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Last update: 2026-10-23
2026-10-22 · Genetics and Genomics
Kyle Feola, Peter M Douglas
The steroid hormone dafachronic acid may carry the effects of reduced mTOR activity between tissues to coordinate metabolism and longevity across the body.
DOI: 10.7554/elife.1131252026-10-22 · Neuroscience
Hugo Marques, Kyle Thomas, Megan R Carey, Rhuna Gibbs, Samuel J Sober
During locomotion, the coordinated activity of dozens of muscles shapes the kinematic features of each stride, including systematic changes in limb movement across walking speed. Motor units, each of which consists of a single motor neuron and the muscle fibers it innervates, contribute to the total activation of each muscle through their recruitment and firing rate when active. However, it remains unknown how the nervous system controls locomotor speed by changing the firing of individual motor units. To address this, we combined quantitative behavioral analysis of mouse locomotion with single motor unit recordings from the lateral and long heads of the triceps brachii, which drive monoarticular extension of the elbow and biarticular movements of the elbow and shoulder, respectively. In contrast to prior studies employing bulk electromyography (EMG) to examine muscle activity, our recordings revealed the diversity of spike patterning across motor units, as well as systematic differences in motor unit activity across muscles and locomotor speeds. First, motor unit activity differed significantly across the lateral and long heads, suggesting differential control of these two closely apposed elbow extensor muscles. Second, we found that individual units were recruited probabilistically (during only a subset of strides), showing that the highly repeatable bulk EMG signals observed across strides, in fact, reflect varying subsets of individual motor units. Finally, although recruitment probability and firing rate both increased at faster walking speeds, increases in recruitment were proportionally larger than rate changes, and recruitment of individual units accompanied changes in limb kinematics. Together, these results reveal how the firing of individual motor units varies systematically across muscles and walking speeds to produce flexible locomotor behavior.
DOI: 10.7554/elife.1058292026-10-22 · Computational and Systems Biology
Alexander Martin, Aryan R Marri, Benjamin N Szymanski, Bruce A Bamber, Chelyan A Edwards, Jenna Kaake, Lana Awa, Lilian G Jerow, Md Zubayer Hossain Saad, Robert McCullumsmith, William G Ryan
Olfactory-driven behaviors are essential for animal survival, but mechanisms for decoding olfactory inputs remain poorly understood. We have used whole-network Ca 2+ imaging to study olfactory coding in Caenorhabditis elegans . We show that the odorant 1-octanol is encoded combinatorially in the periphery as both an attractant and a repellent. These inputs are integrated centrally, and their relative strengths determine the sensitivity and valence of the behavioral response through modulation of locomotory reversals and speed. The balance of these pathways also dictates the activity of the locomotory command interneurons, which control locomotory reversals. This balance serves as a regulatory node for response modulation, allowing C. elegans to weigh opportunities and hazards in its environment when formulating behavioral responses. Thus, an odorant can be encoded simultaneously as inputs of opposite valence, focusing attention on the integration of these inputs in determining perception, response, and plasticity.
