Science Journals

Fever is a hallmark of malaria. Several studies have linked febrile temperatures to reduced parasite viability, but also to increased cytoadhesion, a key driver of pathology. However, different mechanisms have been proposed to cause changes in cytoadhesion and parasite sensitivity to heat. Here, we demonstrate that exposure of <i>Plasmodium falciparum</i>-infected red blood cells (iRBCs) to physiologically relevant febrile heat stress (39 °C), derived from patient data, enhances cytoadhesion through increased trafficking of the major virulence factor PfEMP1 to the iRBC surface. This phenomenon is not limited to PfEMP1 and common laboratory strains, as it extends to the surface nutrient channel PSAC in four clinical isolates of diverse geographic origin. The increased surface protein display occurs without changes in overall protein expression or parasite developmental progression. Using phosphoproteomics and proximity labelling, we find that elevated temperature also increases trafficking and phosphorylation of exported proteins into the RBC. Enhanced export is likely reliant on the presence of a transmembrane domain as shown by NanoLuc reporter assays. Collectively, our results indicate that febrile temperatures commonly experienced during infection can accelerate protein export, likely at the parasitophorous vacuole. This enhanced export following heat stress is relevant because increased cytoadhesion could influence disease severity through earlier iRBC sequestration and elevated bound parasite mass.

The asymmetry of lipid membranes is tightly regulated in eukaryotic cells, and auditory hair cells are no exception.

Animals flexibly change their behavior depending on context. It is reported that the hippocampus is one of the most prominent regions for contextual behaviors, and its sequential activity shows context dependency. However, how such context-dependent sequential activity is established through reorganization of neuronal activity (remapping) remains unclear. To better understand the formation of hippocampal activity and its contribution to context-dependent flexible behavior, we present a novel biologically plausible reinforcement learning model. In this model, Context selector promotes the formation of context-dependent sequential activity and allows for flexible switching of behavior in multiple contexts. This model reproduces a variety of findings from neural activity, optogenetic inactivation, human fMRI, and clinical research. Furthermore, our model predicts that imbalances in the ratio between sensory and contextual representations in Context selector account for schizophrenia and autism spectrum disorder-like behaviors.

Skin cooling is detected by primary afferents that express the Trpm8 channel, but how this information is conveyed to the brain remains poorly understood. We have previously identified a population of lamina I projection neurons belonging to the anterolateral system (ALS) that receive numerous contacts from Trpm8-expressing primary afferents. Here, using a semi-intact somatosensory preparation, we provide evidence that these cells correspond to the cold-selective ALS neurons identified in previous physiological studies. We also confirm the presence of synapses from Trpm8 afferents onto these cells at the ultrastructural level and with optogenetics. Based on our previous transcriptomic findings, we identify calbindin as a molecular marker, and show that this can be used to target the cold-selective ALS neurons for anterograde tracing studies. We provide evidence that they project to brain regions that have been implicated in thermosensation: the rostralmost part of the lateral parabrachial area, the caudal part of the periaqueductal grey matter, and the posterior triangular and ventral posterolateral nuclei of the thalamus. Our findings provide important insights into the organisation of neuronal circuits that underlie thermoregulation and the perception of cold stimuli applied to the skin.

Learning to adapt voluntary movements to an external perturbation, whether mechanical or visual, is faster during a second encounter than during the first. The mechanisms underlying this phenomenon, known as savings, remain unclear. Recent studies propose that the high dimensionality of neural control enables the retention of learning traces that may facilitate savings. To test this idea, we used MotorNet, a framework for training recurrent neural networks (RNNs) to control biomechanical models of the human upper limb. RNNs were trained to perform reaching movements with a velocity-dependent force field (FF) and without (NF) in the sequence NF1 (baseline), FF1 (adaptation), NF2 (washout), and FF2 (re-adaptation). RNNs showed behaviural signatures of savings in the absence of any explicit contextual input signalling the presence or absence of the FF. Savings was more robust in RNNs with larger numbers of units. We identified a component of RNN activity associated with savings—a shift in preparatory activity that persisted even after washout. Displacing this preparatory activity in the direction of the shift enhanced savings, whereas perturbations in the opposite direction reduced or eliminated savings. These findings suggest a potential neural basis for motor memory retention underlying savings that is reliant on the high dimensionality of neural circuits for control, and is independent of cognitive or strategic learning.

