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bioRxiv2023

Global control of cellular physiology by biomolecular condensates through modulation of electrochemical equilibria

Control of the electrochemical environment in living cells is typically attributed to ion channels. Here we show that the formation of biomolecular condensates can modulate the electrochemical environment in cells, which affects processes globally within the cell and interactions of the cell with its environment. Condensate formation results in the depletion or enrichment of certain ions, generating intracellular ion gradients. These gradients directly affect the electrochemical properties of a cell, including the cytoplasmic pH and hyperpolarization of the membrane potential. The modulation of the electrochemical equilibria between the intra- and extra-cellular environments by biomolecular condensates governs charge-dependent uptake of small molecules by cells, and thereby directly influences bacterial survival under antibiotic stress. The shift of the intracellular electrochemical equilibria by condensate formation also drives a global change of the gene expression profile. The control of the cytoplasmic environment by condensates is correlated with their volume fraction, which can be highly variable between cells due to the stochastic nature of gene expression at the single cell level. Thus, condensate formation can amplify cell-cell variability of the environmental effects induced by the shift of cellular electrochemical equilibria. Our work reveals new biochemical functions of condensates, which extend beyond the biomolecules driving and participating in condensate formation, and uncovers a new role of biomolecular condensates in cellular regulation.

cell biology↗

bioRxiv2023

Parkin R274W mutation affects muscle physiology via the PARIS-PGC-1α pathway

Recessive mutations in the Parkin gene (PRKN) are the most common cause of young-onset inherited parkinsonism. Parkin is a multifunctional E3 ubiquitin ligase that plays a variety of roles in the cell including the degradation of proteins and the maintenance of mitochondrial homeostasis, integrity, and biogenesis via the PARIS-PGC-1 pathway. In 2001 the R275W mutation in the PRKN gene was identified in two unrelated families with a multigenerational history of postural tremor, dystonia and parkinsonism. Drosophila models of Parkin R275W showed selective and progressive degeneration of dopaminergic neuronal clusters, mitochondrial abnormalities, and prominent climbing defects. In the Prkn mouse orthologue, the amino acid R274 corresponds to human R275. Here we described a muscle phenotype in R274W +/+ mice and discovered that a defective Parkin-PARIS-PGC-1 pathway may impact mitochondrial biogenesis and, eventually, myoblast proliferation and differentiation.

animal behavior and cognition↗

bioRxiv2023

Alpha9alpha10 knockout mice show altered physiological and behavioral responses to signals in masking noise

Medial olivocochlear (MOC) efferents modulate outer hair cell motility through specialized nicotinic acetylcholine receptors to support encoding of signals in noise. Transgenic mice lacking the alpha9 subunits of these receptors (9KOs) have normal hearing in quiet and noise, but lack classic cochlear suppression effects and show abnormal temporal, spectral, and spatial processing. Mice deficient for both the alpha9 and alpha10 receptor subunits (910KOs) may exhibit more severe MOC-related phenotypes. Like 9KOs, 910KOs have normal auditory brainstem response (ABR) thresholds and weak MOC reflexes. Here, we further characterized auditory function in 910KO mice. Wildtype and 910KO mice had similar ABR thresholds and acoustic startle response (ASR) amplitudes in quiet and noise, and similar frequency and intensity difference sensitivity. 910KO mice had larger ABR Wave I amplitudes than wildtypes in quiet and noise, but the noise:quiet amplitude ratio suggested 910KOs were more susceptible to masking effects for some stimuli. 910KO mice also had larger startle amplitudes in tone backgrounds than wildtypes. Overall, 910KO mice had grossly normal auditory function in quiet and noise, though their larger ABR amplitudes and hyperreactive startles suggest some auditory processing abnormalities. These findings contribute to the growing literature showing mixed effects of MOC dysfunction on hearing.

neuroscience↗

bioRxiv2023

Gut microbiota influences foraging onset without affecting division of labor and associated physiological hallmarks in honeybees

Gut microbes can impact cognition and behavior, but whether they regulate division of labor in animal societies is unknown. We addressed this question using honeybees since they exhibit division of labor between nurses and foragers and because their gut microbiota can be manipulated. Using automated behavioral tracking and controlling for co-housing effects, we show that gut microbes influence the age at which bees start foraging but have no effects on the time spent in a foraging area and number of foraging trips. Moreover, the gut microbiota did not influence hallmarks of behavioral maturation such as body weight, cuticular hydrocarbon (CHC) profile, hypopharyngeal gland size, and the proportion of bees maturing into foragers. Overall, this study shows that the honeybee gut microbiota does not affect division of labor but rather plays an important function in controlling the onset of bee foraging.