DOI: 10.7554/elife.1048282026-10-21 · Cell Biology
Jitendra Kumar, Kanika Sharma, Ravi Prakash Yadav, Santosh Kumar, Shravan K Uppulapu, Sujata Kumari, Vikas Kumar, William J Paradee
Sumoylation is a post-translational modification that can regulate different physiological functions. Increased sumoylation, specifically conjugation of SUMO2/3 (small ubiquitin-like modifier 2/3), is detrimental to vascular health. However, the molecular mechanism mediating this effect is poorly understood. We used cell-based assays and mass spectrometry to show that p66Shc is a direct target of SUMO2 and that SUMO2 regulates p66Shc function via lysine-81 modification. To determine the effects of SUMO2-p66ShcK81 on vascular function, we generated Shc1 K81R mice and crossbred them toLdlr -/- mice to induce hyperlipidemia. Next, to determine p66ShcK81-SUMO2ylation-induced changes in endothelial cell signaling, we performed mass spectrometry followed by Ingenuity Pathway Analysis. Our data reveal that p66Shc mediates the effects of SUMO2 on endothelial cells. Mass spectrometry identified that SUMO2 modified lysine-81 in the unique collagen homology-2 domain of p66Shc. SUMO2ylation of p66Shc increased phosphorylation at serine-36, causing it to translocate to the mitochondria, a step critical for the oxidative function of p66Shc. Notably, sumoylation-deficient p66Shc (p66ShcK81R) was resistant to SUMO2-induced p66ShcS36 phosphorylation and mitochondrial translocation. Shc1 K81R mice were resistant to endothelial dysfunction induced by SUMO2ylation and hyperlipidemia. Ingenuity Pathway Analysis revealed multiple signaling pathways regulated by p66ShcK81-SUMO2ylation in endothelial cells, highlighting JAK-STAT as a major pathway affected by SUMO2-p66ShcK81. Collectively, our work reveals SUMO2-p66Shc signaling as a fundamental regulator of vascular endothelial function. We discovered that p66ShcK81 is an upstream modification regulating p66Shc signaling and mediates hyperlipidemia-induced endothelial dysfunction and oxidative stress.
DOI: 10.7554/elife.1063442026-10-21 · Neuroscience
Isabel A Muzzio, Manuel M Ramos-Alvarez, Marc E Normandin, Matthew R Lopez, Pedro M Ogallar
Adaptive behavior requires assigning emotional value to sensory cues and generalizing to similar stimuli. The prelimbic cortex (PL) is critical for threat expression and discrimination, yet its neuronal ensembles undergo substantial turnover over time. How stable population codes emerge despite this reorganization remains unknown. Using longitudinal calcium imaging in freely moving mice, we tracked PL activity for 30 days during auditory discriminative fear learning and retrieval. Despite substantial ensemble turnover, stable graded representations persisted in PL populations. A generalized linear model showed that the tone threat value explained graded activity better than freezing, indicating that PL primarily encodes stimulus significance. Population similarity across stimulus presentations was highest for shock-associated and highly generalized tones, suggesting a stable population code underlying threat generalization. Stable neurons preserved graded gradients across sessions, whereas learning modulated the rate of dynamic frequency-selective neurons. Together, these populations enabled stable threat-value coding despite ongoing ensemble reorganization.
DOI: 10.7554/elife.1111772026-10-21 · Ecology
Alex Gill, Ary Hoffmann, Lauren Coakley, Lucy Hayward, Mel Berran, Monica Stelmach, Paul A Umina, Perran Ross, Qiong Yang, Sheik Nadeem Elahee Doomun, Sonia Sharma, Xinyue Gu
Endosymbiotic bacteria can affect many ecological attributes of their insect hosts, including (in herbivorous insects) how they interact with plants where they feed. This raises the issue of whether deliberate endosymbiont introductions could be used to decrease crop damage caused by insect pests. Here, we investigate how transinfecting Rickettsiella viridis and Regiella insecticola endosymbionts into a novel pest aphid host, the Russian wheat aphid ( Diuraphis noxia ), influences population growth, alate production, dispersal ability, and crop damage. Both the Rickettsiella (originating from pea aphids) and Regiella (from green peach aphids) were stably maintained in their new host where they had contrasting effects. Rickettsiella increased the severity of aphid feeding damage on wheat and barley, resulting in greater leaf loss, chlorotic streaking, and higher aphid populations, whereas Regiella reduced aphid population growth and the severity of feeding damage by aphids. Their effects on dispersal morphology also differed: Regiella had no detectable impact on alate incidence, while Rickettsiella consistently suppressed wing formation in small cages, and in larger mesocosms with multiple wheat plants this endosymbiont suppressed dispersal. Endosymbiont-mediated changes in feeding damage did not involve the main plant immune response pathways: transinfected and wild type aphids induced similar levels of jasmonic acid, jasmonic acid-isoleucine, and salicylic acid in plant tissues, even though these plant defenses were strongly activated during aphid feeding. Novel endosymbionts can therefore modulate the severity of plant feeding damage by aphids as well as influencing aphid dispersal. Potential applications in controlling pest D. noxia populations are discussed.