The integration-segregation theory proposes that early facilitation and later inhibition (i.e. inhibition of return [IOR]) in exogenous attention arises from the competition between cue-target event integration and segregation. Although widely supported behaviorally, the theory lacked direct neural evidence. Here, we used event-related functional magnetic resonance imaging (fMRI) in human participants with an optimized cue-target paradigm to test this account. Cued targets elicited stronger activation in the frontoparietal attention networks, including the bilateral frontal eye field (FEF), intraparietal sulcus (IPS), right temporoparietal junction (TPJ), and left dorsal anterior cingulate cortex (dACC), consistent with the notion of attentional demand of reactivating the cue-initiated representations for integration. In contrast, uncued targets engaged the medial temporal cortex, particularly the bilateral parahippocampal gyrus (PHG) and superior temporal gyrus (STG), reflecting the segregation processes associated with new object-file creation and novelty encoding. These dissociable activations provide the first direct neuroimaging evidence for the integration-segregation theory. Moreover, we observed neural interactions between IOR and cognitive conflict, suggesting a potential modulation of conflict processing by attentional orienting. Taken together, these findings provide new insights into exogenous attention by clarifying the neural underpinnings of integration and segregation and uncovering the interaction between spatial orienting and conflict processing.

Genomic stability is critical for cellular function; however, in the central nervous system, highly metabolically active differentiated neurons are challenged to maintain their genome over the organismal lifespan without replication. DNA damage in neurons increases with chronological age and accelerates in neurodegenerative disorders, resulting in cellular and systemic dysregulation. Distinct DNA damage response strategies have evolved with a host of polymerases. The Y-family translesion synthesis (TLS) polymerases are well known for bypassing and repairing damaged DNA in dividing cells. However, their expression, dynamics, and role, if any, in enduring postmitotic differentiated neurons of the brain are completely unknown. We show through systematic longitudinal studies for the first time that DNA polymerase kappa (POLK), a member of the Y-family polymerases, is highly expressed in mouse neurons. With chronological age, there is a progressive and significant reduction of nuclear POLK with a concomitant accumulation in the cytoplasm that is predictive of brain tissue age. The reduction of nuclear POLK in old brains is congruent with an increase in DNA damage markers. The nuclear POLK colocalizes with damaged sites and DNA repair proteins. The cytoplasmic POLK accumulates with stress granules and endo/lysosomal markers. Nuclear POLK expression is significantly higher in GABAergic interneurons (INs) compared to excitatory pyramidal neurons and lowest in non-neurons, possibly reflective of the inherent biological differences such as firing rates and neuronal activity. INs associated with microglia have significantly higher levels of cytoplasmic POLK in old age. Finally, we show that neuronal activity itself can lead to an increase in nuclear POLK levels and a reduction of the cytoplasmic fraction. Our findings open a new avenue in understanding how different classes of postmitotic neurons deploy TLS polymerase(s) to maintain their genomic integrity over time, which …

Gata3 is an essential transcription factor for the development of several distinct immune cell lineages such as T cells, natural killer (NK) cells, and innate lymphoid cells (ILCs). As such, the levels and timing of <i>Gata3</i> expression are critical for directing lineage fate decisions. The <i>Gata3</i> locus has a complex and dynamic distal regulatory enhancer landscape. Recently, we identified a non-coding RNA, <i>Dreg1</i>, located immediately upstream of the classic +280 kb T/NK cell enhancer (Tce1). To test its function, we excised the <i>Dreg1</i> locus in mice and observed a selective reduction of group 2 ILCs (ILC2) across multiple tissues, but mature T, NK, and other ILC lineages remained unchanged. In bone marrow, common innate lymphoid cell progenitors (ILCPs) increased while ILC2 progenitors (ILC2P) decreased, with a modest reduction of <i>Gata3</i> in upstream progenitors consistent with an early developmental bottleneck. Chromatin profiling showed the Dreg1 locus is accessible in early lymphoid progenitors and became decorated with H3K27ac in ILCP in a Tcf1-dependent manner. Furthermore, Tcf1-deficient cells did not express <i>Dreg1</i> and showed alterations in the epigenetic landscape of the <i>Dreg1</i> locus. Finally, we discovered that potential homologues of <i>Dreg1</i> harboured in a syntenic enhancer of <i>GATA3</i> are also highly expressed in human ILC2. Taken together, we conclude that <i>Dreg1</i> is a Tcf1-dependent non-coding RNA critical for fine tuning the high level of <i>Gata3</i> required for the optimal development of the ILC2 lineage.

