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2026-03-31
Javier González-Maeso, Jessica L Maltman
Human neurons derived from stem cells show increased structural complexity and stronger synaptic connections after exposure to psilocin, the active metabolite of the psychedelic psilocybin.
2026-03-31
Aizhen Guo, Baojie Duan, Changmin Hu, Lei Zhang, Liu Chen, Lu Lu, Pingping Chen, Qiang Jiang, Yifan Wang, Yingyu Chen
Nucleomodulins are a class of effector proteins secreted by bacterial pathogens that translocate into the host cell nucleus to modulate nuclear processes. However, their target proteins and underlying molecular mechanisms remain poorly understood in mycobacteria. Herein, we identified a conserved hypothetical protein Rv1075c, designated MgdE, as a nucleomodulin that enhances mycobacterial intracellular survival. MgdE undergoes nuclear translocation via two nuclear localization signals, KRIR 108-111 and RLRRPR 300-305 , and interacts with ASH2L and WDR5, two subunits of the host histone methyltransferase COMPASS complex. This interaction suppresses histone H3 lysine 4 (H3K4) methylation-mediated transcription of pro-inflammatory genes, including IL6 and IL1Β , thereby promoting mycobacterial survival in both macrophages and mice. Our study provides the first experimental evidence that a bacterial nucleomodulin facilitates intracellular survival by directly targeting the host COMPASS complex. These findings advance our understanding of mycobacterial pathogenesis by revealing a novel mechanism that contributes to its intracellular survival strategy.
2026-03-27
Daphna Shohamy, Michael Neil Shadlen, Yaniv Abir
A central purpose of exploration is to reduce goal-relevant uncertainty. Consequently, individuals often explore by focusing on areas of uncertainty in the environment. However, people sometimes adopt the opposite strategy, one of avoiding uncertainty. How are the conflicting tendencies to approach and avoid uncertainty reconciled in human exploration? We hypothesized that the balance between avoiding and approaching uncertainty can be understood by considering capacity constraints. Accordingly, people are expected to approach uncertainty in most cases, but to avoid it when overall uncertainty is highest. To test this, we developed a new task and used modeling to compare human choices to a range of plausible policies. The task required participants to learn the statistics of a simulated environment by active exploration. On each trial, participants chose to explore a better-known or lesser-known option. Participants generally chose to approach uncertainty; however, when overall uncertainty about the choice options was highest, they instead avoided uncertainty and chose to sample better-known objects. This strategy was associated with faster decisions and, despite reducing the rate of observed information, it did not impair learning. We suggest that balancing approaching and avoiding uncertainty reduces the cognitive costs of exploration in a resource-rational manner.
2026-03-26
Felipe A Court, Francisco Muñoz-Carvajal, Mario Sanhueza, Nicole Sanhueza
Aging is characterized by a decline in essential sensory functions, including olfaction, which is crucial for environmental interaction and survival. This decline is often paralleled by the cellular accumulation of dysfunctional mitochondria, particularly detrimental in post-mitotic cells such as neurons. Mitochondrial stress triggers the mitochondrial unfolded protein response (UPR MT ), a pathway that activates mitochondrial chaperones and antioxidant enzymes. Critical to the efficacy of the UPR MT is the cellular chromatin state, influenced by the methylation of lysine 9 on histone 3 (H3K9). While it has been observed that the UPR MT response can diminish with an increase in H3K9 methylation, its direct impact on age-related neurodegenerative processes, especially in the context of olfactory function, has not been clearly established. Using Drosophila , we demonstrate that an age-dependent increase in H3K9 trimethylation by the methyltransferase dSetdb1 reduces the activation capacity of the UPR MT in olfactory projection neurons leading to neurodegeneration and loss of olfactory function. Age-related neuronal degeneration was associated with morphological alterations in mitochondria and an increase in reactive oxygen species levels. Importantly, forced demethylation of H3K9 through knockdown of dSetdb1 in olfactory projection neurons restored the UPR MT activation capacity in aged flies, and suppressed age-related mitochondrial morphological abnormalities. This in turn prevented age-associated neuronal degeneration and rescued age-dependent loss of olfactory function. Our findings highlight the effect of age-related epigenetic changes on the response capacity of the UPR MT , impacting neuronal integrity and function. Moreover, they suggest a potential therapeutic role for UPR MT regulators in age-related neurodegeneration and loss of olfactory function.