DOI: 10.7554/elife.1112552026-10-21 · Biochemistry and Chemical Biology
DOI: 10.7554/elife.1134742026-10-21 · Neuroscience
Alon Boaz Baram, Kristopher T Jensen, Maneesh Sahani, Mathias Sablé-Meyer, Peter T Doohan, Sandra Reinert, Thomas Akam, Timothy E Behrens
Planning is critical for adaptive behaviour in a changing world, because it lets us anticipate the future and adjust our actions accordingly. While prefrontal cortex is crucial for this process, it remains unknown how planning is implemented in neural circuits. Prefrontal representations were recently discovered in simpler sequence memory tasks, where different populations of neurons represent different future time points. We demonstrate that combining such representations with the ubiquitous principle of neural attractor dynamics allows circuits to solve much richer problems, including planning. This is achieved by embedding the environment structure directly in synaptic connections to implement an attractor network that infers desirable futures. The resulting ‘spacetime attractor’ excels at planning in challenging tasks known to depend on the prefrontal cortex. Recurrent neural networks trained by gradient descent on such tasks learn a solution that precisely recapitulates the spacetime attractor – in representation, in dynamics, and in connectivity. Analyses of networks trained across different environment structures reveal a generalisation mechanism that rapidly reconfigures the world model used for planning, without the need for synaptic plasticity. The spacetime attractor is a testable mechanistic theory of planning. If true, it would provide a path towards detailed mechanistic understanding of how prefrontal cortex structures adaptive behaviour.
DOI: 10.7554/elife.1097572026-10-21 · Microbiology and Infectious Disease
DOI: 10.7554/elife.1135512026-10-21 · Neuroscience
Alice M Xue, Anthony D Wagner, Anthony M Norcia, Jenna Jokhani
Ongoing experience is continuously processed in the context of past events. Divergence between current experience and memory-based predictions (i.e., a mnemonic prediction error; MPE) is theorized to be a signal that encoding, as opposed to retrieval, should be prioritized. We asked how MPEs place demands on control and attention-related processes, and whether these demands differ as a function of prediction strength. We investigated these questions across two experiments, wherein we recorded scalp electroencephalography and/or pupillometry as 101 young human adults performed an associative memory task. Strong MPEs, more so than weak MPEs, increased physiological indices of cognitive control (frontal theta), attention (posterior alpha and pupil size), and arousal (pupil size). Greater cognitive control (frontal theta) during strong MPEs promoted better learning of prediction-violating (i.e., unexpected) stimuli. Collectively, these findings reveal multiple pathways through which the mind and brain respond adaptively to violations of strong mnemonic predictions.
DOI: 10.7554/elife.1096782026-10-20 · Neuroscience
Feifei Yu, Honghui Zheng, Jiyuan Tang, Shaohua Ma, Yilin Feng, Zitian Wang
Genetic evidence implicates immune dysfunction in Alzheimer’s disease (AD), yet the neuroimmune mechanisms operating in human tissue remain poorly defined. Here, we establish a modular human forebrain organoid platform that systematically integrates human induced pluripotent stem cell-derived microglia and CD8 + T cells to reconstitute multicellular AD pathology. This system enables functional interrogation of both innate and adaptive immune components in a human-relevant context. Using this platform, we demonstrate that microglia mediate amyloid-β clearance and neuronal maturation but also drive inflammatory activation and recruit CD8 + T cells through CCL4/5 signaling via CCR1/5 and CXCR3, establishing a neuroinflammatory feedback loop. Pharmacological targeting of CCR5 or CXCR3 blocks T cell recruitment and modulates autophagy in a microglia-dependent manner. This modular organoid platform provides a versatile tool for dissecting neuron–immune interactions and enables cell-type-specific therapeutic screening in human neuroinflammatory disease models.