HIV-1 entry into susceptible cells requires the dynamic interaction of its envelope (Env) glycoprotein with the host cell receptor CD4 and a co-receptor, either CCR5 or CXCR4. While the core molecular mechanisms driving Env-receptor interactions and subsequent membrane fusion are well characterized, the precise nanoscale spatial reorganization of these co-receptors at the viral binding site remains poorly defined. In this study, we employed single-particle tracking total internal reflection fluorescence (SPT-TIRF) microscopy to quantitatively analyze nanoscale organizational changes of CXCR4 on the surface of human CD4⁺ T cells following binding by X4-tropic HIV-1. Our data reveal that both recombinant X4-gp120 and virus-like particles expressing physiological levels of X4 Env proteins (gp120 and gp41) promote CXCR4 clustering, a phenomenon linked to cell infection. Furthermore, these ligands induced oligomerization of CXCR4^R334X, a naturally occurring mutant associated with WHIM syndrome that supports HIV-1 infection, but fails to oligomerize in response to CXCL12. Our findings establish a link between CXCR4 clustering and HIV-1 infection, enhancing our understanding of the initial events in viral attachment and entry. These results further suggest that HIV-1 depends on a specific spatial arrangement of co-receptors, distinct from that induced by their natural chemokine ligands, highlighting the critical role of cell-surface receptor spatial organization in dictating cellular function.

Individuals, even with matched genetics and environment, show substantial phenotypic variability. This variability may be part of a bet-hedging strategy, where populations express a range of phenotypes to ensure survival in unpredictable environments. In addition, phenotypic variability between individuals (‘bet-hedging’), individuals also show variability in their phenotype across time, even absent external cues. There are few evolutionary theories that explain random shifts in phenotype across an animal's life, which we term drift in individual phenotype. We use individuality in locomotor handedness in <i>Drosophila melanogaster</i> to characterize both bet-hedging and drift. We use a continuous circling assay to show that handedness spontaneously changes over timescales ranging from seconds to the lifespan of a fly. We compare the amount of drift and bet-hedging across a number of different fly strains and show independent strain-specific differences in bet-hedging and drift. We show manipulation of serotonin changes the rate of drift, indicating a potential circuit substrate controlling drift. We then develop a theoretical framework for assessing the adaptive value of drift, demonstrating that drift may be adaptive for populations subject to selection pressures that fluctuate on timescales similar to the lifespan of an animal. We apply our model to real-world environmental signals and find patterns of fluctuations that favor random drift in behavioral phenotype, suggesting that drift may be adaptive under some real-world conditions. These results demonstrate that drift plays a role in driving variability in a population and may serve an adaptive role distinct from population-level bet-hedging.

Respiration is governed by a widespread network of cortical and subcortical structures. This complex communication between the brain and lungs is altered in pathological conditions. Apnoea – the cessation of respiration – is a common condition in infants, particularly those born prematurely. Apnoea in infants is believed to relate to immaturity of brainstem respiratory centres; involvement of the cortex in respiration in infants has yet to be explored. We investigated if there was any evidence for cortical coupling with respiration in newborn humans and whether it relates to apnoea. Using simultaneous electroencephalography (EEG) and impedance pneumography, we investigated interactions between cortical and respiratory activity (known as cortico-respiratory coupling) using phase-amplitude coupling. We show that cortico-respiratory coupling is present in premature and term newborns (104 recordings from 68 infants; 34.5±2.6 weeks postmenstrual age), identifying an interplay between breathing phase and EEG amplitude. We further shed light on the biological meaning by revealing that the strongest coupling occurs during inspiration and that cortical activity precedes respiration, with coupling strongest over frontocentral regions. Whilst our study was limited in spatial resolution, and determining causality is challenging, we believe these findings support the notion that the cortico-respiratory coupling observed here constitutes communication between cortical motor areas and lung effectors. Moreover, we show that cortico-respiratory coupling is negatively correlated with the rate of apnoea, revealing novel insight into this common and potentially life-threatening neonatal pathology.

