Biology subjects

Suzuki, T.

Publications and source records attributed to Suzuki, T..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Reduced cortico-accumbal excitatory input due to Nav1.2 haploinsufficiency impairs sociability independently of dopamine

Mutations in SCN2A, which encodes the voltage-gated sodium channel Nav1.2, are associated with a wide spectrum of neurodevelopmental and neuropsychiatric disorders, including epilepsy, autism spectrum disorder (ASD), and schizophrenia. Although dysfunction of SCN2A-dependent neural circuits has been implicated in these disorders, the circuit mechanisms underlying social behavioral abnormalities remain poorly understood. Here, we investigated the neural circuit basis of social behavioral deficits associated with Scn2a dysfunction, focusing on the nucleus accumbens (NAc), a key hub in cortico-limbic circuits that regulates emotional and motivational behaviors. Using conditional genetic and chemogenetic approaches in mice, we examined the roles of dorsal telencephalic excitatory neurons, including those in the cerebral cortex, hippocampus, and amygdala, as well as parvalbumin-positive fast-spiking interneurons (PV FSIs) in the NAc. Mice with Scn2a haploinsufficiency in dorsal telencephalic excitatory neurons (Scn2afl/+/Emx1-Cre) exhibited reduced sociability in the three-chamber social interaction test. Similarly, chemogenetic inhibition of NAc PV FSIs decreased sociability without affecting locomotor activity or anxiety-like behavior. Scn2afl/+/Emx1-Cre mice also showed a trend toward reduced prepulse inhibition of the acoustic startle response. Notably, dopamine release into the NAc in the Scn2afl/+/Emx1-Cre and systemic Scn2a heterozygous knockout (Scn2a+/-) mice was largely comparable to that in control mice. Together, these findings indicate that reduced activity of dorsal telencephalic excitatory neurons or NAc PV FSIs is sufficient to impair sociability independently of mesolimbic dopamine hypofunction. Our results highlight a potential role of cortico-accumbal circuits in social behavioral deficits associated with SCN2A dysfunction.

neuroscience↗

bioRxiv2026

Autopsy-based longitudinal multi-organ high-dimensional profiling reveals lineage plasticity in TRK-inhibitor-resistant secretory breast carcinoma

Secretory breast carcinoma (SBC) is typically indolent, yet mechanisms underlying aggressiveness and therapeutic resistance to tropomyosin receptor kinase inhibitors (TRKi) remain unclear. Autopsy-based longitudinal multi-organ high-dimensional profiling of metastatic TRKi-resistant SBC demonstrated histopathological heterogeneity, including secretory and squamous components, arising from a shared clonal origin. Integrated genomic and transcriptomic analyses revealed hierarchical transcriptional rewiring consistent with a lineage-plastic state, suggesting a potential link to tumor aggressiveness and therapeutic resistance.

pathology↗

bioRxiv2026

Parallel analysis of voltage-gated sodium channel subunits reveals preferential colocalizations of beta-1/Nav1.1 and beta-2/Nav1.2

Voltage-gated sodium channels (VGSCs) are conventionally described as heterotrimers composed of one alpha and two beta subunits. However, the patterns of co-expression of alpha- and beta-subunits in neurons remain unclear. In the present study, we report that alpha- (Nav1.1, Nav1.2, and Nav1.6) and beta- (beta-1 and beta-2) subunits are densely expressed in axon initial segments (AISs) of neurons in the neocortex, hippocampus and cerebellum at postnatal days 14-15 (P14-15) and 8-9 weeks (8-9W). These distributions are largely unique and partially overlapping among brain regions. Notably, in the neocortex and hippocampus, AISs of presumptive parvalbumin-positive inhibitory neurons are positive for Nav1.1 and beta-1, whereas those of excitatory ones are positive for Nav1.2 and beta-2. Similarly, AISs of cerebellar basket cells, which are inhibitory neurons, are positive for Nav1.1 and beta-1, whereas those of granule cells, which are excitatory neurons, are positive for Nav1.2 and beta-2. Nav1.6 is expressed in many of these neurons. Some subunits exhibited distinct distribution patterns at the two postnatal stages analyzed, possibly because of their developmental changes of subcellular localizations. Taken together, these results indicate that combinations of VGSC subunits are largely unique among different neuronal subpopulations. These findings provide a useful reference for understanding the distribution and interactions of VGSC subunits in the brain.