DOI: 10.7554/elife.1117302026-10-20 · Neuroscience
Erin A Clark, Liwei Sun, Ruixuan Xiao, Ryan W Kirk, Sacha B Nelson
A critical phase of mammalian brain development takes place after birth. Neurons of the mouse neocortex undergo dramatic changes in their morphology, physiology, and synaptic connections during the first postnatal month, while properties of immature neurons, such as the capacity for robust axon outgrowth, are lost. The genetic and epigenetic programs controlling prenatal development are well studied, but our understanding of the transcriptional mechanisms that regulate postnatal neuronal maturation is comparatively lacking. By integrating chromatin accessibility and gene expression data from two subtypes of neocortical pyramidal neurons in the neonatal and maturing brain, we predicted a role for the Krüppel-like factor (KLF) family of transcription factors in the developmental regulation of neonatally expressed genes. Using a multiplexed CRISPR interference (CRISPRi) knockdown strategy, we found that a shift in expression from KLF activators (Klf6, Klf7) to repressors (Klf9, Klf13) during early postnatal development functions as a transcriptional ‘switch’ to first activate, then repress a set of shared targets with cytoskeletal functions including Tubb2b and Dpysl3 . We demonstrate that this switch is buffered by redundancy between KLF paralogs, which our multiplexed CRISPRi strategy is equipped to overcome and study. Our results indicate that competition between activators and repressors within the KLF family regulates a conserved component of the postnatal maturation program that may underlie the loss of intrinsic axon growth in maturing neurons. This could facilitate the transition from axon growth to synaptic refinement required to stabilize mature circuits.
DOI: 10.7554/elife.1065102026-10-19 · Cell Biology
Masayuki Miura, Natsuki Shinoda, Nozomi Hanawa, Yutaro Hama
Caspases are cysteine-aspartic proteases that mediate both lethal and non-lethal cellular outcomes, including the promotion of tissue growth. However, the mechanisms underlying the differential regulation of these activities remain unclear. We have previously shown that among the two Drosophila executioner caspases, Dcp-1 and Drice, Dcp-1 promotes tissue growth in a non-lethal manner, independent of canonical apoptotic signaling. Herein, we demonstrated that overexpressed Dcp-1, but not Drice, was activated without canonical apoptosome components. TurboID-based proximity labeling revealed distinct proximal proteomes, among which Sirtuin 1, an Atg8a deacetylase, which promotes autophagy, was specifically required for Dcp-1 activation. Autophagy-related genes, including Bcl-2 family members Debcl and Buffy , are required for Dcp-1 activation. Structure-based prediction using AlphaFold3 further identified Bruce, an autophagy-regulated inhibitor of apoptosis, as a Dcp-1-specific regulator acting outside the apoptosome-mediated pathway. Physiologically, Bruce suppresses wing tissue growth. These findings indicate that non-lethal Dcp-1 activity is governed by the autophagy–Bruce axis, enabling distinct non-lethal functions independent of cell death.
DOI: 10.7554/elife.1098762026-10-19 · Cell Biology
Abdul Rishad, Abhikarsh Gupta, Adish Dani, Atharva R Yande, Kalyaneswar Mandal, Kunal M Jagetiya, Megumi Yamashita, Mohammad Shahrooei, Monika Vig, Murali Prakriya, Ramanathan Sowdhamini, Resmi Bera, Sandra Ammann, Sreejith Raran-Kurussi, Sritama Datta, Vikas R Tiwari, Vishal Malik
Mutations in Syntaxin11 (STX11), a Q-SNARE, result in a fatal immune disorder known as familial hemophagocytic lymphohistiocytosis 4 (FHLH4) in human patients. A key diagnostic feature of FHLH4 is defective T and natural killer cell cytotoxicity. Here, we show that STX11 directly binds and regulates Orai1, the pore-forming subunit of calcium release-activated calcium (CRAC) channels. CRAC channels enable store-operated calcium entry (SOCE) from the extracellular space and are crucial for granule exocytosis and nuclear factor of activated T cells (NFAT)-dependent gene expression in activated lymphocytes. STX11 depletion strongly inhibited SOCE, CRAC currents, NFAT activation, interleukin-2 gene expression, and degranulation in FHLH4 patient T lymphocytes and cell lines without affecting membrane trafficking. Remarkably, defects of cytolytic granule exocytosis, as well as interleukin-2 expression, could be reversed by ionomycin in patient T lymphocytes, and a constitutively active, H134S, mutant of Orai1 rescued calcium entry in STX11-depleted cells. Further analyses showed that STX11 ‘primes’ Orai1 for optimal on-site multimeric assembly, which was Stim independent but required for gating. Priming of ion channel pore subunits is, therefore, a primary function of specific SNAREs which may have preceded their role in membrane trafficking and vesicle fusion.