Head-mounted miniscopes have enabled functional fluorescence imaging in freely moving animals. However, current technology is limited to recording at most two spectrally distinct fluorophores, severely restricting the number of identifiable cell types. Here, we introduce multiplexed neuronal imaging (Neuroplex), a pipeline combining miniscope Ca²⁺ recordings with in vivo multiplexed confocal spectral imaging to distinguish nine projection-defined neuronal subtypes through the same GRIN lens. By co-registering defined neurons with fluorophore-specific spectral fingerprints via linear unmixing, we link projection-defined identities to behaviorally relevant neuronal activity. This approach overcomes spectral constraints of miniscopes, enabling circuit-level dissection of behavior in single animals.

Mating in insects typically triggers a post-mating response (PMR) in females, characterized by reduced receptivity to re-mating and increased oviposition, which ensures numerous and viable offspring and male paternity. This PMR is induced by male seminal factors, such as sex peptide in <i>Drosophila melanogaster</i>, as well as intrinsic female signaling components. The latter signaling remains poorly understood in most insects, including the devastating rice pest, the brown planthopper (BPH) <i>Nilaparvata lugens</i>. Here, we show that the neuropeptide corazonin (CRZ) and its receptor (CrzR) are critical for the PMR in female BPHs. Peptide injection, RNAi knockdown, and CRISPR/Cas9 mutagenesis confirm that intact CRZ signaling reduces re-mating frequency and increases ovulation in mated BPH females. The CrzR is highly expressed in the female reproductive tract, and CrzR knockdown phenocopies CRZ diminishment. Importantly, female CRZ/CrzR signaling is required for male seminal factors, such as the peptide maccessin, to induce the PMR; with disrupted <i>CrzR</i> signaling, injection of seminal fluid or maccessin fails to reduce female receptivity. Notably, CRZ is not produced in male accessory glands (MAGs) of BPHs and thus not transferred during copulation. We furthermore demonstrate that also in <i>D. melanogaster</i> disrupted CRZ signaling increases female re-mating and reduces oviposition, while CRZ injection suppresses virgin receptivity and increases oviposition. Finally, we detected no CRZ in the MAG of <i>D. melanogaster,</i> supporting its role as an endogenous signal in the female PMR also in this species. In summary, our findings reveal a conserved role of endogenous CRZ signaling in regulating the female PMR and demonstrate that female CRZ signaling and male-derived signals cooperate to induce post-mating transitions in BPHs and <i>D. melanogaster</i>. CRZ is a paralog of the peptide gonadotropin-releasing hormone, known to regulate reproduction in v…

Politicians are reducing public funding for science and dismantling scientific institutions for ideological reasons in Argentina and the United States. It appeared as if something similar could happen in the Netherlands, but the collapse of a coalition government led to a reprieve. How should the scientific community respond to such crises?

Selective attention involves prioritising relevant sensory input while suppressing irrelevant stimuli. It has been proposed that oscillatory alpha-band activity (~10 Hz) aids this process by functionally inhibiting early sensory regions. However, recent studies have challenged this notion. Our EEG and MEG studies aimed to investigate whether human alpha oscillations serve as a 'gatekeeper' for downstream signal transmission. We first observed these effects in an EEG study and then replicated them using MEG, which allowed us to localise the sources. We employed a cross-modal paradigm where visual cues indicated whether upcoming targets required visual or auditory discrimination. To assess inhibition, we utilised frequency-tagging, simultaneously flickering the fixation cross at 36 Hz and playing amplitude-modulated white noise at 40 Hz during the cue-to-target interval. Consistent with prior research, we observed an increase in posterior alpha activity following cues signalling auditory targets. However, remarkably, both visual and auditory frequency-tagged responses amplified in anticipation of auditory targets, correlating with alpha activity amplitude. Our findings suggest that when attention shifts to auditory processing, the visual stream remains responsive and is not hindered by occipital alpha activity. This implies that alpha modulation does not solely regulate 'gain control' in early visual areas but rather orchestrates signal transmission to later stages of the processing stream.

