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bioRxiv2025

Tissue-like compression stiffening in biopolymer networks induced by aggregated and irregularly shaped inclusions

Biological tissues experience mechanical compression under various physiological and pathological conditions and often exhibit compression stiffening, in which their stiffness increases during compression, a phenomenon that plays a crucial role in regulating cell behavior and maintaining mechanical homeostasis. However, most isolated biopolymer networks, such as fibrin and collagen hydrogels that form the extracellular matrix and actin network that forms the internal cytoskeleton, undergo compression softening, raising questions about how tissues achieve compression stiffening despite the softening properties of their extracellular and intracellular matrix components. Previous studies have shown that spherical inclusions at large volume fractions can induce compression stiffening in biopolymer networks, but they do not account for the effects of aggregation and irregular morphologies of cellular assemblies or other components in tissues. Here, we demonstrate a novel mode of compression stiffening induced by aggregated or irregularly shaped inclusions that occurs at significantly lower volume fractions. Using carbonyl iron particles and coffee ground particles, we find that the morphological diversity of inclusions enables tissue-like compression stiffening at a low volume fraction of inclusions. Through a set of experiments and computational analyses, we demonstrate that these particles can percolate at low volume fractions. We further show that the percolation of stiff inclusions creates a stress-supporting network and enables tension-dominated stress propagation in fibrin fibers, both of which drive macroscopic stiffening during compression. These findings provide insights into the regulation of tissue stiffness and have implications for designing biomaterials with physiologically relevant mechanical properties for biomedical applications. Significance StatementBiological tissues experience a variety of mechanical forces. Many tissues, such as brain, liver, fat, and blood clots, become stiffer under physiological compressive loads, a property known as compression stiffening. In contrast, most biopolymer networks, which are the primary structural components for tissues, soften under compression. Here, we show that incorporating a small amount of aggregated or irregularly shaped particles into biopolymer gels induces robust compression stiffening. These inclusions percolate through the gel and rearrange non-affinely under compression, stretching surrounding fibers and contributing to mechanical reinforcement. Together, these effects reproduce tissue-like compression stiffening. Our findings not only provide new physical models for understanding tissue mechanics but also offer insights for designing biomaterials to achieve physiologically relevant mechanical responses.

biophysics↗

bioRxiv2025

Reactivation of threat conditioning memory in humans: disentangling the effects on emotional memory and cognitive biases.

Learning to detect and respond to threats is fundamental for survival and is often modeled through threat conditioning (TC) paradigms. While these paradigms reliably produce implicit memories that elicit physiological and behavioral responses to conditioned stimuli (CS), less is explored about how TC influences cognitive and emotional biases, particularly those implicated in anxiety disorders, such as threat overestimation and negative stimulus representation. In this study, we investigated the dynamic interaction between the reactivation of the implicit threat memory and these cognitive biases using a validated TC paradigm in humans. In Experiment 1, participants underwent TC on Day 1, followed by a memory reactivation session (incomplete reminder: one unreinforced CS+) and a highly demanding working memory (HWM) task, used as an amnesic manipulation, or a control condition on Day 2. On Day 3, memory retention was tested using a simplified, single-trial protocol (one CS+, one CS-, and one neutral CS), followed by tasks assessing threat valuation and representation. Results indicated that the HWM task administered post-reactivation significantly reduced skin conductance responses (SCRs) and attenuated cognitive biases, without altering expectancy of the unconditioned stimulus (US). In Experiment 2, we evaluated the effect of varying reactivation frequency (none, one, or two reminders) on implicit memory and cognitive biases. While repeated reactivations generalized the conditioned response to other stimuli, cognitive and emotional biases remained stable, suggesting a dissociation between memory generalization and evaluative processing. These findings demonstrate that implicit threat memories can be selectively modified through post-reactivation interventions, affecting both physiological and cognitive-emotional domains. Importantly, the distinct effects of memory reactivation and reconsolidation on physiological versus cognitive outcomes support the existence of temporally and functionally dissociable mechanisms. This research highlights the need to consider cognitive biases alongside physiological responses when evaluating memory-based interventions and offers novel insight into mechanisms underlying anxiety maintenance and treatment.

