Biology subjects

Kikuchi, Y.

Publications and source records attributed to Kikuchi, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

A Proof-of-Concept Study on Attached Spirulina Cultivation Under Microgravity and Partial Gravity Aboard the ISS

Microalgal attached cultivation circumvents gas-liquid separation issues of liquid-suspended cultivation, yet performance under reduced gravity remains unevaluated. As a proof-of-concept, we evaluated Arthrospira platensis (Spirulina) cultivation under artificial 1G, 1/6G, and microgravity ({micro}G) on the International Space Station. Spirulina expanded without cell detachment, medium floating, or component separation, with relative radial growth rates of 0.28%0.5 day-1 (1G), 0.22%0.5 day-1 (1/6G), and 0.17-0.21%0.5 day-1 ({micro}G), demonstrating feasibility in space.

bioengineering↗

bioRxiv2026

Ordinal position in auditory sequences is encoded in population dynamics in macaque frontal cortex

The ability to extract structure from sensory sequences requires tracking not only stimulus identity but also ordinal position within a sequence. How and where ordinal information is represented in the primate brain remains unclear. Here, we recorded activity in populations of single neurons simultaneously from auditory cortex and ventrolateral prefrontal cortex in macaques passively listening to structured auditory sequences. Population-level analyses revealed that frontal cortex activity evolved progressively across the sequence, occupying distinct regions of neural state space for successive ordinal positions. In contrast, auditory cortex population activity reset with each element, producing stereotyped, stimulus-locked trajectories. Consistent with this dissociation, frontal cortex populations robustly decoded ordinal position independently of stimulus identity, whereas auditory cortex showed weak positional decoding despite strong identity representations. Frontal neurons further exhibited longer intrinsic timescales and reduced synchronization to element presentation, supporting integration of information across multiple elements. Together, these findings identify frontal activity as a key substrate for ordinal position encoding during auditory sequence processing, while auditory cortex primarily supports element-specific sensory representations.

neuroscience↗

bioRxiv2026

Cancer-associated nucleolar morphological changes coincide with altered subcompartment organization and accelerated nascent rRNA trafficking in breast cancer cells

Nucleolar alterations are characteristic features of cancer cells; however, how changes in the overall morphology relate to internal subcompartment organization and ribosomal RNA (rRNA) dynamics remains unclear. In this study, the nucleolar organization of non-transformed MCF-10A mammary epithelial cells and MDA-MB-231 breast cancer cells was quantitatively compared. MDA-MB-231 cells exhibited differences in nucleolar morphology, accompanied by altered spatial organization of the dense fibrillar component and granular component, and accelerated intranucleolar trafficking of nascent rRNA. Pharmacological perturbation with SU056 shifted multiple structural and dynamic parameters toward an MCF-10A-like profile. Conversely, transient physicochemical perturbation with 1,6-hexanediol induced several MDA-MB-231-like nucleolar features in MCF-10A cells, which returned to their untreated profile after washout. These findings support the view that cancer-associated nucleolar alterations are an integrated reorganization across morphological, spatial, and dynamic dimensions. The observed reversibility further indicates that cancer-associated nucleolar organization can be remodeled in response to perturbations. By linking the morphology, subcompartment organization, and nascent rRNA dynamics within a common framework, this study provides a basis for exploring the establishment, maintenance, and remodeling of distinct nucleolar profiles in cancer.

cancer biology↗

bioRxiv2026

PLCXD2 preferentially hydrolyzes phosphatidylinositol and supports retinal lipid homeostasis and photoreceptor integrity

PLCXD proteins have been linked to phosphoinositide metabolism for more than a decade, and PLCXD2 activity has been associated with phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] depletion, yet its preferred direct substrate has remained unresolved. Here, cellular lipidomics showed that catalytically active PLCXD2 reduced the major phosphatidylinositol (PI) 38:4 species, with more modest phosphoinositide changes and increased diacylglycerol (DAG) and phosphatidic acid (PA). Using recombinant PLCXD2 and acyl-chain-matched substrates, we found that PLCXD2 hydrolyzed PI substantially more efficiently than PI(4,5)P2 and most other phosphoinositides tested. In Plcxd2-deficient retina, PI abundance was preserved, whereas DAG and PA were reduced without broad changes in major membrane phospholipid classes. PLCXD2 loss was associated with early structural abnormalities at the photoreceptor-bipolar synaptic interface, followed by outer nuclear layer thinning and reduced electroretinographic a-wave responses. These findings identify PLCXD2 as a PI-preferring mammalian PLC and reveal an endogenous role in retinal lipid homeostasis and outer retinal integrity.