evolutionary biology↗

bioRxiv2024

Physiological JNK3 Concentrations Are Higher in Motor-related and Disease-implicated Brain Regions of C57BL6/J Mice

The c-Jun N-terminal kinase 3 (JNK3) is a stress-responsive protein kinase primarily expressed in the central nervous system (CNS). JNK3 exhibits nuanced neurological activities, such as roles in behavior, circadian rhythms, and neurotransmission, but JNK3 is also implicated in cell death and neurodegeneration. Despite the critical role of JNK3 in neurophysiology and pathology, its localization in the brain is not fully understood due to a paucity of tools to distinguish JNK3 from other isoforms. While previous functional and histological studies suggest locales for JNK3 in the CNS, a comprehensive and higher resolution of JNK3 distribution and abundance remained elusive. Here, we sought to define the anatomical and cellular distribution of JNK3 in adult mouse brains. Data reveal the highest levels of JNK3 and pJNK3 were found in the cortex and the hippocampus. JNK3 possessed neuron-type selectivity as JNK3 was present in GABAergic, cholinergic, and dopaminergic neurons, but was not detectable in VGLUT-1-positive glutamatergic neurons and astrocytes in vivo. Intriguingly, higher JNK3 signals were found in motor neurons and relevant nuclei in the cortex, basal ganglia, brainstem, and spinal cord. While JNK3 was primarily observed in the cytosol of neurons in the cortex and the hippocampus, JNK3 appeared commonly within the nucleus in the brainstem. These distinctions suggest the potential for significant differences between JNK3 actions in distinct brain regions and cell types. Our results provide a significant improvement over previous reports of JNK3 spatial organization in the adult CNS and support continued investigation of JNK3s role in neurophysiology and pathophysiology.

neuroscience↗

bioRxiv2024

Mind the blank: behavioral, experiential, and physiological signatures of absent-mindedness

Does being awake necessarily mean being conscious of something? This study investigates the phenomenon of Mind Blanking (MB), characterized by an "emptiness of mind", comparing it with Mind Wandering (MW) and On-task (ON) states. Using a sustained attention task and electroencephalogram monitoring, behavioral and neurophysiological signatures of MB were examined in 62 participants. MB exhibited a specific pattern of behavioral lapses, as well as decreased fast oscillatory activity and complexity over posterior electrodes compared to MW. Functional connectivity analyses revealed decreased long-range inter-areal connectivity during MB, compared to both ON and MW states. Event-related potentials with source reconstruction and temporal decoding techniques indicated a significant disruption in visual processing during MB, starting from 200 ms post stimulus and echoing into the late-stage of visual processing, suggesting a disruption of conscious access to sensory information during MB. EEG-derived markers allowed the prediction of mental states at the trial level, offering a finer view of conscious dynamics than subjective reports alone. Overall, these findings challenge the notion of the wakeful conscious mind as inherently content-oriented, suggesting that MB reflects genuine gaps in the stream of conscious thoughts, arising from disruptions in the generation or accessibility of thought content. SIGNIFICANCE STATEMENTEmploying cutting-edge neurophysiological techniques on high-density electroencephalographic recordings, our study unveils unique neurophysiological markers of mind blanking, a phenomenon characterized by lapses in conscious content amidst the flow of wakeful consciousness. Distinguished from content-oriented states such as on-task and mind-wandering, mind blanking appears to be a distinct mental state. Furthermore, we demonstrate the feasibility of decoding consciousness dynamics solely from EEG features, transcending the limitations of intermittent subjective reports. Our findings thus not only provide a novel framework for investigating the stream of consciousness but also challenge the conventional notion that wakefulness invariably signifies being conscious of something.

neuroscience↗

bioRxiv2024

Global sensitivity analysis for investigation of bacterial physiology in complex media with FBA-PRCC

In this paper we propose the use of FBA-PRCC approach, which is based on sampling flux space and global sensitivity analysis (GSA), for analysis of the GEM FBA solution space in the nutrient-rich environment. We identify two new modes of interaction between species and metabolites: attraction and avoidance and propose the way of their use. We have shown that sensitivity coefficients provide additional information about behavior of the bacteria in the nutrient-rich environment in comparison to standard knockouts, FVA and CoPE-FBA analysis.