neuroscience↗

bioRxiv2025

Cytochrome b5 reductase 4 efficiently reduces Neuroglobin and Cytoglobin

Cytoglobin and Neuroglobin are heme-containing proteins expressed in most vertebrates, including mammals, with still not completely defined physiological roles. Most of the putative functions of cytoglobin/neuroglobin, such as oxygen binding or nitric oxide dioxygenation, rely on the heme iron being in the ferrous (Fe2+) oxidation state. Therefore, it is very possible that reducing systems are active in the cell to maintain both proteins in the ferrous state. We have previously shown that the cytochrome b5 reductase isoform 3/ cytochrome b5 system, the canonical reductase of hemoglobin and myoglobin, can reduce cytoglobin at very fast rates, consistent with a possible physiological role. However this reducing system is unable to reduce neuroglobin, which to date lacks a validated, physiologically feasible reducing system. Here we have studied the interaction of cytochrome b5 reductase isoform 4 with cytoglobin and neuroglobin and found that cytochrome b5 reductase 4 can reduce cytoglobin at rates comparable to those observed with cytochrome b5 reductase 3/ cytochrome b5. Remarkably, it can also reduce neuroglobin efficiently. Studying different surface mutations of cytoglobin and neuroglobin we note that some cytoglobin mutations, in particular R84E and K116E decrease reduction rates by more than 10-fold, whereas surface mutations in neuroglobin that were shown to impair the interaction of neuroglobin with cytochrome c (E60K/D73K/E87K) show little effect on the reduction rates. We conclude that cytochrome b5 reductase 4 can supplement cytochrome b5 reductase 3/ cytochrome b5 roles for cytoglobin reduction in vivo and is a strong candidate for a physiological role as neuroglobin reductase.

biochemistry↗

bioRxiv2025

Upregulation of the AcrAB2NodT efflux pump confers antibiotic resistance at the cost of collateral metal sensitivity

Bacterial resistance to antibiotics (AB) such as {beta}-lactams, fluoroquinolones, and aminoglycosides often emerges through mutations that alter AB targets, reduce membrane permeability, or increase the activity of AB-modifying enzymes and efflux pumps. Yet the physiological costs associated with AB resistance remain poorly understood. In Caulobacter vibrioides, a {Delta}tipR mutant that which constitutively upregulates the RND pump AcrAB2nodT, displays heightened sensitivity to copper (Cu), revealing a physiological vulnerability driven by the energetic burden imposed by excessive efflux activity. Deletion of acrAB2nodT in the {Delta}tipR background restored Cu resistance to wild-type levels, confirming the role of pump overexpression in metal sensitivity. Morphological and microscopy analyses revealed that pump overexpression leads to cell envelope defects and compromised fitness. To disentangle the effects of pump abundance from efflux activity, we engineered an AcrB2 transport-impaired mutant. This variant also rescued Cu resistance, demonstrating that high expression and active transport contribute to the observed toxicity. Notably, this sensitivity was not limited to Cu; the {Delta}tipR mutant also exhibited increased susceptibility to other transition metals, including zinc (Zn), nickel (Ni) and cadmium (Cd), suggesting a broader vulnerability linked to metal stress. Mechanistically, pump overexpression depleted the proton motive force, reduced ATP levels, and impaired motility, all of which are essential for Cu stress adaptation. This physiological tradeoff highlights the importance of precise efflux regulation and reveals a potential therapeutic vulnerability: targeting the cost of pump upregulation could enhance the efficacy of antimicrobial treatments. ImportanceWhile efflux pumps primarily protect bacteria from AB, their excessive activity can impose a fitness cost. This study underscores a crucial tradeoff between resistance and cellular fitness by connecting Cu sensitivity to heightened AcrAB2NodT efflux pump expression in Caulobacter vibrioides. This work challenges the assumption that more efflux always benefits the cell and shows that unregulated pump activity can undermine survival under metal stress. These findings broaden our understanding of bacterial stress physiology and suggest new ways to combat antimicrobial resistance by targeting the hidden costs of resistance mechanisms. Understanding this balance between resistance and fitness opens new perspectives for combination therapy against multidrug-resistant bacteria.