DOI: 10.7554/elife.1113352026-10-19 · Neuroscience
DOI: 10.7554/elife.1134842026-10-16 · Chromosomes and Gene Expression
Adhithi R Raghavan, Andreas Hochwagen, Hannah G Blitzblau, Jonathan Houseley, Kieron May, Neem J Patel, Vijayalakshmi V Subramanian
In many organisms, meiotic crossover recombination is suppressed near the extreme ends of chromosomes. Here, we show that multiple, often chromosome-specific, suppressive mechanisms with differing ranges contribute to the consistently low enrichment of recombination-promoting axis proteins and the downregulation of DNA double-strand breaks (DSBs) within 20 kb of telomeres in Saccharomyces cerevisiae . Suppression of axis proteins is associated with cis -encoded signals and correlates with reduced coding density, although whether this sequence feature actively drives suppression remains to be determined. In addition, axis protein suppression requires the histone methyltransferase Dot1 and the Sir silencing complex. We show that Dot1 suppresses Sir complex activity at least in part independently of its canonical target, H3K79, to downmodulate axis protein deposition near chromosome ends. In parallel, the Sir complex, but not Dot1, suppresses the induction of DSBs at a small number of cryptic hotspots by limiting the openness of promoters, the preferred sites of meiotic DSB formation. Much of the reduced DSB induction near chromosome ends persists in dot1 and sir3 mutants, indicating that additional layers of regulation contribute to the robust reduction of meiotic recombination effectors near chromosome ends.
DOI: 10.7554/elife.1101892026-10-16 · Genetics and Genomics
Chung-Chih Liu, Nicolas Seban, Supriya Srinivasan
The intestine integrates food-derived cues to coordinate organismal physiology, yet the molecular specialization of discrete regions along the intestinal epithelium remains unclear. Here, we generate cell type-specific translatomes of the Caenorhabditis elegans intestine during fasting and refeeding using discrete promoters for the anterior quartet of intestinal cells (INT1) and the remaining eight pairs of intestinal cells (INT2-9). We found that the anterior-most INT1 cells are a translationally distinct intestinal subcompartment that is particularly enriched for immune- and stress response genes. Functional assays using novel INT1-specific genes emerging from this study reveal that these specialized cells play a previously unappreciated role in pathogen avoidance and organismal survival. A second critical function of INT1 cells is their role in sensing and responding to the contents of the gut lumen. We show that luminal pyruvate is the key signal linking bacterial nutrients in the gut to secretion of the gut insulin antagonist INS-7. These findings establish INT1 as sentinel enteroendocrine cells that integrate metabolic and immune cues to couple food status with immune and endocrine responses. Our studies also provide a rich resource for dissecting segment-specific intestinal biology, an overlooked and fertile area for future research.
DOI: 10.7554/elife.1092372026-10-16 · Developmental Biology
DOI: 10.7554/elife.1132902026-10-16 · Neuroscience
Baozhi Yang, Bo Peng, Li Cao, Niewen Hu, Pei Ouyang, Shuai Gao, Xiaoyu Li, Yanxia Rao, Yue Cao, Yuxiao Jin, Yuxin Li
In situ glia-to-neuron conversion induced by a single transcription factor is a promising regenerative strategy for treating central nervous system injuries and neurodegenerative diseases. Previous studies reported that NeuroD1 can induce microglia-to-neuron cross-lineage conversion and improve recovery after brain injury. However, these findings remain controversial. To examine the ability of NeuroD1 in inducing microglia-to-neuron conversion, we employed virus-free genetic lineage tracing systems in mice to specifically induce NeuroD1 expression in microglia and track the cell fate of NeuroD1-expressing cells at multiple timepoints. Meanwhile, we longitudinally monitored NeuroD1-expressing microglia via two-photon imaging and characterized their transcriptional profile by single-cell RNA sequencing. All observations across these methods revealed that NeuroD1-expressing cells retained their microglia identity and cannot convert into neurons, under either physiological and injury conditions. Instead, sustained expression of NeuroD1 induced microglial apoptosis in vivo. Collectively, our findings provide strong evidence that NeuroD1 is not sufficient to induce microglia-to-neuron conversion. This study further highlights the importance of rigorous lineage tracing and cell fate mapping strategies for validating in situ glia-to-neuron conversion.