biochemistry↗

bioRxiv2026

Characterizing in vivo degradation of electrospun biodegradable nanofibers by size-exclusion chromatography

Biodegradable electrospun nanofiber (NF) scaffolds have emerged as promising materials for tissue engineering applications, including vascular grafts, because their mechanical properties and degradability can be tuned. However, their in vivo degradation behavior remains poorly understood. In this study, we characterized the in vivo degradation profiles of representative biodegradable NF materials widely used in small-caliber vascular graft research, namely polycaprolactone (PCL), poly(D,L-lactide) (PLA), polyglycolic acid (PGA), and a PCL/PLA blend, by monitoring molecular weight changes in subcutaneous and vascular environments. Electrospun NF sheets were implanted subcutaneously in mice, and tubular NF grafts were implanted into the abdominal aorta of rats. Samples were harvested for up to 48 weeks after implantation and analyzed primarily by size-exclusion chromatography (SEC) to assess time-dependent changes in molecular weight. Scanning electron microscopy (SEM) and solid-state 13C nuclear magnetic resonance (NMR) were additionally performed to evaluate ultrastructural and chemical changes associated with degradation. SEC analysis revealed distinct material-specific degradation patterns. PCL showed the slowest degradation and retained a relatively high weight-average molecular weight (Mw) in both environments. PLA exhibited marked environment dependence, with near-complete degradation in the subcutaneous environment by 48 weeks, whereas scaffold structure was maintained in the vascular environment. The PCL/PLA blend showed earlier reduction in the high-molecular-weight fraction than PCL, indicating faster scaffold breakdown. PGA degraded most rapidly and could not be evaluated beyond 2 weeks in the subcutaneous model or in the vascular model because of early graft rupture. SEM analysis further demonstrated that progressive loss of fibrous ultrastructure over time was a common feature across all materials. In addition, NF scaffolds became resistant to organic solvent after implantation in vivo, and solid-state 13C NMR analysis of the solvent-insoluble fractions detected polymer-derived signals together with additional signals consistent with biological constituents. These findings indicate that in vivo degradation of biodegradable NF scaffolds is material dependent, environment dependent, and more complex than simple hydrolytic chain cleavage alone. This study provides a quantitative framework for evaluating NF degradability and offers new insight into the design of biodegradable vascular grafts. HighlightsO_LISEC quantified long-term in vivo degradation of PCL, PLA, PGA, and PCL/PLA. C_LIO_LIDegradation was both material dependent and implantation environment dependent. C_LIO_LIIn vivo nanofiber degradation involved structural and chemical changes beyond hydrolysis. C_LI

bioengineering↗

bioRxiv2025

Horizontal acquisition of nicotine catabolism gene cluster drives the assembly of tobacco root microbiota community

BackgroundPlant roots are hotspots for interactions with soil microbes, where a characteristic bacterial community structure is formed. Plant specialized metabolites often play pivotal roles in this assembly process. However, the molecular basis underlying root microbiota responses to these bioactive compounds, and how such metabolic interactions shape the assembly of host-specific root microbiota, remain largely unknown. Nicotine is a toxic alkaloid predominantly produced by the genus Nicotiana, and the genus Arthrobacter is known as one of the nicotine-degrading bacteria in the tobacco root microbiota. In this study, we used the tobacco-Arthrobacter interaction system as a model and integrated comparative genomics and experimental genetic manipulation assays to uncover the role of bacterial catabolism capacity for host specialized metabolites in shaping host-specific root microbiota. ResultsNicotine catabolism genes are uniquely found in the Arthrobacter strains derived from nicotine-containing environments, and this restricted gene distribution is driven by a plasmid-mediated horizontal gene transfer. To assess the ecological consequences of this genomic adaptation in Arthrobacter fitness in tobacco roots, we conducted adaptation assays under both in vitro and in planta conditions using genetically manipulated Arthrobacter and tobacco mutants, which are impaired in nicotine catabolism and biosynthesis, respectively. Nicotine improves Arthrobacter colonization to the tobacco roots through both catabolism-dependent and catabolism-independent mechanisms. Bacterial community analysis using a synthetic community approach further demonstrated that these metabolic interactions, mediated by tobacco nicotine biosynthesis and its catabolism by Arthrobacter, jointly affect root microbiota composition. ConclusionsOur findings illustrated that bacterial catabolic capacity toward host-derived plant specialized metabolites is key for successful root colonization. This metabolic adaptation is driven by plasmid-mediated horizontal gene transfer and ultimately shapes the structure of the overall root microbiota community.