microbiology↗

bioRxiv2025

Mothers respond to biological pup calls with heart rate changes in Japanese house bats, Pipistrellus abramus

Maternal care is essential for offspring survival in mammals, especially in colonial species where mothers must recognize their own young among many. In the Japanese house bat, Pipistrellus abramus, mothers identify their pups using acoustic cues, particularly isolation calls (ICs) produced by newborns. However, the physiological mechanisms underlying such maternal recognition remain largely unknown. Here, we investigated maternal emotional responses of mother bats to pup calls by measuring heart rate (HR) changes during controlled playback experiments. We recorded ICs from 2-day-old pups and echolocation calls (ECs) from 30-day-old pups, then presented these sounds to mothers after their pups had become independent. HR significantly increased in response to calls from the mothers own pups--both ICs and ECs--but not to calls from non-family pups. Among all stimuli, ECs from their own older pups evoked the largest HR increase, indicating strong physiological arousal and suggesting sustained maternal responsiveness despite developmental changes in call structure. In contrast, ECs from an unfamiliar adult also induced HR elevation, possibly reflecting general social arousal rather than maternal recognition. These findings demonstrate that P. abramus mothers exhibit selective physiological arousal to their own pups vocalizations, and that HR provides a sensitive physiological index of maternal motivation and recognition based on dynamic acoustic information.

animal behavior and cognition↗

bioRxiv2025

Reconstitution of lamin assembly on nuclear pore complex-containing membranes

Intermediate filaments called lamins line the metazoan nuclear envelope and organize the nucleus and genome. Unlike actin and microtubules, purified intermediate filament proteins assemble into non-physiological structures, making it difficult to connect lamin functions to their assembly and regulation. To overcome this challenge and shed light on physiological lamin assembly mechanisms, we conducted biochemical studies of lamin-B3 endogenously present in Xenopus laevis egg extracts, which recapitulate physiological context. When we mimicked nucleoplasm conditions, which would support assembly of lamin filaments in in-tact cells, lamin-B3 assembled into higher-order structures resembling filamentous meshworks without accompanying nuclear assembly. This ectopic lamin assembly occurs on nuclear pore complex-containing membranes, but does not apparently recruit known nuclear lamina components, demonstrating that a lamin assembly process is partially separable from the rest of the nuclear lamina and nucleus. This assembly assay in the physiological context of cellular components opens the door to further dissecting nuclear lamina function in nuclear organization. SummaryMimicking nucleoplasm conditions in Xenopus laevis egg extracts triggers a lamin assembly reaction independent of nucleus assembly, giving new insights into potential lamin assembly mechanisms.

cell biology↗

bioRxiv2025

SimUrine: A Novel, Fully Defined Artificial Urinary Media for Enhanced Microbiological Research of Urinary Bacteria