systems biology↗

bioRxiv2024

The physiology of bud dormancy and cell cycle status in grapevine

Evaluating the cell cycle status during dormancy of multicellular organisms is problematic. This is particularly so for woody perennial buds, where dormant and quiescent states are diffuse, and the organ may remain visibly unchanged for six to nine months of the year. In this study, we investigate cell cycle status of dormant grapevine buds by measuring mitotic index using an optimised method developed for grapevine bud tissue. The experimental material showed a dynamic range in the depth of dormancy, declining from 200 days in March to less than 60 days in May and 30 days in August, measured as the time to reach 50% bud burst in forcing conditions. Despite these differences, flow cytometry analysis showed that most nuclei isolated from these buds were arrested at the G1 phase. Ultrastructure analysis of the cells in the region of the shoot apical meristem confirmed that the mitotic activities of buds remained low at all time points, together with the development of starch grains and the relative absence of organelle development. HIGHLIGHTThe cell cycle and ultrastructure data suggest interesting evidence correspond to the growth resumption capacity of grapevine cv. Cabernet Sauvignon buds, i.e., absence of mitosis activities regardless of dormancy depth and starch accumulation irrespective of chilling accumulation.

plant biology↗

bioRxiv2024

An Anatomical and Physiological Basis for Coincidence Detection Across Time Scales in the Auditory System

Animals navigate the auditory world by recognizing complex sounds, from the rustle of a predator to the call of a potential mate. This ability depends in part on the octopus cells of the auditory brainstem, which respond to multiple frequencies that change over time, as occurs in natural stimuli. Unlike the average neuron, which integrates inputs over time on the order of tens of milliseconds, octopus cells must detect momentary coincidence of excitatory inputs from the cochlea during an ongoing sound on both the millisecond and submillisecond time scale. Here, we show that octopus cells receive inhibitory inputs on their dendrites that enhance opportunities for coincidence detection in the cell body, thereby allowing for responses both to rapid onsets at the beginning of a sound and to frequency modulations during the sound. This mechanism is crucial for the fundamental process of integrating the synchronized frequencies of natural auditory signals over time.

neuroscience↗

bioRxiv2024

Physiological correlates of a simple saccadic-decision task in superior colliculus

Our vision is best only in the center of our gaze, and we use saccadic eye movements to direct gaze to objects and features of interest. We make more than 180,000 saccades per day, and accurate and efficient saccades are crucial for most visuo-motor tasks. Saccades are typically studied using small point stimuli, despite the fact that most real-world visual scenes are composed of extended objects. Recent studies in humans have shown that the initiation latency of saccades is strongly dependent on the size of the target (the "size-latency effect"), perhaps reflecting a tradeoff between the cost of making a saccade to a target and the expected information gain that would result. Here, we investigate the neuronal correlates of the size-latency effect in the macaque superior colliculus. We analyzed the latency variations of saccades to different size targets within a stochastic accumulator model framework. The model predicted a steeper increase in activity for smaller targets compared to larger ones. Surprisingly, the model also predicted an increase in saccade initiation threshold for larger targets. We found that the activity of intermediate-layer SC visuomotor neurons is in close agreement with the model predictions. We also found evidence that these effects may be a consequence of the visual responses of SC neurons to targets of different sizes. These results shed new light on the sources of delay within the saccadic system, a system that we heavily depend upon in the performance of most visuo-motor tasks.

neuroscience↗

bioRxiv2024

Does Vibrotactile Stimulation of the Auricular Vagus Nerve Enhance Working Memory? A Behavioral and Physiological Investigation

BackgroundWorking memory is essential to a wide range of cognitive functions and activities. Transcutaneous auricular VNS (taVNS) is a promising method to improve working memory performance. However, the feasibility and scalability of electrical stimulation are constrained by several limitations, such as auricular discomfort and inconsistent electrical contact. ObjectiveWe aimed to develop a novel and practical method, vibrotactile taVNS, to improve working memory. Further, we investigated its effects on arousal, measured by skin conductance and pupil diameter. MethodThis study included 20 healthy participants. Behavioral response, skin conductance, and eye tracking data were concurrently recorded while the participants performed N-back tasks under three conditions: vibrotactile taVNS delivered to the cymba concha, earlobe (sham control), and no stimulation (baseline control). ResultsIn 4-back tasks, which demand maximal working memory capacity, active vibrotactile taVNS significantly improved the performance metric d compared to the baseline but not to the sham. Moreover, we found that the reduction rate of d with increasing task difficulty was significantly smaller during vibrotactile taVNS sessions than in both baseline and sham conditions. Arousal, measured as skin conductance and pupil diameter, declined over the course of the tasks. Vibrotactile taVNS rescued this arousal decline, leading to arousal levels corresponding to optimal working memory levels. Moreover, pupil diameter and skin conductance level were higher during high-cognitive-load tasks when vibrotactile taVNS was delivered to the concha compared to baseline and sham. ConclusionOur findings suggest that vibrotactile taVNS modulates the arousal pathway and could be a potential intervention for enhancing working memory. HighlightsO_LIVibrotactile stimulation of the auricular vagus nerve increases general arousal. C_LIO_LIVibrotactile stimulation of the auricular vagus nerve mitigates arousal decreases as subjects continuously perform working memory tasks. C_LIO_LI6 Hz Vibrotactile auricular vagus nerve stimulation is a potential intervention for enhancing working memory performance. C_LI

bioengineering↗

bioRxiv2024

Biologically informed machine learning modeling of immune cells to reveal physiological and pathological aging process

