| Mid-zone hepatocytes trade proliferation for survival via Atf4-Chop axis in early acute liver injury |
Zhu, Y. |
2026-07-24 |
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Hepatocytes undergo extensive proliferation to facilitate liver repair after injury, yet early adaptive changes prior to proliferation remain unclear. Here, we report that during early acetaminophen (APAP)-induced liver injury, hepatocytes exhibit transient proliferation suppression that is most pronounced in mid-zone hepatocytes, consistent with zonal APAP metabolism. While spatial transcriptomics (ST) provided robust evidence for this arrest in the mid-zone, support for a similar arrest in pericentral hepatocytes was limited. Integrating ST with immunohistochemistry and functional studies, we identified a unique mid-zone stress-response program centered on the Atf4-Chop axis, which suppresses proliferation via the cell cycle inhibitor Btg2. Together, our findings support a model in which mid-zone hepatocytes transiently prioritize stress adaptation over proliferation, thereby preserving regenerative capacity for subsequent liver repair. |
| Antifungal activity and mechanisms of D-limonene against Fusarium oxysporum, a pathogen of potato dry rot |
Xia, Q. |
2026-07-24 |
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BACKGROUND: Potato dry rot (PDR), caused by Fusarium species, seriously threatens potato production and postharvest quality. Although limonene has demonstrated antifungal activity, previous studies have mainly focused on limonene-containing essential oils or phe-notypic growth inhibition, while its cellular and molecular mechanisms and application potential against PDR remain insufficiently understood. RESULTS: D-limonene inhibited the growth of Fusarium oxysporum in a concentra-tion-dependent manner, with a half-maximal inhibitory concentration (IC) of 8.32 L/mL. It also altered hyphal morphology, reduced pathogenicity and spore germination, decreased spore viability, and changed the chitin-associated fluorescent brightener 28 staining pattern. Tran-scriptome analysis identified 1,884 differentially expressed genes, including 1,027 downreg-ulated and 857 upregulated genes. Kyoto Encyclopedia of Genes and Genomes analysis and targeted annotation screening revealed extensive remodeling of cell-wall-related processes. Gene Set Enrichment Analysis further indicated suppression of ergosterol biosynthesis and ribosome biogenesis. D-limonene also increased sensitivity to temperature, salinity, and oxi-dative stresses and showed additive and synergistic interactions with mancozeb and hymexazol, respectively. CONCLUSION: Our results reveal that D-limonene shows potential as a bio-based component for the integrated management of PDR, providing a theoretical basis for its application. |
| Early-life medial pulvinar disruption drives schizophrenia-relevant prefrontal inhibitory and cognitive deficits in primates |
Scott, J. T. |
2026-07-24 |
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Schizophrenia is thought to arise from disrupted postnatal maturation of prefrontal circuits, but the developmental events linking early vulnerability to adult cortical dysfunction remain unclear. Here, we tested whether the primate medial pulvinar, a higher-order thalamic nucleus interconnected with prefrontal cortex, contributes to prefrontal maturation. Bilateral medial pulvinar lesions in neonatal marmosets altered adolescent prefrontal diffusion trajectories and produced adult working memory deficits, the latter of which did not follow comparable lesions in adulthood. Early-life lesioned animals showed reduced thalamocortical input to layer 3 parvalbumin interneurons, diminished prefrontal gamma power, reduced parvalbumin expression, and immature-like physiology in fast-spiking interneurons. These findings reveal a developmental window in which thalamic input shapes prefrontal inhibitory maturation, suggesting that some forms of cortical dysfunction in psychiatric disease originate not in the cortex itself, but in its thalamic inputs. |
| Opposite and complementary roles of the two calcium thresholds for inducing LTP and LTD in models of striatal projection neurons |
Trpevski, D. |
2026-07-24 |
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Synaptic plasticity has been shown to occur when calcium, flowing into the synapse due to incoming stimuli, surpasses a threshold level. This threshold level is modifiable through a process called metaplasticity. Some neurons, such as the striatal projection neurons, use different sources of calcium as the signal for synaptic strengthening (long-term potentiation, LTP) or weakening (long-term depression, LTD), resulting in them having two thresholds for inducing plasticity. In this study, we show that metaplasticity enables synapses undergoing both LTP and LTD during learning to selectively express just one form of plasticity (either LTP or LTD). To show this, we use the linear and nonlinear feature binding problem (FBP and NFBP) because their input patterns share features, exposing synapses to such competing LTP and LTD processes. In particular, we identify opposite and complementary roles of metaplasticity in the two thresholds for inducing LTP and LTD: metaplasticity in one threshold (e.g. LTD) allows synaptic plasticity of the opposite type (e.g. LTP) to be properly expressed. This happens because metaplasticity in the LTD threshold protects strengthened synapses from weakening, thus allowing them to persistently increase during learning (and encode learned patterns). Similarly, metaplasticity in the LTP threhsold prevents weakened synapses from strengthening, thus allowing them to persistently decrease. Under more general conditions for triggering metaplasticity, reversal learning can also be solved, demonstrating metaplasticity's importance for solving the plasticity-stability dilemma. Finally, we show that even though a single calcium threshold is sufficient for solving the FBP, NFBP and reversal learning, two calcium thresholds allow separate control over LTP and LTD. |