Urinary tract infections represent one of the most prevalent bacterial diseases, yet current diagnostic and research methodologies are hampered by inadequate culture media that fail to replicate the bladder biochemical environment. Conventional artificial urine formulations contain undefined components, lack essential nutrients, or inadequately support urinary microbiome (urobiome) growth. To address these limitations, we developed SimUrine, a fully defined synthetic urine medium that aims to replicate human bladder chemistry while supporting diverse microbial growth requirements. SimUrine was systematically developed through iterative optimization of multi-purpose artificial urine, incorporating defined concentrations of carbon sources, vitamins, trace elements, and amino acids within physiologically relevant ranges. The modular design enables component substitution without complete reformulation, facilitating customization for culturomics, antimicrobial susceptibility testing, and microbial ecology studies, while reducing batch-to-batch variability associated with authentic urine. Performance evaluation demonstrated SimUrines capability to support growth of fastidious urobiome members, including Lactobacillus species, Aerococcus urinae, and Corynebacterium riegelii, which fail to proliferate in conventional minimal media. Physicochemical characterization confirmed that SimUrine formulation exhibits properties within normal human urine ranges for density, conductivity, osmolarity, and viscosity, ensuring physiological relevance. Clinical applications revealed reduced antibiotic susceptibility compared to standard media, suggesting more accurate representation of in vivo conditions. Co-culture experiments using Escherichia coli and Enterococcus faecalis demonstrated previously unobserved microbial interactions, highlighting SimUrines utility for investigating urobiome dynamics. SimUrine represents a significant advancement in urobiome research methodology, providing a standardized, reproducible platform for investigating urobiome under physiologically relevant conditions, potentially improving fundamental understanding and clinical diagnostic approaches. IMPORTANCEUrinary tract infections affect millions globally, yet current research and diagnostic methods rely on inadequate culture media that fail to replicate the bladders unique biochemical environment. This fundamental limitation has hindered accurate UTI research and potentially compromised clinical treatment decisions. SimUrine addresses this critical gap as the first fully defined synthetic urine medium that mimics human bladder chemistry while supporting growth of diverse urinary microbes. The breakthrough enables cultivation of urobiome organisms in a minimal medium that resembles natural conditions, revealing novel microbial interactions that influence urinary health. Crucially, SimUrine demonstrates different antimicrobial susceptibility patterns compared to standard clinical media, suggesting current testing protocols may inaccurately predict treatment outcomes. This standardized, reproducible platform eliminates the variability of authentic urine samples while maintaining physiological relevance, potentially transforming urobiome research methodology and improving clinical diagnostic accuracy for urinary tract infections worldwide.

microbiology↗

bioRxiv2025

Early life adversity shapes life history trade-offs between growth and reproduction in free-ranging rhesus macaques

Life history theory predicts that organisms allocate resources across physiological processes to maximize fitness. Under this framework, early life adversity (ELA)--which often limits energetic capital--could shape investment in growth and reproduction, as well as trade-offs between them, ultimately contributing to variation in evolutionary fitness. Using long-term demographic, behavioral, and physiological data for 2,100 females from a non-human primate population, we tested whether naturally-occurring ELA influences investment in the competing physiological demands of growth and reproduction. By analyzing ELA, growth, and reproduction in the same individuals, we also assessed whether adversity intensifies trade-offs between life history domains. We found that ELA influenced life history patterns, and was associated with modified growth, delayed reproductive maturity, and small adult body size. Different types of ELA sometimes had distinct reproductive outcomes--e.g., large group size was linked to faster reproductive rates, while low maternal rank predicted slower ones. Adversity also amplified trade-offs between growth and reproduction: small body size was a stronger predictor of delayed and reduced reproductive output in females exposed to ELA, compared to those not exposed. Finally, we examined how traits modified by ELA related to lifetime reproductive success. Across the population, starting reproduction earlier and maintaining a moderate reproductive rate conferred the greatest number of offspring surviving to reproductive maturity. These findings suggest that ELA impacts key life history traits as well as relationships between them, and can constrain individuals from adopting the most optimal reproductive strategy. Significance StatementEarly life adversity (ELA) can have lasting effects on evolutionary fitness (e.g., the number of surviving offspring an animal produces); however, the paths connecting ELA to fitness--for example by influencing growth, reproductive timing or rate, or trade-offs between these processes--remain unclear. Leveraging long-term behavioral, physiological, and demographic data from 2,100 female rhesus macaques, we found that ELA-exposed females exhibited growth and reproductive schedules associated with less-optimal lifetime fitness outcomes. Further, ELA intensified trade-offs between growth and reproduction, suggesting that affected individuals face steeper energetic constraints. Our findings highlight the long-lasting impacts of ELA on traits of evolutionary and biomedical importance in a non-human primate model with relevance to humans.