DOI: 10.7554/elife.1120832026-10-16 · Cell Biology
DOI: 10.7554/elife.1134972026-10-16 · Neuroscience
Alice Weiglein, Arman Behrad, Ayaka Fukushima, Franziska Behnke, Gauri Kaushik, Juliane Thoener, Maia Lisandra M Wang, Markus Dörr, Martin Strauch, Michael Schleyer, Naoko Toshima, Oliver Kobler
Two evolutionary highly conserved functions of dopamine are to carry ‘teaching’ signals during associative learning and to control movement. In mammals and humans, these functions are generally thought to be produced by different populations of neurons. Here, we investigated in the larva of Drosophila melanogaster whether both these functions can be induced by the same individual dopaminergic neurons in the central brain. Focusing on the dopaminergic neurons of the DL1 cluster, we asked whether the optogenetic activation of individual neurons established associative punishment and/or safety memories, controlled the retrieval of the established memories, and acutely modulated locomotion. We found that each neuron had a unique yet overlapping set of behavioural effects. Several individual neurons both established a memory and modulated acute locomotion by increasing the animals’ bending and decreasing their velocity. Our results demonstrate that individual dopaminergic neurons can fulfil a surprisingly broad range of functions in different behavioural contexts. Given the highly conserved roles of the dopaminergic system across the animal kingdom, this study raises the question whether a similarly diverse functionality can be found also in other animals, including humans.
DOI: 10.7554/elife.1061482026-10-15 · Plant Biology
Brice Letcher, Carine Rey, Daniel Bouyer, Emma Désert, Evelyne Duvernois-Berthet, Jeremy Just, Marie Monniaux, Patrice Morel, Pierre Chambrier, Quentin Cavallini-Speisser, Suzanne Rodrigues Bento
In flowering plants, floral organ identity is specified by the combinatorial action of homeotic genes. While the role of these genes in the early specification of organ identity is well established, their late function throughout floral organ development and in specific cell types is much less characterized. In particular, since plant organs are structured in clonally independent cell layers, whether and how homeotic identity interacts with cell layer identity is unknown. We have previously identified cell layer-specific mutants for the petal identity gene PhDEF in petunia flowers, resulting in drastically different petal phenotypes whether PhDEF is expressed in the petal epidermis or in the mesophyll. In this study, using a combination of single-cell RNA-Seq and chromatin immunoprecipitation on phdef cell layer-specific mutants, we find that PhDEF regulates a different set of target genes in the petal epidermis and mesophyll, with a major regulatory action in the epidermis. We uncover a high diversity of binding profiles in PhDEF target genes, with a complex combination of layer-specific or non-specific binding sites, and a much more prominent binding of PhDEF in the epidermis than in the mesophyll. Our study highlights that floral homeotic genes like PhDEF can have different regulatory actions in different cell contexts, here different cell layers, demonstrating that cell layer identity indeed influences the regulatory processes underlying homeotic identity.