2026-03-25
Carlos J Camacho, Dane K Hoffman, Elisabeth Altendorfer, Fabiola Balmir, Judith L Yanowitz, Kara A Bernstein, Marilina Raices, McKenzie K Grundy, Monica P Colaiacovo, Nicola Silva, Wei Li
Double-strand breaks (DSBs) are the most deleterious lesions experienced by our genome. Yet, DSBs are intentionally induced during gamete formation to promote the exchange of genetic material between homologous chromosomes. While the conserved topoisomerase-like enzyme Spo11 catalyzes DSBs, additional regulatory proteins—referred to as ‘Spo11 accessory factors’—regulate the number, timing, and placement of DSBs during meiotic prophase, ensuring that SPO-11 does not wreak havoc on the genome. Despite the importance of the accessory factors, they are poorly conserved at the sequence level, suggesting that these factors may adopt unique functions in different species. In this work, we present a detailed analysis of the genetic and physical interactions between the DSB factors in the nematode Caenorhabditis elegans, providing new insights into conserved and novel functions of these proteins. This work shows that HIM-5 is the determinant of X-chromosome-specific crossovers and that its retention in the nucleus is dependent on DSB-1, the sole accessory factor that interacts with SPO-11. We further provide evidence that HIM-5 mediates interactions with the different accessory factors subgroups, providing insights into how components on the DNA loops may interact with the chromosome axis.
2026-03-25
Alex George, Caitlin Johnson, Dillon E King, Dorothy A Erie, Emily E Beard, Emma L Dolan, Evan Corden, Hunter Wilkins, Ian Ryde, Joel Meyer, Matthew J Satusky, Raluca Gordân, Susan K Murphy, Wei Zhu, Yuning Zhang
Mitochondria lack nucleotide excision repair; however, mitochondrial DNA (mtDNA) is resistant to mutation accumulation following DNA damage. These observations suggest additional damage sensing or protection mechanisms. Transcription Factor A, Mitochondrial (TFAM) compacts mtDNA into nucleoids and binds differentially to certain forms of DNA damage. As such, TFAM has emerged as a candidate for protecting mtDNA or sensing damage. To examine the possibilities that TFAM might protect DNA from damage or act as a damage sensing protein for irreparable forms of mtDNA damage, we used live-cell imaging and HeLa cell-based assays, atomic force microscopy (AFM), and high-throughput protein-DNA binding assays to characterize the binding properties of human TFAM to ultraviolet-C (UVC) irradiated DNA and the cellular consequences of UVC irradiation. Our cell data show increased TFAM mRNA after exposure and suggest an increase in mtDNA degradation without a loss in mitochondrial membrane potential that might trigger mitophagy. Our protein-DNA binding assays indicate a reduction in sequence specificity of TFAM following UVC irradiation and a redistribution of TFAM binding throughout the mitochondrial genome. Our AFM data show increased compaction of DNA by TFAM in the presence of damage. Despite the TFAM-mediated compaction of mtDNA in vitro, we do not observe any protective effect of increased TFAM protein on DNA damage formation in cells or in vitro. Increased TFAM protein did not alter levels of mtDNA damage over time after UVC exposure in vivo, but knockdown of TFAM did alter mtDNA damage levels in HeLa cells both at baseline and after UVC exposure. Taken together, these studies indicate that UVC-induced DNA damage alters TFAM binding and promotes compaction by TFAM in vitro. We hypothesize that TFAM may act as a damage sensing protein in vivo, sequestering damaged genomes to prevent mutagenesis by facilitating removal or suppression of replication.