| Perceiving less or perceiving unreliably? Disentangling thermosensory sensitivity and precision in the contexts of ageing and neuropathy |
Courtin, A. S. |
2026-07-24 |
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Thermal perception is determined not only by sensitivity but also by precision. Yet, the latter is often overlooked in thermosensation and pain research. This study examined how ageing and diabetic polyneuropathy (DPN) affect these parameters and whether assessing both sensitivity and precision can aid in distinguishing patients from healthy controls. Using Bayesian hierarchical models, we estimated psychometric function thresholds (sensitivity) and slopes (precision) for cold detection, warm detection, cold pain, and heat pain stimuli delivered at the volar forearm, in a cross-sectional sample of 75 healthy adults (aged 21-80) and 33 patients with DPN. We also estimated these parameters separately for each participant and used the resulting estimates in classification analyses. Ageing was associated with elevated cold and warm detection thresholds, elevated cold pain thresholds, and reduced cold detection slope. Patients with DPN showed similar patterns: higher detection thresholds and lower cold detection slopes while pain-related parameters were largely unaffected. These findings indicate that ageing and neuropathy produce qualitatively similar changes in thermosensory function, particularly affecting cold detection. Classification based on single parameters successfully discriminated patients from controls, except when warm detection or heat pain slopes were used. Combining threshold and slope parameters for a given modality did not significantly improve classification accuracy but combining all parameters across all modalities led to the best performance, with excellent accuracy (AUROCC: .84, 95% CI [.75.91]). Modelling both thresholds and slopes provides a more comprehensive view of sensory decline and may enhance the detection of early or subtle sensory dysfunction. |
| Electroconvulsive stimulation drives cortical spreading depression dependent immediate early gene expression in mice |
Ladret, H. J. |
2026-07-24 |
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Electroconvulsive therapy (ECT) is a highly effective treatment for several psychiatric disorders, though its biological mechanisms remain unclear. Its therapeutic action has traditionally been attributed to the generalized seizure ECT induces. However, this view is challenged by the recent finding that electroconvulsive stimulation (ECS) can trigger a cortical spreading depression (CSD). Because CSD triggers massive intracellular molecular changes, we hypothesized that it could be a key mediator of ECT's therapeutic, plasticity-inducing effects. We observed similar neuronal oscillations following ECS in mice and patients undergoing ECT. We show that CSD drives increased expression of the immediate early gene Fos, a key marker of neuronal plasticity, and is associated with factors that predict positive ECT therapeutic outcome. Our results suggest that the therapeutic efficacy of ECT may be mediated by CSD. This challenges the seizure-centric model and implies that CSD, a currently unmonitored neurophysiological event, may serve as a more relevant biomarker for predicting and optimizing therapeutic outcomes of ECT. |
| Rat mediodorsal thalamic subdivisions differentially modulate the sensory and affective components of pain through distinct prefrontal pathways. |
Iben-Daoudi, H. |
2026-07-24 |
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The mediodorsal thalamus (MD) modulates pain through thalamocortical regulation of the mPFC. Yet, MD is often treated as a single anatomical and functional entity despite marked internal heterogeneity. Here, we tested whether medial-central MD (MDmc) and lateral MD (MDl) subdivisions exert dissociable control over sensory-discriminative and affective-motivational components of pain by engaging the anterior cingulate cortex (ACC) and prelimbic cortex (PrL). Using subdivision-selective excitotoxic lesions in rats, combined with anterograde tracing, laminar activity mapping, and projection-specific optogenetic manipulation of MDmc and MDl terminals in ACC or PrL, we determined the contribution of each subdivision and the underlying MD-PFC circuit mechanisms. Behaviorally, MDmc and MDl lesions induced mechanical and thermal hypersensitivity, but only MDmc lesions increased pain-related avoidance. Anatomical analyses showed that MDl preferentially innervated ACC PV cells, whereas MDmc more strongly targeted ACC SOM cells. Lesions further produced subdivision-dependent reorganization of nociception-evoked cFos activity in layers 2/3 and 5 and altered PV/SOM interneuron recruitment. Optogenetic manipulations revealed pathway-specific effects: MDmc-ACC/PrL manipulations enhanced nociceptive gain and avoidance, whereas MDl-ACC inhibition increased hypersensitivity while reducing avoidance, and MDl-PrL inhibition increased both nociceptive sensitivity and avoidance. Together, these findings identify MD subdivision-specific thalamocortical pathways that recruit distinct inhibitory microcircuits within ACC and PrL, thereby differentially shaping sensory-discriminative and affective-motivational components of pain. |