microbiology↗

bioRxiv2025

Transcranial ultrasound stimulation selectively enhances fronto-temporal context-guided memory

There is substantial scientific interest in advancing knowledge on the control mechanisms supporting adaptive memory and improving approaches that can enhance cognition through brain stimulation. We implemented a non-invasive focal Transcranial Ultrasound Stimulation (TUS) approach with known longer-lasting post-stimulation effects in two rhesus macaques performing a novel context-dependent memory-sequencing task implemented on multiple touchscreens within their home units. Consistently in both monkeys, TUS to the anterior, but not posterior, medial temporal lobe enhanced performance under stable memory-sequencing contexts. TUS to the medial prefrontal cortex, on the other hand, selectively improved performance when contexts were unstable and the monkey needed to adapt to both a change in context and temporal sequence. These findings provide positive causal evidence of a functional dissociation within fronto-temporal memory circuits and pave the way for advancing non-invasive approaches to improve cognitive function and the study of neural circuits under focal enhancement across species. IMPACT STATEMENTTranscranial ultrasound stimulation of the prefrontal-hippocampal network selectively enhances context-guided memory in macaques, demonstrating that non-invasive brain stimulation can causally improve, rather than only disrupt, memory circuits.

neuroscience↗

bioRxiv2025

Soil pH as an external filter shaping insect-microbe gut symbiosis

BackgroundMany animals and plants establish intimate symbiotic relationships with specific microorganisms acquired from the environment. Given the immense diversity of environmental microbiomes, selecting appropriate partners from such a vast microbial pool poses a critical challenge for host organisms. To meet this challenge, hosts have evolved sophisticated internal partner-choice mechanisms that ensure stable associations with beneficial microbes. However, because these symbionts primarily inhabit external environments, environmental conditions themselves are also expected to play pivotal roles in the establishment of symbiosis. Despite this expectation, the mechanistic role of external environmental filters in shaping the intended symbiosis remains largely unexplored. Focusing on stink bugs, which acquire their symbiotic bacteria from soil each generation, we investigated how soil properties influence the establishment of gut symbiosis in terrestrial insects. ResultsMicrobiome analyses confirmed that Burkholderia sensu lato overwhelmingly dominates a specific gut organ in six stink bug species from the superfamilies Coreoidea and Lygaeoidea, including serious agricultural pests (relative abundance ranging from 74.5% to 100%). Rearing experiments with isolated Burkholderia revealed that insects were strictly dependent on this symbiont; failure to acquire it from soil severely reduced host growth and reproduction, indicating that the availability of symbionts from soil represents an ecological bottleneck. Field surveys identified patches of exceptionally high stink bug density in weedy fields with soil pH <7.0, whereas such aggregations were absent in fields with pH [≥]7.0. Laboratory experiments with collected field soils showed that the abundance of Burkholderia in soils was negatively correlated with soil pH, and stink bugs readily acquired their symbionts from soils with pH <7.0 but rarely from soils with pH [≥]7.0. Experimental manipulations of soil pH followed by rearing experiments confirmed that increasing soil pH to 7-8 markedly suppressed symbiont acquisition by the host, likely by impairing symbiont growth and motility. ConclusionsWe demonstrate that, beyond host-intrinsic mechanisms, a soil chemical property externally filters symbiotic bacteria prior to colonization inside the host. These findings reveal that, alongside host physiology, environmental conditions--mediated through the soil and host gut microbiomes--shape the assembly, maintenance, and evolution of host-microbe symbiotic associations.