evolutionary biology↗

bioRxiv2025

Comprehensive healthspan assessments and influence of sex as a biological variable in aging rats

Rats share a significant amount of genetic and physiological similarity with humans. Many biological processes and pathways are conserved between rats and humans, making rats a suitable model for studying various aspects of human health and disease. Using rats as an aging model offers a more ethical alternative to using larger, longer-lived animals like primates. Rats are easier to handle in laboratory settings, as compared to non-human primates, both of which have physiological functions like humans. To date, there are very few studies which have comprehensively studied age-related changes in rat physiology. Here we present a longitudinal assessment of several aspects of Brown-Norway rat physiology and histopathology using molecular and functional assessments at 6-, 17- and 27 months of age. Our studies thus provide age-related healthspan parameters, which can be used as reference for genetic or pharmacological rat models of aging.

animal behavior and cognition↗

bioRxiv2025

Glucose levels impact the morphology and cell-type composition of human cerebral organoids

Human cerebral organoids, derived from pluripotent stem cells, are powerful models for studying human brain development. The understanding of how morphogens can be used to guide patterning and differentiation has matured rapidly, however, the influence of basal media components on organoid development remains unclear. Standard organoid media frequently contain non- physiological concentrations of nutrients, including glucose, a central regulator of cellular metabolism and signaling. Here, we examine how glucose availability shapes cerebral organoid growth, morphology, and cell-type composition by comparing conventional hyperglycemic media to media with glucose levels more closely resembling physiological conditions. We find that organoids derived from multiple human pluripotent stem cell lines can grow in physiological glucose, but exhibit altered growth rates, structural features, and lineage distributions. In H9 embryonic stem cell-derived organoids, inhibition of the mTOR pathway under physiological glucose restores neurodevelopmental cell types otherwise diminished in these conditions. These findings highlight glucose as a key determinant of organoid lineage specification and cellular signaling. Importantly, however, glucose modulation does not reduce variability across organoids or cell lines, underscoring the need to better understand and control sources of heterogeneity to improve organoid models.

cell biology↗

bioRxiv2025

Using a wearable EEG device to examine age trends in sleep macro- and micro-architecture across adolescence

Adolescence is a period of distinct maturational changes in sleep physiology. Age-related trends in sleep physiology have been captured using laboratory-based polysomnography, a method limited by logistical burden and high cost. We tested the ability of the accessible Dreem3 sleep EEG headband to replicate established age effects in sleep physiology from late childhood through early adulthood. Typically developing youth (N=100, 9-26 years) completed 3-4 consecutive nights of at-home sleep recording. We estimated age-related trends across eight macro-architecture and 15 micro-architecture variables with known age effects, and conducted exploratory analyses of 24 additional variables. Dreem replicated established age trends, including increases in non-rapid eye movement (NREM) stage 2, and decreases in N3, time in bed, NREM delta and theta power with increasing age. Exploratory analysis revealed age effects in twelve variables, including decreases in spindle activity with increasing age. Sleep EEG wearables offer an accessible way to characterize sleep physiology development.

neuroscience↗

bioRxiv2025

An image-computable, spatio-chromatic RF model of the midget RGC mosaic across the retina