2026-03-25
Dongze Song, Hongru Zhang, Lizhong Yan, Muhan Yang, Qi Zhang, Ruixing Zhang, Shaowei Zhao, Shian Wu, Xueli Fu, Yang Zhang, Yuejia Wang, Yunfeng Wang, Ziguang Wang
Oncogenic Ras is known to induce DNA replication stress, leading to cellular senescence or death. In contrast, we found that it can also trigger polyploid Drosophila ovarian nurse cells to die by inducing aberrant division stress. To explore intrinsic protective mechanisms against this specific form of cellular stress, here, we conducted a genome-wide genetic screen and identified the E2 enzyme Uev1A as a key protector. Reducing its expression levels exacerbates the nurse cell death induced by oncogenic Ras , while overexpressing it or its human homologs, UBE2V1 and UBE2V2, mitigates this effect. Although Uev1A is primarily known for its non-proteolytic functions, our studies demonstrate that it collaborates with the E3 APC/C complex to mediate the proteasomal degradation of Cyclin A, a key cyclin that drives cell division. Furthermore, Uev1A and UBE2V1/2 also counteract oncogenic Ras -driven tumorigenesis in diploid cells, suppressing the overgrowth of germline tumors in Drosophila and human colorectal tumor xenografts in nude mice, respectively. Remarkably, elevated expression levels of UBE2V1/2 correlate with improved survival rates in human colorectal cancer patients harboring oncogenic KRAS mutations, indicating that their upregulation could represent a promising therapeutic strategy.
2026-03-24
Christopher R Dorsett, Jeffery N Stirman, Spencer LaVere Smith, Yiyi Yu
Among brain areas, axonal projections carry channels of information that can be mixed to varying degrees. Here, we assess the rules for the network consisting of the primary visual cortex and higher visual areas (V1-HVA) in mice. We use large field-of-view two-photon calcium imaging to measure correlated variability (i.e. noise correlations, NCs) among thousands of neurons, forming over a million unique pairs, distributed across multiple cortical areas simultaneously. The amplitude of NCs is proportional to functional connectivity in the network, and we find that they are robust, reproducible statistical measures and are remarkably similar across stimuli, thus providing effective constraints to network models. We used these NCs to measure the statistics of functional connectivity among tuning classes of neurons in V1 and HVAs. Using a data-driven clustering approach, we identify approximately 60 distinct tuning classes found in V1 and HVAs. We find that NCs are higher between neurons from the same tuning class, both within and across cortical areas. Thus, in the V1-HVA network, mixing of channels is avoided. Instead, distinct channels of visual information are broadcast within and across cortical areas, at both the micron and millimeter length scales. This principle for the functional organization and correlation structure at the individual neuron level across multiple cortical areas can inform and constrain computational theories of neocortical networks.
2026-03-24
Amanda Ross, Damien Portevin, Daniela Brites, Hellen Charles Hiza, Jacques Fellay, Jerry Hella, Klaus Reither, Liliana K Rutaihwa, Lluis Quintana-Murci, Maxime Rotival, Michaela Zwyer, Mohamed Sasamalo, Sebastien Gagneux, Sonia Borrell, Zhi Ming Xu
Infectious diseases have affected humanity for millennia and are among the strongest selective forces. Tuberculosis (TB) is an ancient disease, caused by the human-adapted members of the Mycobacterium tuberculosis complex (MTBC). The outcome of TB infection and disease is highly variable, and co-evolution between human populations and MTBC strains may account for some of this variability. Particular human genetic ancestries have been associated with higher susceptibility to TB, but sociodemographic aspects of the disease can confound such associations. Here, we studied 1000 TB patients from Dar es Salaam, Tanzania, together with their respective MTBC isolates, by combining human and bacterial genomics with clinical data. We found that the genetic background of the TB patient population was strongly influenced by migrations of Bantu-speaking populations from West Africa, which contrasts with the corresponding MTBC genotypes that were mainly introduced from outside Africa. These findings suggest a recent evolutionary history of co-existence between the human and MTBC populations in Dar es Salaam. We detected no evidence of an effect of human genetic ancestry, or MTBC phylogenetic diversity alone, nor their interaction, on TB disease severity. There was also no evidence of an association between human variation genome-wide and TB disease severity. Treatment-seeking, social, and environmental factors are likely to be the main determinants of disease severity at the point of care in this patient population.