microbiology↗

bioRxiv2025

Human Interleukin-4-Dependent Facilitation of Human IgG Production in PBL-NOG-hIL-4-Tg mice

Immune-humanized mice provide valuable experimental models for evaluating immune-based therapies, yet the induction of human antigen-specific IgG production remains limited due to species-specific incompatibilities. Our previous work demonstrated that NOG-hIL-4-Tg mice, which express human interleukin-4 (IL-4), support human T and B cell maintenance and enable antigen-specific IgG production following transplantation of human peripheral blood mononuclear cells (PBMCs). In this study, we investigated how IL-4 enhances antibody responses in this model. Flow cytometry and histological analysis revealed that human B cell maintenance was associated with specific plasma hIL-4 concentration ranges at supraphysiological levels. T and B cell receptor repertoire analysis using next-generation sequencing showed that clonal diversity remained largely conserved for one month and decreased to three months post-engraftment. Immunoglobulin repertoire profiling confirmed IgG class switching in an IL-4-concentration-dependent manner. Among the IgG subclasses, IgG3 increased during the first and second months and then decreased thereafter. In contrast, IgG1 tended to increase over time; however, the proportion of IgG subclass varied among individual donors. Following immunization with two distinct peptide antigens, the mice produced enhanced levels of antigen-reactive IgG. However, many B cell clones also exhibited weak responses to unrelated third-party antigens, likely reflecting insufficient affinity maturation. Histological evaluation showed tertiary lymphoid structure (TLS)-like accumulations of B and T cells in the spleen, although fully developed germinal centers were absent. Taken together, these findings demonstrate that NOG-hIL-4-Tg mice maintain human B cells within a regulated IL-4 environment, promote early formation of splenic tertiary lymphoid structures, and support IgG production characterized by clonal expansion, class switching, and somatic hypermutation. These results confirm that human IL-4 expression supports human antibody responses in the PBL-NOG-hIL-4-Tg mouse system. (278)

immunology↗

bioRxiv2025

Evolution in spatiotemporal infection patterns of Burkholderia sensu lato lineages in the gut of Riptortus pedestris

Many plants and animals form specific symbioses with microorganisms, relying on bidirectional interactions between hosts and bacteria. However, the knowledge about the evolution of symbiont traits enabling such specificity remains very limited. The bean bug Riptortus pedestris acquires Caballeronia from environmental soil and harbors it in its gut symbiotic organ. This bug-Caballeronia symbiosis is an ideal model to clarify the evolutionary process of symbiotic bacteria because members of their outgroups, such as Paraburkholderia and Pandoraea, can also colonize the host symbiotic organ but are outcompeted when co-inoculated with the native symbiont, Caballeronia. In this study, mechanisms underpinning the competitiveness of Caballeronia inside the insect gut were investigated. First, comparative microscopy revealed that Caballeronias success in the gut is largely attributed to its ability to migrate rapidly to the M4 region through chemotaxis, wherein a cheA insertion mutant showed significantly delayed infection speed and lower competitiveness against wild-type. In addition, Paraburkholderia and Pandoraea frequently formed biofilm-like aggregates in the midgut, which could delay their colonization. By contrast, Caballeronia formed no biofilm-like aggregates, at least inside the insect gut. This study reveals that Caballeronia symbiont has evolved traits like chemotaxis and reaction against AMP to establish an efficient and exclusive symbiotic relationship with their bean bug host. Although the genetic and molecular bases of the chemotaxis and the cell aggregates remain unclear, it is strongly suggested that the dynamic gain and loss of these traits enables Caballeronia to specifically associate with the insect host, R. pedestris. ImportanceRiptortus pedestris, a major soybean pest in East Asia, acquires symbiotic bacteria from the environment every generation, yet its gut is consistently and specifically colonized by Caballeronia species. The evolutionary traits that underlie this strong symbiotic specificity remain poorly understood. Here, we demonstrate that Caballeronia insecticola has acquired two key traits: positive chemotaxis toward the symbiotic organ and tolerance to host-derived antimicrobial peptides (AMPs). Using comparative colonization assays with wild-type, chemotaxis-deficient mutants, a non-symbiotic sister group, and their common ancestor, we show that these adaptations enable Caballeronia to outcompete other bacteria within the host gut. Our findings provide direct evidence that specific ecological and behavioral traits contribute to the establishment of exclusive symbiotic associations, shedding light on how symbiotic specificity can evolve even in horizontally transmitted systems. This work offers novel insights into the evolutionary dynamics of host-microbe interactions.