neuroscience↗

bioRxiv2026

Reduced activity of nucleus accumbens parvalbumin-expressing fast- spiking inhibitory neurons causes convulsive seizures

Pathogenic mutations in STXBP1, which encodes Munc18-1, a synaptic protein essential for synaptic vesicle exocytosis and neurotransmission, and in SCN2A, which encodes the voltage-gated sodium channel Nav1.2 (II subunit), have been identified in patients with epilepsy. Although haploinsufficiency of either Stxbp1 or Scn2a in cortical excitatory neurons induces epileptic phenotypes in mice and a reduction of cortico-striatal, especially cortico-striatal parvalbumin-expressing fast-spiking interneurons (FSIs), excitatory transmission has been suggested to be the basis, the subcortical circuits remain poorly understood. In this study, we investigated which striatal subregions FSIs are responsible for the epileptic seizures. Using chemogenetic approach, we selectively suppressed FSI activity in either the nucleus accumbens (NAc) or the dorsal striatum (caudate-putamen, CPu) of mice. Suppression of FSIs in the NAc induced outwardly-recognized convulsive seizures accompanied by epileptiform discharges in the electrocorticographic (ECoG) analysis, whereas inhibition of FSIs in the CPu resulted in epileptiform discharges without overt convulsions. Notably, focal suppression of FSIs in either the anterior or medial region of the NAc shell (NAcSh), but not in other NAc subregions, was sufficient to trigger convulsive seizures. These findings identify FSIs in the anteromedial shell of the NAc as a critical hub for convulsive seizure generation and provide new insights into the striatal circuit mechanisms underlying STXBP1- or SCN2A-associated epilepsies.

neuroscience↗

bioRxiv2026

Lactate dehydrogenase is associated with cholesterol/lipid metabolism, and fluvastatin plus dipyridamole suppresses canine hemangiosarcoma growth in patient-derived xenograft models

Tumor cells commonly exhibit aerobic glycolysis and produce lactate despite oxygen availability. Lactate dehydrogenase (LDH) catalyzes pyruvate-lactate interconversion and regulates intracellular lactate levels. Endothelial cells also depend on glycolysis for ATP production, which prompted us to investigate LDH in canine hemangiosarcoma (HSA), a malignant endothelial tumor. We inhibited LDH with (R)-GNE-140 or sodium oxamate in two canine HSA cell lines (HU-HSA-2 and HU-HSA-3) and generated HU-HSA-3 clones with knockout of LDHA or LDHB to evaluate the effects of LDH perturbation. (R)-GNE-140 and sodium oxamate suppressed proliferation and reduced global histone lactylation levels in both cell lines. mRNA-sequencing (mRNA-seq) of (R)-GNE-140-treated HU-HSA-2 cells identified cholesterol/lipid metabolism-related gene sets among the top negatively enriched pathways. Representative cholesterol/lipid metabolism genes responded differently depending on cell lines and inhibitors. (R)-GNE-140 decreased these genes in HU-HSA-2 but not HU-HSA-3, whereas sodium oxamate decreased them in HU-HSA-3 with limited effects in HU-HSA-2. In HU-HSA-3, LDHA and LDHB knockout clones decreased SREBP2 expression and reduced the number of lipid droplets. Fluvastatin, a cholesterol metabolism inhibitor, inhibited HSA cell growth in vitro but did not significantly suppress tumor growth in two HSA patient-derived xenograft (PDX) models. In contrast, combined fluvastatin and dipyridamole treatment inhibited proliferation in vitro and tumor growth in PDX models. Collectively, these results suggest a context-dependent association between LDH and cholesterol/lipid metabolism in canine HSA cell lines and provide a rationale for further evaluation of combined cholesterol pathway inhibition.

cancer biology↗

bioRxiv2026

A macrocyclic peptide-based fusion inhibitor targeting SARS-CoV-2 Spike S2 subunit