DOI: 10.7554/elife.1131542026-10-15 · Neuroscience
Eero Simoncelli, Gizem Rufo, Jonathan Winawer, William Broderick
The ability of humans to discriminate and identify spatial patterns varies across the visual field and is generally worse in the periphery than in the fovea. This decline in performance is revealed in many kinds of tasks, from detection to recognition. A parsimonious hypothesis is that the representation of any visual feature is blurred (spatially averaged) by an amount that differs for each feature, but that in all cases increases with eccentricity. Here, we examine models for two such features: local luminance and spectral energy. Each model averages the corresponding feature in pooling windows whose diameters scale linearly with eccentricity. We performed perceptual experiments with synthetic stimuli to determine the largest window scaling for which human and model discrimination abilities match (the ‘critical’ scaling). We used much larger stimuli than those of previous studies, subtending 53.6 by 42.2° of visual angle. We found that the critical scaling for the luminance model was approximately one-fourth that of the energy model and, consistent with earlier studies, that the estimated critical scaling value was smaller when discriminating a synthesized stimulus from a natural image than when discriminating two synthesized stimuli. Moreover, we found that initializing the generation of the synthesized images with natural images reduced the critical scaling value when discriminating two synthesized stimuli, but not when discriminating a synthesized from a natural image stimulus. Together, the results show that critical scaling is strongly affected by the image statistic (pooled luminance vs. spectral energy), the comparison type (synthesized vs. synthesized or synthesized vs. natural), and the initialization image for synthesis (white noise vs. natural image). We offer a coherent explanation for these results in terms of alignments and misalignments of the models with human perceptual representations.
DOI: 10.7554/elife.905542026-10-15 · Microbiology and Infectious Disease
Robert P de Vries, Silke Rimaux
Bovine mammary tissue can support infection and replication of diverse influenza A viruses and may provide an environment in which different viral strains can co-infect cells.
DOI: 10.7554/elife.1131012026-10-14 · Physics of Living Systems
Jonasz Slomka, Luiz GM Silva, Markus Holzner, Robert M Boes, Robert Naudascher, Roman Stocker, Stefano Brizzolara
Most fish species are ectothermic and rely on behavioral strategies to control their body temperature in heterothermal environments. Both thermotaxis and thermokinesis have been suggested as important underlying mechanisms. However, to what extent these behaviors allow fish to respond to rapid (timescales of minutes) and strong thermal disturbances, like those caused by anthropogenic water releases into natural freshwater systems, is poorly understood. Here, we quantify this response for a salmonid species with a novel laboratory approach coupled with image-based tracking. We exposed brown trout parr ( Salmo trutta ), acclimated to 12 °C, to rapidly forming cold- and warm-water interfaces with temperatures ranging from 4 to 20 °C. We found that fish actively avoided colder water (≤8 °C) through a rapid response that combined thermotaxis and thermokinesis. In contrast, fish did not avoid warmer water and frequently crossed interfaces having temperature contrasts of up to 8 °C. This study shows that brown trout parr swiftly deploy multiple behavioral strategies to minimize exposure to cold water and take advantage of warm water, illustrating their capability to cope with rapidly occurring thermal alterations.
DOI: 10.7554/elife.991262026-10-14 · Cell Biology
DOI: 10.7554/elife.1134722026-10-14 · Computational and Systems Biology
Federico Germani, Giovanni Spitale
Large language models are very good at providing concise answers. But if we only see the answer without knowing the original question or the context behind it, that answer may not be very useful. The important issue is not simply how much information an AI summary removes but whether we can still recover the missing context. Thus, AI literature tools should also report how much information was removed and how recoverable their omissions are.
DOI: 10.7554/elife.1131372026-10-13 · Physics of Living Systems
Alexander Kovalev, Anna Steyer, Daniel Masiga, Dennis Petersen, Dianah Katiti, Elisabeth Meyer-Natus, Laura Hauf, Markus Engstler, Sebastian Büsse, Stanislav Gorb, Stephan Löwe, Wolfgang Böhme, Yoko Matsumura
Human African trypanosomiasis (HAT) is a neglected tropical disease transmitted by infected tsetse flies (Glossina spp.) in sub-Saharan Africa. Infected tsetse flies can transmit trypanosomes, including Trypanosoma brucei subspecies that cause HAT in humans, as well as other trypanosome species that cause animal African trypanosomiasis in domestic animals and infect wildlife. Tsetse flies feed on a broad spectrum of hosts, including humans, elephants, buffaloes, rhinos, hippos, turtles, and monitor lizards. To understand how the insects can penetrate such diverse skin types, we detailed the anatomical structures involved in tsetse blood feeding, their mechanical properties, and the forces exerted by the fly during probing. We found that the tsetse fly’s feeding apparatus does not rely on exceptionally unique structures or extraordinary forces. Instead, the tsetse fly has evolved subtle yet highly efficient adaptations, which include a labellum equipped with arrays of small teeth. When combined with a robust retraction movement of the proboscis, these structures create lesions on various types of skin, thus facilitating blood pool feeding on a broad host spectrum.