2026-03-24
Alejandro Rodriguez Gama, Jay R Unruh, Jeffrey J Lange, Jianzheng Wu, Malcolm Cook, Randal Halfmann, Shriram Venkatesan, Tayla Miller, William D Bradford, Xiaoqing Song
How minute pathogenic signals trigger decisive immune responses is a fundamental question in biology. Classical signaling often relies on ATP-driven enzymatic cascades, but innate immunity frequently employs death fold domain (DFD) self-assembly. The energetic basis of this assembly is unknown. Here, we show that specific DFDs function as energy reservoirs through metastable supersaturation. Characterizing all 109 human DFDs, we identified sequence-encoded nucleation barriers specifically in the central adaptors of inflammatory signalosomes, allowing them to accumulate far above their saturation concentration while remaining soluble and poised for activation. We demonstrate that the inflammasome adaptor ASC is constitutively supersaturated in vivo, retaining energy that powers on-demand cell death. Swapping a non-supersaturable DFD in the apoptosome with a supersaturable one sensitized cells to sublethal stimuli. Mapping all DFD nucleating interactions revealed that supersaturated adaptors are triggered to polymerize specifically by other DFDs in their respective pathways, limiting potentially deleterious crosstalk. Across human cell types, adaptor supersaturation strongly correlates with cell turnover, implicating this thermodynamic principle in the trade-off between immunity and longevity. Profiling homologues from fish and sponge, we find nucleation barriers to be conserved across metazoa. These findings reveal DFD adaptors as biological phase change materials in thermal batteries to power cellular life-or-death decisions on demand.
2026-03-24
Bernd Weber, Johannes Schultz, Maria Gädeke, Omar Salah Ahmed, Rene Hurlemann, Tom Eric Willems
This study investigated the neural mechanisms involved in feelings of interpersonal guilt and responsibility evoked by social decisions in humans. In two studies (one during fMRI), participants repeatedly chose between safe and risky monetary outcomes in social contexts. Across conditions, each participant chose for both themselves and a partner ( Social condition), or the partner chose for both themselves and the participant ( Partner condition), or the participant chose just for themselves ( Solo condition, control). If the risky option was chosen in the Social or Partner condition, participant and partner could each receive either the high or the low outcome of a lottery with 50% probability, independently of each other. Participants were shown the outcomes for themselves and for their partner on each trial and reported their momentary happiness every few trials. As expected, participant happiness decreased following both low lottery outcomes for themselves and for the partner. Crucially, happiness decreases following low outcomes for the partner were larger when the participant rather than their partner had made the choice, which fits an operational definition of guilt. This guilt effect was associated with BOLD signal increase in the left anterior insula. Connectivity between this region and the right inferior frontal gyrus varied depending on choice and experimental condition, suggesting that this part of prefrontal cortex is sensitive to guilt-related information during social choices. Variations in happiness were well explained by computational models based on participants’ and partners’ rewards and reward prediction errors. A model-based analysis revealed a left superior temporal sulcus cluster that tracked partner reward prediction errors that followed participant choices. Our findings identify neural mechanisms of guilt and social responsibility during social decisions under risk.
2026-03-23
Aishwarya Chhatre, Devanjan Sinha, Olivia Majhi, Tanvi Chaudhary
Reactive oxygen species (ROS), predominantly derived from mitochondrial respiratory complexes, have emerged as key molecules influencing cell fate decisions like maintenance and differentiation. These redox-dependent events are mainly considered to be cell intrinsic in nature; on the contrary, our observations indicate involvement of these oxygen-derived entities as intercellular communicating agents. In Drosophila male germline, Germline Stem Cells (GSCs) and neighbouring Cyst Stem Cells (CySCs) maintain differential redox thresholds where CySCs have higher redox state compared to the adjacent GSCs. Disruption of the redox equilibrium between the two adjoining stem cell populations by depleting Superoxide Dismutases (SODs), especially Sod1, results in deregulated niche architecture and loss of GSCs, which was mainly attributed to loss of contact-based receptions and uncontrolled CySC proliferation due to ROS-mediated activation of self-renewing signals. Our observations hint towards the crucial role of differential redox states where CySCs containing higher ROS function not only as a source of their own maintenance cues but also serve as non-autonomous redox moderators of GSCs. Our findings underscore the complexity of niche homeostasis and predicate the importance of intercellular redox communication in understanding stem cell microenvironments.