In the olfactory system, adult-neurogenesis results in the continuous reorganization of synaptic connections and network architecture throughout the animal’s life. This poses a critical challenge: How does the olfactory system maintain stable representations of odors amidst this ongoing circuit instability? Utilizing a detailed spiking network model of early olfactory circuits, we uncovered dual roles for adult-neurogenesis: one that both supports representational stability to faithfully encode odor information, and also one that facilitates plasticity to allow for learning and adaptation. In the main olfactory bulb, adult-neurogenesis affects neural codes in individual mitral and tufted cells but preserves odor representations at the neuronal population level. By contrast, in the olfactory piriform cortex (PCx), both individual cell responses and overall population dynamics undergo progressive changes due to adult-neurogenesis. This leads to representational drift, a gradual alteration in stimulus-evoked activity patterns. Both processes are dynamic and depend on experience such that repeated exposure to specific odors reduces the drift due to adult-neurogenesis; thus, when the odor environment is stable over the course of adult-neurogenesis, it is spike-timing-dependent plasticity that leads representations to remain stable in the PCx; when those olfactory environments change, adult-neurogenesis allows cortical representations to track environmental change. Whereas perceptual stability and plasticity due to learning are often thought of as two distinct, often contradictory processes in neuronal coding, we find that adult-neurogenesis serves as a shared mechanism for both. In this regard, the quixotic presence of adult-neurogenesis in the mammalian olfactory bulb that has been the focus of considerable investigation in chemosensory neuroscience may be the mechanistic underpinning behind an array of complex computations.

Meiotic drivers are selfish genetic elements that distort fair segregation. The <i>wtf</i> genes are poison-antidote meiotic drivers that are experiencing rapid diversification in fission yeasts. However, gene duplication alone is insufficient to drive the diversification of <i>wtf</i> genes, given the poison encoded by a newly duplicated <i>wtf</i> gene can be detoxified by the antidote encoded by the original <i>wtf</i> gene. Here, we analyze the evolution of <i>wtf</i> genes across 21 strains of <i>Schizosaccharomyces pombe</i>. Knocking out each of 25 <i>wtf</i> genes in <i>S. pombe</i> strain 972h- separately does not attenuate the yeast growth, indicating that the <i>wtf</i> genes might be largely neutral to their carriers in asexual life cycle. Interestingly, <i>wtf</i> genes underwent recurrent and intricate recombination. As proof of principle, we generate a novel meiotic driver through artificial recombination between <i>wtf</i> drivers, and its encoded poison cannot be detoxified by the antidotes encoded by their parental <i>wtf</i> genes but can be detoxified by its own antidote. Therefore, we propose that recombination can generate new meiotic drivers and thus shape the diversification of the <i>wtf</i> drivers.

The world constantly changes, with the underlying state of the world shifting from one regime to another. The ability to detect a regime shift, such as the onset of a pandemic or the end of a recession, significantly impacts individual decisions, as well as governmental policies. However, determining whether a regime has changed is usually not obvious, as signals are noisy and reflective of the volatility of the environment. We designed an fMRI paradigm that examines a stylized regime-shift detection task. Human participants showed systematic overreaction and underreaction: Overreaction was most commonly seen when signals were noisy, but when environments were stable and change is possible but unlikely. By contrast, underreaction was observed when signals were precise but when environments were unstable and hence change was more likely. These behavioral signatures are consistent with the <i>system-neglect</i> computational hypothesis, which posits that sensitivity or lack thereof to system parameters (noise and volatility) is central to these behavioral biases. Guided by this computational framework, we found that individual subjects’ sensitivity to system parameters was represented by two distinct brain networks. Whereas a frontoparietal network selectively represented individuals’ sensitivity to signal noise but not environment volatility, the ventromedial prefrontal cortex (vmPFC) showed the opposite pattern. Further, these two networks were involved in different aspects of regime-shift computations: while vmPFC correlated with subjects’ beliefs about change, the frontoparietal network represented the strength of evidence in favor of regime shifts. Together, these results suggest that regime-shift detection recruits belief-updating and evidence-evaluation networks and that under- and overreactions arise from how sensitive these networks are to the system parameters.