DOI: 10.7554/elife.1101512026-10-13 · Neuroscience
Daiki Sekizawa, Jun Kitazono, Masafumi Oizumi, Mikito Ogino
Investigating the dynamics of neural networks, which are governed by connectivity between neurons, is a fundamental challenge in neuroscience. Because passive (spontaneous) activity provides only limited information for estimating connectivity, perturbation-based approaches are widely applied in neuroscience as they can evoke underlying hidden dynamics. However, the characteristics of such perturbations have typically been designed based on empirical or biological intuition. To enable more accurate estimation of connectivity, we propose a data-driven and theoretically grounded framework for optimally designing perturbation inputs, based on formulating the neural model as a control system. The core theoretical insight underlying our approach is that neural signals observed in the passive state lack sufficient latent information, which leads to failures in the system identification. Perturbations reveal these hidden dynamics and lead to improved estimation. Guided by these insights, we derive a theoretical basis for optimizing perturbation inputs that minimize estimation errors in neural system identification. Building upon this, we further explore the relationship of this theory with stimulation patterns commonly used in neuroscience, such as frequency, impulse, and step inputs. We demonstrate the effectiveness of this framework for neuroscience through simulations grounded in experimental paradigms, such as neural state classification and optimal control of neural states. Our theoretical analysis, together with multiple simulations, consistently shows that perturbations designed according to our framework achieve substantially more accurate system identification compared to the conventional, intuition-based inputs. This study provides a theoretical foundation for designing perturbation inputs to achieve accurate estimation of neural dynamics. This, in turn, enables reliable discrimination of neural states such as levels of consciousness and pathological conditions, and facilitates precise control of their transitions toward recovery from abnormal states.
DOI: 10.7554/elife.1100302026-10-13 · Cell Biology
Eric O Long, Erin J Adams, George M Mastorakos, Jamie Rossjohn, Jan Petersen, Jinghua Lu, Joyce Chiu, Kristof T Nolan, Peter D Sun, Philip J Hogg, Priyanka Chaurasia, Saurav Majumder, Sumati Rajagopalan
Human Leukocyte Antigen (HLA)-G is selectively expressed by fetal trophoblast cells that encounter maternal natural killer (NK) cells early in pregnancy. In response to HLA-G, the endosomal NK cell receptor KIR2DL4 induces a transcriptional program to support placental development. Structural features of KIR2DL4 that control HLA-G binding and endocytosis are unclear. Random mutagenesis revealed that three cysteines in the first immunoglobulin domain of KIR2DL4 regulate endocytosis and uptake of HLA-G. The atypical Cys10–Cys28 disulfide bond in the KIR2DL4 structure is an allosteric disulfide with potential to switch to a conventional Cys28–Cys74 bond. KIR2DL4 in human cells exists in both disulfide-bonded states, as shown by mass spectrometry analysis. The Cys10–Cys28 bond in a Cys74Ser KIR2DL4 mutant was reduced by protein disulfide isomerase (PDI) in vitro. Inhibition of PDI prevented HLA-G uptake by KIR2DL4 in NK cells. Mutants in the Cys10–Cys28 configuration endocytosed spontaneously but did not bind HLA-G. Conversely, KIR2DL4 with a Cys28–Cys74 bond was detectable at the plasma membrane and internalized soluble HLA-G. A purified Cys10Leu KIR2DL4 mutant bound HLA-G with micromolar affinity in a peptide-dependent manner. Thus, allosteric disulfide-mediated conversion from an inactive to an HLA-G binding form regulates KIR2DL4 trafficking and a functional response that promotes fetal development.
DOI: 10.7554/elife.111018