2026-03-23
Gabriele Sakalauskaite, Guoshou Teo, Huiyi Tay, Hyungwon Choi, Li Na Zhao, Matthew J Watt, Mengchao Yan, Paul R Burton, Philipp Kaldis, Pradeep Narayanaswamy, Qing Zhao, Rachel Liyu Lim, Ruoyu Wang, Sonia Youhanna, Sungdong Lee, Umur Keles, Volker M Lauschke, William De Nardo, Ye Xie, Yi Zhong, Youngrae Kim
Metabolic dysfunction-associated steatotic liver disease (MASLD) is often asymptomatic early on but can progress to irreversible conditions like cirrhosis. Due to limited access to human liver biopsies, systematic and integrative molecular resources remain scarce. In this study, we performed transcriptomic analyses on liver and metabolomic analyses on liver and plasma samples from morbidly obese individuals without liver pathology or at early-stage MASLD. While the plasma metabolomic profile did not fully mirror liver histological features, dual-omics integration of liver samples revealed significantly remodeled lipid and amino acid metabolism pathways. Integrative network analysis uncoupled metabolic remodeling and gene expression as independent features of hepatic steatosis and fibrosis progression, respectively. Notably, GTPases and their regulators emerged as a novel class of genes linked to early liver fibrosis. This study offers a detailed molecular landscape of early MASLD in obesity and highlights potential targets of obesity-linked liver fibrosis.
2026-03-23
Yang Fu, Zhao Wang
Gaining the ability to kill rival microbes is not always an advantage for bacteria in complex gut microbiomes.
2026-03-23
Daniel E Goldberg, Melissa Rosenthal
Artemisinin-based combination therapies (ACTs) remain the mainstay of treatment for Plasmodium falciparum malaria, despite reports of ACT treatment failure. ACTs consist of an artemisinin and a longer-lived partner drug, which is often a quinoline. Given that heme is central to the mechanism of action of artemisinins and some quinolines, we hypothesized that these antimalarials would exhibit strong drug-drug interactions. Previous studies using standard 48 hr or 72 hr assays identified additive to mildly antagonistic interactions between artemisinins and quinolines. Here, we sought to re-evaluate these interactions using a pulsing assay that better mimics the short in vivo half-life of artemisinins. We found that chloroquine (CQ), piperaquine (PPQ), and amodiaquine substantially antagonize dihydroartemisinin (DHA), the active metabolite of artemisinins. CQ-DHA antagonism was notably exacerbated in CQ-resistant parasites, resulting in a superantagonistic phenotype in isobolograms. Further, we found that CQ co-treatment conferred artemisinin resistance to Kelch 13 wild-type parasites in the ring-stage survival assay. Using a small molecule probe (Ac-H-FluNox) to measure chemically reactive heme in live parasites, we determined that quinolines block artemisinin activation by rendering cytosolic heme inert. Finally, we probed beyond traditional ACTs, evaluating interactions of the proposed triple ACT, DHA-PPQ-mefloquine, as well as OZ439-quinoline combinations, which were all found to be antagonistic. Collectively, these in vitro data suggest that peroxide-quinolines may have liabilities as combination therapies.
2026-03-20
Haiping Hao, John Paul Donohue, Jose M Abril, Karen Larisssa Pereira de Castro, Kuo-Chieh Liao, William K Russell, William S Fagg
Recognition of the intron branch point during spliceosome assembly is a multistep process that can influence mRNA structure and levels. A branch point sequence motif UACUAAC is variably conserved in eukaryotic genomes, but in some organisms, more than one protein can recognize it. Here, we show that SF1 and Quaking (QKI) compete for a subset of intron branch sites with the sequence ACUAA in mammalian cells. SF1 activates exon inclusion through this sequence, but QKI represses the inclusion of alternatively spliced exons with this intron branch point sequence. Using mutant reporters derived from a natural intron with two branch site-like sequences, we find that when either branch point sequence is mutated, the other is utilized; however, when both are present, neither is used due to high-affinity binding and strong splicing repression by QKI. QKI occupancy at the dual branch site directly prevents SF1 binding and the subsequent recruitment of spliceosome-associated factors. Finally, ectopic expression of QKI in budding yeast (which lacks QKI ) is lethal, at least in part due to widespread splicing repression. In conclusion, QKI can function as a splicing repressor by directly competing with SF1/BBP for a subset of branch point sequences that closely mirror its high-affinity binding site.