microbiology↗

bioRxiv2025

Inverse modeling unveils governing law of mechano-chemical dynamics of epithelial migration

Collective cell migration is fundamental to tissue homeostasis and underlies biological processes such as wound healing and cancer invasion. Previous work has proposed governing equations to describe how chemical and mechanical inputs regulate these movements, but the quantitative validity of such models remains to be thoroughly assessed. Here, we developed a machine-learning framework that infers the governing equation from live-cell imaging data. Applied to epithelial sheet migration driven by MAPK/ERK, our approach quantitatively predicted single-cell movement from local chemical and mechanical cues. Examination of the learned equations further indicated that cells process environmental signals by computing their spatiotemporal derivatives. Moreover, when applied to individual cells, our framework revealed cell-cell heterogeneity in the underlying migratory rules. Our framework offers a powerful tool for predictive modeling of multicellular dynamics in both physiological and pathological settings.

systems biology↗

bioRxiv2025

Bacteria break through one-micrometer-square passages by flagellar wrapping

Confined spaces are omnipresent in the micro-environments, including soil aggregates and intestinal crypts, yet little is known about how bacteria behave under such conditions where movement is challenging due to limited diffusion. Stinkbug symbiont Caballeronia insecticola navigates a narrow gut passage about one micrometer in diameter to reach the stinkbugs symbiotic organ. Here, we developed a microfluidic device mimicking the hosts sorting organ, wherein bacterial cells are confined in a quasi-one-dimensional fashion, and revealed that this bacterium wraps flagellar filaments around its cell body like a screw thread to control fluid flow and generate propulsion for smooth and directional movement in narrow passages. Physical simulations and genetic experiments revealed that hook flexibility is essential for this wrapping; increasing hook rigidity impaired both wrapping motility and infectivity. Thus, flagellar wrapping likely represents an evolutionary innovation, enabling bacteria to break through confined environments using their motility machinery.

microbiology↗

bioRxiv2024

Harnessing the Biosynthetic Diversity of Actinomycetes: Discovery of Unique Natural Products through Comparative Genomic and Metabolic Analysis

Actinomycetes, rich in biosynthetic gene clusters (BGCs), are important sources of natural products (NPs). However, the rate of discovering novel NPs from actinomycetes has declined, indicating the need for a new strategy to obtain NPs. Herein, we present a strategy for the efficient discovery of novel NPs. First, we performed a comprehensive analysis of BGCs in actinomycetes, evaluating the average number and types of BGCs per genus to identify prolific NP producers. Our analysis revealed that certain actinomycetes strains, such as those in the family Pseudonocardiaceae, possess a greater number of BGCs than Streptomyces. In addition, these strains tend to possess strain-specific BGCs compared with others. To facilitate the identification of strain-specific compounds, we developed a comparative metabolic analysis method using molecular networking. Applying this method to eight Pseudonocardiaceae strains, we successfully discovered two novel peptides, lentindoles A (1) and B (2), featuring a 6/5/6 and 6/5/5 tricyclic ring system, respectively, along with their possible biosynthetic precursor, lentindole C (3). Our result demonstrates that the effectiveness of our developed strategy, which is expected to accelerate the discovery of novel NPs.

microbiology↗

bioRxiv2024

Wild gut microbiome suppresses the opportunistic pathogen Aeromonas in medaka under domesticated rearing conditions