The immune system undergoes progressive functional remodeling from neonatal stages to old age. Therefore, understanding how aging shapes immune cell function is vital for precise treatment of patients at different life stages. Here, we constructed the first transcriptomic atlas of immune cells encompassing human lifespan, ranging from newborns to supercentenarians, and comprehensively examined gene expression signatures involving cell signaling, metabolism, differentiation, and functions in all cell types to investigate immune aging changes. By comparing immune cell composition among different age groups, HLA highly expressing NK cells and CD83 positive B cells were identified with high percentages exclusively in the teenager (Tg) group, whereas CD4_CTL precursors were exclusively enriched in the supercentenarian (Sc) group. Notably, we found that the biological age (BA) of pediatric COVID-19 patients with multisystem inflammatory syndrome accelerated aging according to their chronological age (CA). Besides, we proved that inflammatory shift-myeloid abundance and signature correlate with the progression of complications in Kawasaki disease (KD). Finally, based on those age-related immune cell compositions, we developed a novel BA prediction model, PHARE (https://xiazlab.org/phare/), which applies to both scRNA-seq and bulk RNA-seq data. Overall, our study revealed changes in immune cell proportions and function associated with aging, both in health and disease, and provided a novel tool for successfully capturing features that accelerate or delay aging.

immunology↗

bioRxiv2024

Tumoroid-on-a-Plate (ToP): Physiologically Relevant Cancer Model Generation and Therapeutic Screening

Employing three-dimensional (3D) in vitro models, including tumor organoids and spheroids, stands pivotal in enhancing cancer therapy. These models bridge the gap between 2D cell cultures and complex in vivo environments, effectively mimicking the intricate cellular interplay and microenvironmental factors found in solid tumors. Consequently, they offer versatile tools for comprehensive studies into cancer progression, drug responses, and tailored therapies. In this study, we present a novel open-surface microfluidic-integrated platform called the Tumoroid-on-a-Plate (ToP) device, designed for generating intricate predictive 3D solid tumor models. By incorporating a tumor mass, stromal cells, and extracellular matrix components, we successfully replicate the complexity of glioblastoma (GBM) and pancreatic adenocarcinoma (PDAC) within our system. Using our advanced ToP model, we were able to successfully screen the effect of various GBM extracellular matrix compositions, such as Collagen and Reelin, on the invasiveness of the GBM cells with the ToP model. The ToP in vitro model also allowed for the screening of chemotherapeutic drugs such as temozolomide and iron-chelators in a single and binary treatment setting on the complex ECM-embedded tumoroids. This helped to investigate the toxic effect of different therapeutics on the viability and apoptosis of our in vitro GBM and PDAC cancer models. Additionally, by co-culturing human-derived fibroblast cells with PDAC tumoroids, the pro-invasive impact of the stromal component of the tumor microenvironment on growth behaviour and drug response of the tumoroids was revealed. This study underscores the transformative role of predictive 3D models in deciphering cancer intricacies and highlights the promise of ToP in advancing therapeutic understanding.

bioengineering↗

bioRxiv2024

Molecular and physiological characterization of brassinosteroid receptor BRI1 mutants in Sorghum bicolor

SUMMARYO_LIThe high sequence and structural similarities between BRI1 brassinosteroid receptors of Arabidopsis (AtBRI1) and sorghum (SbBRI1) prompted us to study the functionally conserved roles of BRI in both organisms. C_LIO_LIIntroducing sorghum SbBRI1 in Arabidopsis bri1 mutants restores defective growth and developmental phenotypes to WT levels. C_LIO_LISorghum mutants for SbBRI1 receptors show defective BR sensitivity and impaired growth and development throughout the entire sorghum life cycle. Embryonic analysis of sorghum primary roots permit to trace back root growth and development to early stages, revealing the functionally conserved roles of SbBRI1 receptor in BR perception during meristem development. RNA-seq analysis uncovers the downstream regulation of the SbBRI1 pathway in cell wall biogenesis during cell growth. C_LIO_LITogether, these results uncover that sorghum SbBRI1 receptor protein play functionally conserved roles in plant growth and development, while encourage the study of BR pathways in sorghum and its implications for improving resilience in cereal crops. C_LI

plant biology↗

bioRxiv2024

Marmosets as model systems for the study of Alzheimers disease and related dementias: substantiation of physiological Tau 3R and 4R isoform expression and phosphorylation