Accurate image-computable models of retinal ganglion cell (RGC) mosaics across the retina do not currently exist. Here, we deploy a novel computational frame-work which synthesizes mosaics of linear spatio-chromatic receptive fields (RFs) of ON midget RGCs (mRGCs) by integrating published anatomical, physiological, and optical quality measurements. We use the synthesized mRGC mosaics to simulate both in vivo and in vitro physiological experiments and demonstrate the models consistency with published data. The model enables computation of how visual performance is shaped by the representation of visual information provided by the linear spatiochromatic processing stage of midget RGCs. The developed computational framework carefully accounts for the effect of physiological optics on mRGC responses, enables comparison of in vivo and in vitro data, and allows exploration of how different assumptions about RF organization, such as selectivity for the type of cones pooled by the RF center mechanism, affect physiological responses and psychophysical performance. The open-source and freely available implementation provides a platform for understanding how the linear spatiochromatic receptive field representation of the mRGCs shapes visual performance, as well as a foundation for future work that incorporates response nonlinearities, temporal filtering, and extends to additional RGC mosaics.

neuroscience↗

bioRxiv2025

Luteal-phase resistance training enhances nocturnal heat dissipation and delta power during sleep

Study ObjectivesThis study examined the effects of resistance training on sleep architecture, physiological heat dissipation, and {delta} power in young adult women during the follicular and luteal phases of the menstrual cycle. MethodsNine healthy young women participated in a four-condition crossover protocol comprising (1) follicular phase non-exercise, (2) follicular phase exercise, (3) luteal phase non-exercise, and (4) luteal phase exercise. The exercise condition consisted of 30 minutes of resistance training at 70% of one-repetition maximum performed during the day. During each night, electroencephalography, body temperature, and core body temperature were measured in the home environment. The distal-proximal body temperature gradient (DPG), which is a validated indicator of heat dissipation, was calculated ResultsResistance training enhanced heat dissipation, as reflected by increased DPG values, and increased the proportion of stage N3 sleep during both menstrual cycle phases, with more pronounced effects during the luteal phase. Sleep from bedtime to wake time was divided into four equal segments. Under the luteal phase with exercise, the appearance of stage N3, {delta} power, and the DPG were elevated in the mid-to-late segments of sleep. ConclusionsThese findings suggest that daytime resistance training promotes nocturnal deep sleep and facilitates thermoregulatory heat loss, as indicated by an increased DPG, particularly during the luteal phase when thermoregulation is less stable than the follicular phase. This training may represent a practical intervention to improve sleep quality and physiological recovery in women across different phases of the menstrual cycle. STATEMENT OF SIGNIFICANCEWomen often experience sleep disturbances during the luteal phase of the menstrual cycle, but the physiological mechanisms and effective interventions remain unclear. This study shows that daytime resistance training enhances nighttime heat dissipation and increases slow-wave sleep during this phase. These findings suggest that exercise is a practical approach to alleviate menstrual cycle-related sleep issues. By clarifying how exercise interacts with thermoregulation and sleep across the cycle, this work contributes to understanding female-specific sleep physiology and supports the development of non-pharmacological strategies to improve womens sleep health in women. Future research should examine the long-term effects of daytime resistance training and compare different exercise modalities across diverse populations.

neuroscience↗

bioRxiv2025

Sleep deprivation constrains dynamic configurations of integrated and segregated brain states impacting cognitive performance

The breakdown of cognitive control following sleep deprivation is widely recognised, but the physiological mechanisms and brain signatures that produce this vulnerability have not been resolved. Effective cognition relies on large-scale brain networks flexibly reconfiguring between states of integration and segregation. Here we combined functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and electrocardiography (ECG) collected during cognitive tasks under rested wakefulness, after sleep deprivation, and following a recovery nap to test the hypothesis that sleep deprivation constrains this dynamical repertoire and disrupts its physiological regulation. Using time-resolved functional connectivity and graph theory, we show that sleep deprivation increases the distribution of connections across networks, while reducing the temporal variability of between-network connectivity. Furthermore, dynamic fluctuations between integrated and segregated modes of network topology were dampened, with brain regions spending more time in intermediate configurations and showing greater instability of mode transitions. These alterations were tightly linked to behavioural impairment: participants who exhibited greater contraction toward intermediate topologies also showed poorer task accuracy and slower responses. Under well-rested conditions, thalamic activity peaked prior to transitions into integrated states and was suppressed during transitions into segregated states, consistent with a coordinating role in cortical dynamics. Sleep deprivation weakened and delayed this thalamic coupling. Finally, global and regional fMRI fluctuations were elevated after sleep loss, becoming decoupled from cardiac physiology while more strongly coupled to EEG delta power, further linking reduced arousal to constrained network flexibility. Together, these findings show that sleep deprivation narrows the brains dynamical repertoire, due to disrupted thalamic regulation and changes to the physiological integration with cortical networks.