BackgroundThe gut microbiome plays a crucial role in the metabolic health and pathogen resistance of various host animals. It is also well established that external environmental factors can influence the gut microbiome, leading to differences in its composition. However, the functional implications of these differences remain poorly understood. This study examined the gut microbiome of medaka (Oryzias latipes species complex) by comparing domesticated and wild populations, with the aim of gaining insights into the functional significance of their specific characteristics, particularly those of the wild-type microbiome. ResultsFor the comparative analysis of the gut microbiome, 48 domesticated and 122 wild medaka were collected from multiple laboratories, pet stores and streams across Japan. The results showed that wild medaka exhibited significantly higher gut microbiome diversity, with a broader range of bacterial members. In contrast, the gut microbiome of domesticated medaka harbored lower microbial diversity and was consistently dominated by Aeromonas, a typical opportunistic pathogen in fish. Additionally, 88.6% of Aeromonas isolates from domesticated medaka exhibited haemolytic activity. Moreover, a domesticated rearing experiment with wild populations showed no proliferation or dominance of Aeromonas in their gut, as observed in domesticated medaka. A further rearing experiment revealed that pre-exposing antibiotic-treated medaka to sediments from their natural habitats prevented Aeromonas colonisation, even when reared under domesticated conditions. ConclusionsThese findings suggest that the habitat-derived wild gut microbiome can inhibit Aeromonas proliferation in domesticated fish, highlighting its potential to mitigate opportunistic diseases in aquaculture.

microbiology↗

bioRxiv2024

Identification of anisotropy in chromosome dynamics by principal component analysis using integrated spatial genomics

Eukaryotic interphase chromosomes maintain a three-dimensional structure within the nucleus and undergo fluctuations. It has been reported that such dynamics are involved in transcription, replication, and DNA repair. However, the analysis of chromosomal dynamics has been limited to high-throughput chromosome conformation capture data, which records the contact frequencies between chromosomal regions and lack direct information about the dynamic. Herein, we investigated chromosome fluctuations as polymers based on experimental data from sequential fluorescence in situ hybridization (seqFISH)+ using a multiomics methodology. To describe the principal modes of chromosome fluctuations, we applied principal component analysis to the three-dimensional structure information of single chromosomes in 446 mouse embryonic stem cells (mESCs) obtained from seqFISH+ data analysis for spatial genomics and signals of nuclear factors (SNFs: histone marks, repeat DNAs, and nuclear compartments). We found that chromosome fluctuations exhibit both isotropic and anisotropic modes. The properties of anisotropy in chromosome fluctuation vary among chromosomes and appear to depend on the interaction between repeat DNAs on the chromosomes and nuclear compartments. Furthermore, our principal component analysis revealed anisotropic chromosome fluctuations before and after the mitotic phase, specifically when chromosomes adopt a spindle-like shape. This result suggests the potential involvement of anisotropic chromosomal fluctuations in the transition of nuclear organization during the cell cycle. Our results represent the first study to elucidate the dynamics of chromosomes as polymers based on real multiomics data.

bioinformatics↗

bioRxiv2023

Evolutionary constraint genes implicated in autism spectrum disorder across 2,054 nonhuman primate genomes

