated by various approaches. Here, based on activity-dependent labelling and tissue clearing, we provide direct evidence for functional bulbar columns formed by mitral cells and granule cells that display a uniform morphology.
Drug-induced versus non-pharmacological wakefulness: similar or different states? A whole brain analysis in TRAP2 transgenic mice
Authors: Maciel Renato , Malcey Justin , Chancel Amarine , Brunel Théo , Fort Patrice , Queiroz Claudio Marcos , Luppi Pierre-Hervé
Published: January 2025

A large body of data indicate that the aminergic, cholinergic and hypocretin/orexin neurons are responsible for inducing wakefulness. However, recent data showed that other systems might also play a key role. Further, wakefulness induced by different drugs versus non-pharmacological means could be generated by different populations of neurons. To address these questions, we evaluated at the whole brain level in the same mice using TRAP2 model whether the same neurons were activated by the wake-inducing drugs modafinil and solriamfetol versus non-pharmacological wake. Our results show that several subcortical structures such as the bed nucleus of the stria terminalis, central amygdalar nucleus, paraventricular hypothalamic and thalamic and supraoptic nuclei, lateral parabrachial nucleus and lateral reticular area (including its noradrenergic neurons) are significantly more activated by solriamfetol than modafinil and non-pharmacological wakefulness. In contrast, a second category of structures including the orexin neurons, the parasubthalamic and laterodorsal tegmental nucleus are strongly activated in all types of induced wake. Further, some classical wake systems like the dopaminergic neurons of the ventral tegmental area or the dorsal raphe nucleus and the noradrenergic neurons of the locus coeruleus are either very poorly or not strongly activated. These results reveal that many structures not previously involved in wakefulness might play a key role in regulating the state and that some structures might be more recruited by solriamfetol than modafinil or non-pharmacological wakefulness. Our results are particularly relevant for pathologies such as hypersomnia. They open a new era in the study of the mechanisms responsible for inducing wakefulness.
Interactions of Interaural Time and Level Differences in Spatial Hearing with Cochlear Implants
Authors: Buchholz Sarah , Arndt Susan , Schnupp Jan W. H. , Rosskothen-Kuhl Nicole
Published: January 2025

Normally hearing humans can localize sound sources quite accurately, with minimum audible angles as small as 1°. To achieve this, our auditory pathways combine information from multiple acoustic cues, including interaural time and interaural level differences (ITDs and ILDs). Patients relying on cochlear implants (CIs) to hear the world cannot match normal performance. These deficits are most pronounced in patients with little or no hearing experience early in life, and they appear to result from an impaired sensitivity to ITDs, but not to ILDs. However, little is known about how ITD and ILD sensitivities develop and interact in an early deafened auditory system shortly after CI implantation. We fitted neonatally deafened rats with bilateral CIs, and, providing informative ITDs and ILDs from stimulation onset, trained them to lateralize CI stimuli. These animals were exquisitely sensitive to both ILDs and ITDs of CI stimulus pulses, and combined information from both cues in a weighted sum. Importantly, ITDs are weighted heavily in our CI rats, such that only very modest ITDs pointing in one direction can confound quite large ILDs pointing in the opposite direction. This underlines the importance of informative ITDs for maximizing the potential for spatial hearing with CI devices.

Abstract Figure
Begging costs rather than food received cause brood size effect on growth in zebra finches
Authors: Tangili Marianthi , Briga Michael , Verhulst Simon
Published: January 2025

Altricial species rely on parental provisioning for early-life sustenance, and a larger brood size leads to higher levels of competition between siblings for food provided by the parents. Early-life stress can have severe and lifelong effects on Darwinian fitness. Indeed, it is well established that being reared in a larger brood impairs growth and fitness prospects of birds, but the mechanistic underpinnings of this effect are still largely unknown. Specifically, it is not well known to what extent the reduced growth and fitness prospects of nestlings reared in large broods is due to increased resource allocation to competition versus aper capitareduction in parental provisioning rate, or a combination of the two. We cross-fostered zebra finch (Taeniopygia guttata) chicks into small and large broods, and recorded their growth as well as the behavior of parents and offspring throughout the nestling period. As in previous experiments, growth rate was higher in small broods. In large broods, chicks begged more and parents invested more time feeding which more than compensated for the difference in brood size. We therefore conclude that the lower growth rate for nestlings raised in large broods must be attributed to increased energy expenditure on begging rather than a reduction in the amount of food received. These results suggest significant energetic costs associated with begging and raise the interesting possibility that brood size would not have negatively affected growth in large broods if chicks had not increased their begging effort due to increased levels of competition in nest.