INTRODUCTIONMarmosets have been shown to spontaneously develop pathological hallmarks of Alzheimers disease (AD) during advanced age, including amyloid-beta plaques, positioning them as a model system to overcome the rodent-to-human translational gap for AD. However, Tau expression in the marmoset brain has been understudied. METHODSTo comprehensively investigate Tau isoform expression in marmosets, brain tissue from eight unrelated marmosets across various ages was evaluated and compared to human postmortem AD tissue. Microtubule-associated protein tau (MAPT) mRNA expression and splicing were confirmed by RT-PCR. Tau isoforms in the marmoset brain were examined by western blot, mass spectrometry, immunofluorescence, and immunohistochemical staining. Synaptic Tau expression was analyzed from crude synaptosome extractions. RESULTS3R and 4R Tau isoforms are expressed in marmoset brains at both transcript and protein levels across ages. Results from western blot analysis were confirmed by mass spectrometry, which revealed that Tau peptides in marmoset corresponded to the 3R and 4R peptides in the human AD brain. 3R Tau was primarily enriched in neonate brains, and 4R enhanced in adult and aged brains. Tau was widely distributed in neurons with localization in the soma and synaptic regions. Phosphorylation residues were observed on Thr-181, Thr-217, and Thr-231, Ser202/Thr205, Ser396/Ser404. Paired helical filament (PHF)-like aggregates were also detected in aged marmosets. DISCUSSIONOur results confirm the expression of both 3R and 4R Tau isoforms and important phosphorylation residues in the marmoset brain. These data emphasize the significance of marmosets with natural expression of AD-related hallmarks as important translational models for the study of AD.

systems biology↗

bioRxiv2024

A high-throughput screening platform for discovering bacterial species and small molecules that modify animal physiology

Canonical polyamines such as agmatine, putrescine, and spermidine are evolutionarily conserved metabolites found in nearly all forms of life ranging from bacteria to humans. Recently, interactions between polyamines produced by gut bacteria and human intestinal cells have been proposed to contribute to both Irritable Bowel Syndrome with Diarrhea (IBS-D) and inflammatory bowel diseases. However, the molecular mechanisms that underlie these effects are often unclear due in part to limitations in the methods used to manipulate and study polyamine functions in vivo. Here, we developed a Caenorhabditis elegans based screening platform and a modified LC-MS approach for profiling polyamine metabolites. We combined these methods to make the unexpected discovery that dysfunctional polyamine metabolism in both Gram-negative (E. coli) and Gram-positive (B. subtilis) bacteria can result in the accumulation of a noncanonical polyamine intermediate, N1-Aminopropylagmatine (N1-APA). We further find that N1-APA is produced via spermidine synthase (SpeE) and that it is bioactive when encountered by animals. Specifically, we find that when N1-APA is produced by bacteria in animal intestines it can be transported into intestinal cells via the polyamine transporter CATP-5 where it antagonizes both animal development and mitochondrial function across diverse animal species. Lastly, we find that N1-APA functions analogously to the deoxyhypusine synthase inhibitor GC7. For example, like GC7, N1-APA antagonizes eIF5A hypusination and inhibits the alternative activation of mammalian macrophages. To our knowledge, these findings are the first to demonstrate that N1-APA is a bioactive metabolite and that bacteria can produce a small molecule that functions similarly to existing deoxyhypusine synthase inhibitors. Furthermore, these results suggest an exciting new mechanistic hypothesis for why the loss of speB in gut microbes, including E. coli, has been both linked to inflammatory bowel disease (IBD) in humans and found to drive IBD in germ free mice.

genetics↗

bioRxiv2024

Deciphering the Biochemical and Physiological Mechanisms of Mycobacterium Tuberculosis β-Carbonic Anhydrase 3 and Its Modulators through Mechanistic QSAR Model and Integrated Systems Biology Approaches

Withdrawal StatementThe authors have withdrawn their manuscript owing to the inability to complete the revisions or follow up on the manuscript at this time, due to personal circumstances. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

bioinformatics↗

bioRxiv2024

Physiological modeling and biomechanical insights of cytokine modulation in COVID-19 and pulmonary fibrosis through graph-based approach

bioinformatics↗