| Microglia extract neuronal proteolytic organelles via skoupocytosis |
Pepper, R. |
2026-07-24 |
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Neurons face unique challenges in maintaining protein homeostasis due to their tortuous morphology and extended processes. Proteolytic organelles are typically transported retrogradely towards their soma for degradation where lysosomes are enriched, but some organelles are larger than these neuronal processes, questioning how these organelles are degraded. Here we show that microglia, the resident immune cells of the brain, extract proteolytic organelles from neurons both in vitro and in vivo. Microglia make transient contact with neuronal membranes where proteolytic organelles are stationed beneath. At these sites of interaction, microglia pinch off a small portion of the neuronal process containing the organelle, leaving the rest of the process intact. We term this process skoupocytosis after the Greek word for garbage. Phosphatidylserine (PS) lipase ABHD16a accumulates near these proteolytic organelles and converts PS into lyso-PS to initiate microglial skoupocytosis. Skoupocytosis bypasses the need for retrograde organelle transport, providing homeostatic advantages for neurons that must maintain function in processes that extend extraordinarily long distances from the cell soma. |
| Redistribution of sidechain-sidechain interactions govern ligand-specific binding affinity changes in missense Shank1 PDZ mutants |
Santa, A. |
2026-07-24 |
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Shank proteins represent a family of abundant scaffolds in the postsynaptic density. Their dysfunctions had been identified as possible causes behind autism spectrum disorders and various types of cancer. The remarkably promiscuous PDZ domain of the Shank family is highly conserved through isoforms, and contains a unique dynamic segment, the {beta}2-{beta}3 loop, which is likely to play an important role in ligand selectivity. We used the Shank1 PDZ as a model system to analyze the perturbing effects of five disease-associated missense mutations on the binding of different partner peptides. Using experimental methods and molecular dynamics simulations, we characterized the interactions in detail, focusing on their dynamic aspect. While the investigated mutations in general weaken most interactions, the R736Q mutant, unique in having increased thermal stability, also binds the GKAP peptide with higher affinity than the wild type. Overall, our results show that the perturbing effect of mutations is highly partner-specific and depends on the dynamic rearrangements of both uniformly occurring and ligand-specific residue-residue interactions. |
| The Anaphase Promoting Complex targets the toxic protein Progerin for ubiquitin-dependent degradation via autophagy |
Eskiw, C. H. |
2026-07-24 |
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The premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) results from the accumulation of progerin, a cytotoxic protein generated from a point mutation in the Lamin A/C gene, in the nuclear lamina. Upon the proper stimulation, cells degrade progerin, reversing cellular HGPS phenotypes; however, there is still a gap in our knowledge concerning which pathways are mediating progerin degradation. Previous data has demonstrated that the Anaphase Promoting Complex (APC), a multi-subunit ubiquitin ligase, tagets proteins for degradation, and that a decrease in APC function is linked with cellular aging. To determine if the APC is linked to HGPS disease phenotypes, we performed a meta-analysis of RNA-seq data from skin samples isolated from HGPS patients and identified dysregulation of several genes encoding subunits and substrates of the APC. Stimulation of APC activity decreased progerin protein levels and significantly decreased the number of cells with nuclear blebs. Proximity ligation assays (PLA) demonstrated that APC structure is compromised in HGPS cells and that APC stimulation increases proximity of the APC with progerin. Coimmunoprecipitation revealed that the APC co-activator, CDC20, physically interacted with nuclear lamina proteins. We further demonstrate that APC-mediated progerin degradation occurs through autophagy. Inhibition of the 26S proteasome enhanced progerin degradation, providing additional support for APC mediated-progerin degradation occurring independent of the proteasome. As such, we propose a previously unidentified interaction and mechanism by which cells remove progerin. This finding has impact on potential therapeutic strategies for HGPS, as well as providing further insight into linking the APC with both normal and premature aging. |