neuroscience↗

bioRxiv2025

Tuned to explore: Increased phasic responses to auditory targets and novelty in children regardless of induced tonic arousal

The ability to focus on relevant information while ignoring distractions is critical during childhood, as it supports learning, social interaction, and adaptation to changing environments. This attentional balance is thought to depend in part on arousal regulation, mediated by the activity of the locus coeruleus norepinephrine (LC-NE) system. Moderate levels of arousal are typically associated with optimal cognitive performance. However, the interaction between arousal and attention remains poorly understood in humans, especially during development. In this study, we investigated whether experimentally modulating tonic arousal, the baseline level of physiological alertness, affects attentional processing in children (N = 44, aged 6-8) and adults (N = 46, aged 18-35). Participants performed an active auditory three-stimulus (standard, novel, target) oddball task, designed to assess selective attention to target tones and distraction by novel sounds. Prior to each task block, tonic arousal was manipulated using music or videos varying in arousing content. Physiological responses were recorded continuously (skin conductance, pupil dilation, heart rate) to index both tonic arousal and transient, phasic changes in arousal triggered by task events. While tonic arousal modulation was successful, as confirmed by skin conductance levels, Bayesian analyses provided evidence for no effect of this modulation on subsequent attentional processing. Importantly, children generally exhibited stronger phasic arousal responses, particularly to task-irrelevant novel sounds, reflecting less mature regulation of attention and arousal. These findings show developmental differences in physiological responses to unexpected environmental stimuli and provide physiological evidence of increased distractibility during childhood.

neuroscience↗

bioRxiv2025

APOE4-Aβ synergy drives brain network dysfunction and neuronal lysosomal-ER proteostasis dysregulation in preclinical Alzheimer's disease

Amyloid-{beta} (A{beta}) and APOE4 represent two of the strongest pathological and genetic risk factors for Alzheimers disease (AD), but how these co-pathogens interact during preclinical stages remains undefined. We addressed this question by developing a humanized knock-in model expressing physiological, endogenously regulated human A{beta} and APOE4. Aged AppNLF:APOE4 mice displayed incipient amyloidosis with subtle memory-related changes, consistent with preclinical AD. We found largely distinct, non-overlapping APOE4- and A{beta}-driven functional synaptic, sleep, and behavioral alterations. However, at the transcriptomic level, APOE4xA{beta} had a pronounced detrimental interaction in neuronal populations, whereas glial populations were primarily affected by either genotype. We found APOE4xA{beta} molecular interactions in neuronal populations, including excitatory and inhibitory cells, converged on a core lysosomal-ER proteostasis axis. We propose that APOE4xA{beta} interaction produces an early neuronal pathogenic signature, involving the lysosomal-ER proteostasis axis, preceding functional decline and driving disease progression. APOE4xA{beta}-KI models provide a physiologically relevant platform to study early pathogenesis. HighlightsO_LIEarly synergistic APOE4xA{beta} interaction emerges predominantly at the transcriptomic level in neurons, but not in glial cells. C_LIO_LIAPOE4 and A{beta} drive largely non-overlapping physiological changes in preclinical stages of disease, but converge at the level of network hyperexcitability. C_LIO_LIAPOE4xA{beta} neuronal synergy converges on a conserved lysosomal-ER proteostasis axis. C_LIO_LIHumanized APOE4xA{beta} KI mice provide a physiologically relevant model to dissect early AD pathogenesis in preclinical stages C_LI

neuroscience↗

bioRxiv2025

Effect of human urinary microenvironment and fluid flow on antibiotic and phage therapy efficacy against uropathogenic Escherichia coli