2026-03-20
Aaron J Janowsky, Jack Wiedrick, Michelle C Palumbo, Sheila Benware, Sheila Markwardt, Xiao Shi
All cells secrete extracellular vesicles (EVs) containing nucleic acid cargo, including microRNAs (miRNAs), that regulate the function of receiving cells. G protein-coupled receptors (GPCRs) affect intracellular function via multiple signaling cascades. However, the mechanisms of GPCR intercellular signaling through EV miRNA activity remain unknown. Human U2 osteosarcoma cells expressing native GPCRs were used to selectively stimulate distinct G protein signaling cascades (Gα i , Gα q , Gα 12/13 , and β-arrestin) by members of specific receptor subclasses, including the adenosine receptor A1 (ADORA1), the histamine receptor H1 (HRH1), the frizzled class receptor 4 (FZD4), and the atypical chemokine receptor 3 (ACKR3), respectively. We hypothesized that stimulation of specific classes of GPCRs would cause the release of EVs containing miRNAs with receptor-specific up- or downregulated expression, affecting unique pathological downstream signaling cascades. Receptor-specific agonists dose-dependently increased respective signaling cascade intermediates. We found no change in the quantity of EVs (~200 nm diameter), but there were distinct EV miRNA signatures following stimulation of GPCRs. Network analyses of differentially expressed miRNA and their predicted targets validated the linkage between specific receptors and cell function and pathological states. The data can be used to reverse engineer mechanisms involving EV miRNAs for various physiological and pathological processes. GPCRs are major pharmacological targets, so understanding the mechanisms that stimulate or inhibit GPCR-mediated changes in extracellular miRNA signatures could improve long- and short-term therapeutic and unwanted drug effects.
2026-03-18
Christian Leibold, Hamed Shabani, Hannah Muysers, Jonas-Frederic Sauer, Marlene Bartos, Yuk-Hoi Yiu
The medial prefrontal cortex (mPFC) is thought to support cognitive flexibility by forming and maintaining generalized representations of abstract tasks. The formation of these representations as well as their relation to preexisting representations of contextual or spatial information is incompletely understood. In this study, we analyzed longitudinal one-photon calcium recordings in mice performing an olfaction-guided spatial memory task over an 8-week period that included habituation, training, and sleep epochs. Our results reveal that, while a minority of neurons initially conveyed significant information about the behavior of the animal, the bulk of task-related activity only emerged after the animals reached proficient performance. Although goal arm information is robustly represented at both the single-cell and network levels both during learning and in task-proficient mice, it undergoes significant remapping throughout the learning process. Additionally, we identified the establishment of recurring sequences during learning and their replay at reward locations, with no evidence of them existing during odor sampling phase, during sleep, or before training. Conversely, during odor sampling, information about odor identity is robustly available in the rate coactivation patterns, even before animals reached task proficiency. These findings suggest that the mPFC predominantly establishes generalized task representations de novo during learning, relying only minimally on preexisting spatial representations and that sub-second neural sequences in the mPFC are more likely involved in evaluating behavioral outcomes rather than planning future actions.
2026-03-18
Cara Glynn, Tiago Monteiro
Sharing positive and negative experiences at lab meetings can make a career in science a little less hard, a little more pleasant, and a little more human.
2026-03-17
Diane M Harper, Timothy E Behrens, Yamini Dalal
Taking a radical new approach to the publication process resulted in eLife losing its impact factor, but authors, reviewers, editors and funders support the journal and its efforts to reform scientific publishing.