Humans conceptualize time in terms of space, allowing flexible time construals from various perspectives. We can travel internally through a timeline to remember the past and imagine the future (i.e., mental time travel) or watch from an external standpoint to have a panoramic view of history (i.e., mental time watching). However, the neural mechanisms that support these flexible temporal construals remain unclear. To investigate this, we asked participants to learn a fictional religious ritual of 15 events. During fMRI scanning, they were guided to consider the event series from either an internal or external perspective in different tasks. Behavioral results confirmed the success of our manipulation, showing the expected symbolic distance effect in the internal-perspective task and the reverse effect in the external-perspective task. We found that the activation level in the posterior parietal cortex correlated positively with sequential distance in the external-perspective task but negatively in the internal-perspective task. In contrast, the activation level in the anterior hippocampus positively correlated with sequential distance regardless of the observer’s perspectives. These results suggest that the hippocampus stores the memory of the event sequences allocentrically in a perspective-agnostic manner. Conversely, the posterior parietal cortex retrieves event sequences egocentrically from the optimal perspective for the current task context. Such complementary allocentric and egocentric representations support both the stability of memory storage and the flexibility of time construals.

Sleep plays a critical role in animal physiology, primarily governed by the brain, and its disruption is prevalent in various brain disorders. Mettl5 is associated with intellectual disability (ID), which often includes sleep disturbances. However, the mechanism underlying these sleep disruptions in ID remains poorly understood. In this study, we investigated the sleep phenotypes resulting from <i>Drosophila Mettl5</i> mutations. Rescue experiments revealed that <i>Mettl5</i> functions predominantly within neurons and glia marked by <i>Mettl5</i>-Gal4 to regulate sleep. Previous work established that Mettl5 forms a complex with Trmt112 to influence rRNA methylation. Notably, a mutation in <i>Trmt112</i> recapitulated these sleep disturbances, implicating translational regulation by the Mettl5/Trmt112 complex. Subsequent RNA-seq and Ribo-seq analyses of <i>Mettl5^1bp</i> mutants uncovered downstream effects, including altered expression of proteasome components and clock genes. Rescue experiments confirmed that the net increase in PERIOD protein underlies the sleep phenotype. This study illuminates the interplay between ribosome function, clock genes, and the proteasome in sleep regulation, highlighting the integrated roles of protein synthesis and degradation. These findings could potentially provide an example for in vivo study of rRNA methylation function, expand our understanding of protein homeostasis in sleep, and offer insights into the sleep phenotypes associated with ID.

The population of kisspeptin neurons located in the rostral periventricular area of the third ventricle (RP3V) is thought to have a key role in generating the GnRH surge that triggers ovulation. Using a modified GCaMP fibre photometry procedure, we have been able to record the in vivo population activity of RP3V^KISS neurons across the estrous cycle of female mice. A marked increase in GCaMP activity was detected beginning on the afternoon of proestrus that lasted in total for 13±1 hr. This was comprised of slow baseline oscillations with a period of 91±4 min associated with high-frequency rapid transients. Very little oscillating baseline or transient activity was detected at other stages of the estrous cycle. Concurrent blood sampling showed that the peak of the LH surge occurred 3.5±1.1 hr after the first baseline RP3V^KISS neuron baseline oscillation on the afternoon of proestrus. The time of onset of RP3V^KISS neuron oscillations varied between mice and across subsequent proestrous stages in the same mice. To assess the impact of estradiol on RP3V^KISS neuron activity, mice were ovariectomized and given an incremental estradiol replacement regimen. Minimal patterned GCaMP activity was found in OVX mice, and this was not changed acutely by any of the estradiol treatments. However, on the afternoon of the expected LH surge, the same oscillating baseline activity with associated transients occurred for 7.1±0.5 hr. These observations reveal an unexpected prolonged oscillatory pattern of RP3V^KISS neuron activity that is dependent on estrogen and underlies the preovulatory LH surge as well as potentially other facets of reproductive behavior.