Urinary tract infections (UTI) remain a major global health burden, with high recurrence despite antibiotic treatment. The escalating prevalence of antimicrobial resistance further compromises therapeutic efficacy, contributing to an estimated 260,000 deaths annually. Conventional in vitro susceptibility assays often fail to predict clinical outcomes, underscoring the urgent need for physiologically relevant infection models. Here, we examined how microenvironmental complexity shapes uropathogenic Escherichia coli (UPEC) responses to antibiotics and bacteriophages using: human urine, a three-dimensional urothelial microtissue model (3D-UHU), and a novel mesofluidic system (P-FLO) that introduces physiologically relevant flow dynamics to the 3D-UHU. P-FLO was engineered from cost-effective 3D-printed components compatible with standard Transwell systems. Among the antibiotics tested, nitrofurantoin exhibited the greatest potency in minimum inhibitory concentration assays, but it failed to fully eradicate infection within the more physiological 3D-UHU model. A bacteriophage cocktail (LCPR1) showed markedly reduced activity in urine compared with nutrient-rich media, highlighting the influence of infection-site conditions. In contrast, in 3D-UHU, LCRP1 modulated host responses without reducing bacterial burden. Combination therapy (nitrofurantoin + LCPR1) eliminated planktonic bacteria under static conditions but offered no added benefit against adherent or intracellular populations relative to antibiotic monotherapy. Incorporating flow revealed additional layers of complexity, where shear stress induced bacterial elongation and attachment and altered drug performance, diminishing the efficacy of nitrofurantoin and combination therapy against planktonic populations despite increased drug exposure. Together, these findings demonstrate that the bladder microenvironment and its mechanical forces modulate host-pathogen interactions and profoundly influence UPEC infection dynamics and therapeutic outcomes, emphasizing the need for advanced, physiologically informed models to guide treatment strategies in the post-antibiotic era.

microbiology↗

bioRxiv2025

"Awe-scillations": EEG spectral and complexity representations of awe

Awe is a positive emotion often accompanied by sensations of vastness and unity, with known benefits for well-being and social behavior. However, its neural underpinnings remain poorly understood. We recorded electroencephalography (EEG) and autonomic physiology in 23 healthy older participants while they watched a nature-based audiovisual film and subjectively rated awe events. Awe was the predominant emotion reported - though other positive emotions (e.g., joy) were also highly rated. Awe events were associated with decreased skin conductance level (SCL), and decreased EEG alpha and theta spectral power - physiological changes associated with low arousal and positively valenced emotional states. Interestingly, awe events exhibited increased Lempel Ziv Complexity (LZC) - indicating heightened neural signal entropy and increased richness of the conscious experience. LZC was also positively associated with the intensity of the awe ratings and negatively associated with SCL. Three additional datasets with separate independent induction methods (video clips and pharmacological induction via N,N-dimethyltryptamine) also showed positive occipital LZC associations with awe - suggesting some generalizability of LZC as a neurophysiological marker of awe. These results suggest that awe evokes neurophysiological states linked to the subjective affective experience. Impact StatementAwe, an emotion of increasing interest, has been studied with fMRI and peripheral physiology - but few studies have used electroencephalography (EEG). In this EEG study, we utilize a movie-watching paradigm to explore potential physiological correlates of awe. The results present EEG-based complexity increases as a potential correlate of awe, though showing limited generalization to independent datasets and limited uniqueness compared to joy, another positive emotion.

neuroscience↗