BackgroundSignificant progress has been made in elucidating the genetic underpinning of Autism Spectrum Disorder (ASD). This childhood-onset chronic disorder of cognition, communication and behaviour ranks among the most severe from a public health perspective, and it is therefore hoped that new discoveries will lead to better therapeutic options. However, there are still significant gaps in our understanding of the link between genomics, neurobiology and clinical phenotype in scientific discovery. New models are therefore needed to address these gaps. Rhesus macaques (Macaca mulatta) have been extensively used for preclinical neurobiological research because of remarkable similarities to humans across biology and behaviour that cannot be captured by other experimental animals. MethodsWe used the macaque Genotype and Phenotype (mGAP) resource (v2.0) consisting of 2,054 macaque genomes to examine patterns of evolutionary constraint in known human neurodevelopmental genes. Residual variation intolerance scores (RVIS) were calculated for all annotated autosomal genes (N = 18,168) and Gene Set Enrichment Analysis (GSEA) was used to examine patterns of constraint across ASD genes and related neurodevelopmental genes. ResultsWe demonstrated that patterns of constraint across autosomal genes are correlated in humans and macaques, and that ASD-implicated genes exhibit significant constraint in macaques (p = 9.4 x 10-27). Among macaques, many key ASD genes were observed to harbour predicted damaging mutations. A small number of key ASD genes that are highly intolerant to mutation in humans, however, showed no evidence of similar intolerance in macaques (CACNA1D, CNTNAP2, MBD5, AUTS2 and NRXN1). Constraint was also observed across genes implicated in intellectual disability (p = 1.1 x 10-46), epilepsy (p = 2.1 x 10-33) and schizophrenia (p = 4.2 x 10-45), and for an overlapping neurodevelopmental gene set (p = 4.0 x 10-10) LimitationsThe lack of behavioural phenotypes among the macaques whose genotypes were studied means that we are unable to further investigate whether genetic variants have similar phenotypic consequences among nonhuman primates. ConclusionThe presence of pathological mutations in ASD genes among macaques, and the evidence of similar constraints in these genes to humans, provide a strong rationale for further investigation of genotype-phenotype relationships in nonhuman primates. This highlights the importance of identifying phenotypic behaviours associated with clinical symptoms, elucidating the neurobiological underpinnings of ASD, and developing primate models for translational research to advance approaches for precision medicine and therapeutic interventions.

genetics↗

bioRxiv2023

Hundreds of antimicrobial peptides create a selective barrier for insect gut symbionts

The spatial organization of gut microbiota is crucial for the functioning of the gut ecosystem, although the mechanisms that organize gut bacterial communities in microhabitats are only partially understood. The gut of the insect Riptortus pedestris has a characteristic microbiota biogeography with a multispecies community in the anterior midgut and a mono-specific bacterial population in the posterior midgut. We show that the posterior midgut region produces massively hundreds of specific antimicrobial peptides (AMPs), the Crypt-specific Cysteine-Rich peptides (CCRs) that have membrane-damaging antimicrobial activity against diverse bacteria but posterior midgut symbionts have elevated resistance. We determined by transposon-sequencing the genetic repertoire in the symbiont Caballeronia insecticola to manage CCR stress, identifying different independent pathways, including novel AMP-resistance pathways unrelated to known membrane homeostasis functions as well as cell envelope functions. Mutants in the corresponding genes have reduced capacity to colonize the posterior midgut, demonstrating that CCRs create a selective barrier and resistance is crucial in gut symbionts. Moreover, once established in the gut, the bacteria differentiate into a CCR-sensitive state, suggesting a second function of the CCR peptide arsenal in protecting the gut epithelia or mediating metabolic exchanges between the host and the gut symbionts. Our study highlights the evolution of an extreme diverse AMP family that contributes to establish and control the gut microbiota.

microbiology↗

bioRxiv2023

Activity-induced gene expression in the human brain

Direct electrical stimulation (eSTIM) is widely used clinically, from neurosurgical mapping to therapeutic interventions for neurological and neuropsychiatric disorders1-10. Despite over a century of application, its molecular and cellular underpinnings remain unknown. Here, using state-of-the-art single-nuclei multiomic profiling, we map changes in cell-type-specific gene expression and chromatin accessibility in vivo in the human cortex following eSTIM of neurosurgery patients. eSTIM impacts a network of cells that extends beyond excitatory neurons to include inhibitory neurons, astrocytes, oligodendrocytes and microglia. We observed an upregulation of canonical immediate-early genes (IEGs: FOS, NPAS4, EGR4) in excitatory and inhibitory neurons and induction of cytokine-related genes CCL3 and CCL4 in microglia. The cross-species conservation of this gene signature, together with our examination of a cohort of both epilepsy and cancer patients, underscores the fundamental role of these changes in stimulation-driven plasticity while controlling for disease and environmental confounds. Our study of changes in chromatin accessibility reveals a common code that involves a cell-type specific signature of transcription factor binding motifs for members of the EGR family. By addressing these previously unexplored questions about activity-induced gene expression in vivo in the human brain, our findings challenge the long-standing neuron-centric view of eSTIM, highlighting the broader role of non-neuronal cells, including microglia, in mediating the impact of brain stimulation.

neuroscience↗