The extraction of a phospholipid called phosphatidic acid from the mitochondrial outer membrane is regulated by the curvature of this membrane.

The liver is a complex organ responsible for multiple functions, including metabolism, energy storage, detoxification, bile secretion, and immune regulation. Its highly organized vascular system plays a crucial role in maintaining functional zonation and tissue homeostasis. Within the liver, the hepatic artery, portal vein, hepatic vein, bile duct, and nerve networks intertwine to form an intricate three-dimensional architecture; however, traditional two-dimensional imaging fails to reveal their true spatial relationships, and current three-dimensional imaging methods remain insufficient to capture fine structural details. To achieve comprehensive visualization of these multi-ductal systems, we established a high-resolution three-dimensional imaging platform that combines multicolor perfusion of metallic compound nanoparticles (MCNPs) with an optimized tissue-clearing protocol (Liver-CUBIC), enabling simultaneous 3D reconstruction of the portal vein, hepatic artery, bile duct, and hepatic vein in mouse livers. Based on these data, we identified and defined a previously unrecognized structure located in the outer layer of the portal vein, termed the periportal lamellar complex (PLC). The PLC encircles the portal vein between the vascular endothelium and the perisinusoidal region, exhibits low-permeability barrier characteristics, and contains a distinctive population of CD34⁺Sca-1⁺ endothelial cells. During liver fibrosis, the PLC extends from the portal vein toward the hepatic lobule, forming a structural scaffold that guides bile duct and nerve migration.

Polyphenolic compounds are widely explored for health benefits, including hypertension, but their active ingredients, molecular targets, and mechanisms remain poorly defined. We identify the xanthone Mangostin from <i>Garcinia mangostana</i> as a potent modulator of several potassium channels, with large-conductance K⁺ (BK) channels as its primary target for vasorelaxation. Mangostin-activated BK channels as α subunits alone, in complexes with vascular β1 subunits, and in reconstituted BKα/β1–Ca_v nanodomains. It shifted BK voltage activation to more negative potentials by antagonizing channel closure and promoting channel opening without markedly altering Ca²⁺ sensitivity. Docking, competition, single-channel analysis, and mutagenesis localized the binding site in the pore cavity below the SF, involving gating-critical S6 residues I308, L312, and A316, and suggest that Mangostin stays bound in closed and open states. These findings establish BK channel activation as the core molecular mechanism driving Mangostin’s vascular effects and define its structural mode of action, informing nutraceutical safety assessment and BK-targeted drug design.

Organisational gradients refer to a continuous low-dimensional embedding of brain regions and can quantify core organisational principles of complex systems like the human brain. Mapping how these organisational principles are altered or refined across development and phenotypes is essential to understanding the relationship between brain and behaviour. Taking a developmental approach and leveraging longitudinal and cross-sectional data from two multi-modal neuroimaging datasets, spanning the full neurotypical-neurodivergent continuum, we charted the organisational variability of structural (610 participants, N=390 with one observation, N=163 with two observations and N=57 with three) and functional (512 participants, N=340 with one observation, N=128 with two observations and N=44 with three). Across datasets, despite differing phenotypes, we observe highly similar structural and functional gradients. These gradients, or organisational principles, are highly stable across development, with the exact same ordering across early childhood into mid-adolescence. However, there is substantial developmental change in the strength of embedding within those gradients: by modelling developmental trajectories as non-linear splines, we show that structural and functional gradients are refined across development. Specifically, structural gradients gradually contract in low-dimensional space as networks become more integrated, whilst the functional manifold expands, indexing functional specialisation. The coupling of these structural and functional gradients follows a unimodal-association axis and varies across individuals, with developmental effects concentrated in the more plastic higher-order networks. Importantly, these developmental effects on coupling, in these higher-order networks, are attenuated in the neurodivergent sample. Finally, we mapped structure-function coupling onto dimensions of psychopathology and cognition and demonstrate that dimensions of cognition, su…