2026-03-17
Ashish Lal, Bruna R Muys, Erica C Pehrsson, Ioannis Grammatikakis, Lisa M Jenkins, Mary Guest, Ragini Singh, Raj Chari, Ravi Kumar, Simon Couly, Stefan Ambs, Tsung-Ping Su, Wei Tang, Xiao Ling Li, Xinyu Wen
The tumor suppressor p53 is a transcription factor that controls the expression of hundreds of genes. Emerging evidence indicates that the p53-induced RNA-binding protein ZMAT3 acts as a key splicing regulator that contributes to p53-dependent tumor suppression in vitro and in vivo. However, the mechanism by which ZMAT3 functions within the p53 pathway remains largely unclear. Here, we discovered a function of ZMAT3 in inhibiting transcription of HKDC1 , a hexokinase that regulates glucose metabolism and mitochondrial respiration in human cancer cells. Quantitative proteomics revealed HKDC1 as the most significantly upregulated protein in ZMAT3 -depleted colorectal cancer cells. ZMAT3 depletion resulted in increased mitochondrial respiration, which was rescued by simultaneous depletion of HKDC1 , suggesting that HKDC1 is a critical downstream effector of ZMAT3 . Unexpectedly, ZMAT3 did not bind to HKDC1 RNA or DNA; however, proteomic analysis of the ZMAT3 interactome identified its interaction with the oncogenic transcription factor JUN. ZMAT3 depletion enhanced JUN binding to the HKDC1 locus, leading to increased HKDC1 transcription that was rescued upon JUN depletion, suggesting that JUN activates HKDC1 transcription in ZMAT3-depleted cells. Collectively, these findings uncover a mechanism by which ZMAT3 regulates transcription through JUN and demonstrate that HKDC1 is a key component of the ZMAT3-regulated transcriptome in the context of mitochondrial respiration regulation.
2026-03-16
Huilin Fang, Jan Tünnermann, Jie Sui, Katja Fredriksson, Meike Scheller
Efficiently processing self-related information is critical for cognition, yet the earliest mechanisms enabling this self-prioritization in humans remain unclear. By combining a temporal order judgement task with computational modeling based on the Theory of Visual Attention (TVA), we show how mere, arbitrary associations with the self can fundamentally alter attentional selection of sensory information into aware short-term memory, by enhancing the attentional weights and processing capacity devoted to encoding socially loaded information. This self-prioritization in attentional selection occurs automatically at early perceptual stages but reduces when active social decoding is required. Importantly, the processing benefits obtained from attentional selection via self-relatedness and via physical salience were additive, suggesting that social and perceptual salience captured attention via separate mechanisms. Furthermore, intra-individual correlations revealed an ‘obligatory’ self-prioritization effect, whereby self-relatedness overpowered the contribution of perceptual salience in guiding attentional selection. Together, our findings provide evidence for the influence of self-relatedness during earlier, automatic stages of attentional selection at the gateway to perception, distinct from later post-attentive processing stages.
2026-03-16
Antoine Bouyeure, Daniel Pacheco-Estefan, George Jacob, Jonas Rose, Malte Kobelt, Marie-Christin Fellner, Nikolai Axmacher
When we learn that something is dangerous, a fear memory is formed. However, this memory is not fixed and can be updated through new experiences, such as learning that the threat is no longer present. This process of updating, known as extinction or reversal learning, is highly dependent on the context in which it occurs. How the brain represents cues, contexts, and their changing threat value remains a major question. Here, we used functional magnetic resonance imaging and a novel fear learning paradigm to track the neural representations of stimuli across fear acquisition, reversal, and test phases. We found that initial fear learning creates generalized neural representations for all threatening cues in the brain’s fear network. During reversal learning, when threat contingencies switched for some of the cues, two distinct representational strategies were observed. On the one hand, we still identified generalized patterns for currently threatening cues, whereas on the other hand, we observed highly stable representations of individual cues (i.e. item-specific) that changed their valence, particularly in the precuneus and prefrontal cortex. Furthermore, we observed that the brain represents contexts more distinctly during reversal learning. Furthermore, additional exploratory analyses showed that the degree of this context specificity in the prefrontal cortex predicted the subsequent return of fear, providing a potential neural mechanism for fear renewal. Our findings reveal that the brain uses a flexible combination of generalized and specific representations to adapt to a changing world, shedding new light on the mechanisms that support cognitive flexibility and the treatment of anxiety disorders via exposure therapy.