Continuous emergence of SARS-CoV-2 variants carrying mutations in Spike presents a significant challenge for durable antiviral agents. Here we screen for random 13-amino acid non-mimetic macrocyclic peptides that bind to Spike and identify PA-001 that inhibits SARS-CoV-2 infection with high potency at 0.23-2.9 nM as 50% inhibitory concentration (IC50). PA-001 bound to Spike S2 subunit and inhibited the membrane fusion during virus entry. Through drug-resistant selection, we revealed that PA-001 targeted the fusion peptide proximal region (FPPR) in S2, which has not been recognized as a drug target to date. Consistent with its highly conserved amino acid sequences beyond strains, PA-001 exhibited broad antiviral activity against all tested SARS-CoV-2 variants, in contrast to clinically-approved S1-targeting antibodies that lost activity to Omicron variants. PA-001 suppressed SARS-CoV-2 propagation and disease progression in mouse- and hamster-infection models, both by administration prophylactically and therapeutically. Combination therapy with remdesivir further enhanced antiviral profiles. In clinical phase-I trial, PA-001 was well-tolerated and showed high systemic exposure, with 4,300-10,300-fold concentration of IC50 as maximum plasma concentration by single administration to healthy volunteers. These evidence propose FPPR as an unexpected antiviral drug target accessible by macrocyclic peptides and identify PA-001 as a potent anti-SARS-CoV-2 fusion inhibitor.

microbiology↗

bioRxiv2026

Lhcf9 is a novel negative regulator of non-photochemical quenching in the diatom Chaetoceros gracilis

Photosynthetic organisms in aquatic environments experience rapid fluctuations in light intensity, light quality, and carbon availability, requiring tight regulation of photosynthetic energy conversion. In marine diatoms, non-photochemical quenching (NPQ), particularly energy-dependent quenching (qE), plays a central role in dissipating excess excitation energy as heat. However, excessive NPQ can reduce photosynthetic efficiency under light-limiting or carbon-rich conditions, and how this trade-off is regulated remains poorly understood. Here, we identify CgLhcf9, a previously uncharacterized light-harvesting complex (LHC) protein, as a negative regulator of qE-type NPQ in the centric diatom Chaetoceros gracilis. Expression of CgLhcf9 is induced under low red-light and high CO2 conditions and strongly suppressed by blue light, indicating regulation by both light quality and carbon availability. Functional analyses using CgLhcf9 knockout and overexpression lines reveal that CgLhcf9 suppresses qE: NPQ induction is enhanced in the absence of CgLhcf9, whereas its accumulation downregulates NPQ without affecting other established qE effectors, including Lhcx1 or xanthophyll cycle pigments. Notably, CgLhcf9 accumulation improves cellular growth under light-limiting conditions. These results identify CgLhcf9 as a novel LHC-type regulator that fine-tunes photosynthetic energy dissipation in response to environmental signals. Our findings establish a regulatory mechanism that balances photoprotection, electron transport, and carbon fixation, advancing our understanding of how marine diatoms optimize photosynthesis under fluctuating light and CO2 conditions. Significance statementPhotosynthetic microalgae must balance light-driven electron transport with carbon fixation to maximize growth under fluctuating light and CO2 conditions. While non-photochemical quenching (NPQ) protects photosystems from excess light, excessive NPQ can limit photosynthetic efficiency when light or carbon is limiting. Here, we identify the antenna protein CgLhcf9 as a negative regulator of energy-dependent NPQ in the marine diatom Chaetoceros gracilis. CgLhcf9 integrates light-quality and CO2 signals to suppress NPQ without altering canonical quenching effectors, thereby improving growth under light-limiting conditions. This study reveals a regulatory role for a light-harvesting complex protein in tuning the balance between photoprotection and photosynthetic efficiency, providing insight into how marine diatoms coordinate electron transport and carbon fixation in dynamic environments.

plant biology↗

bioRxiv2026

Effects of microgravity on the three-dimensional morphology of rhizoids in Physcomitrium patens

Rooting systems of plants perceive environmental stimuli and flexibly regulate their growth. Therefore, understanding stimulus perception and response mechanisms is essential for optimizing cultivation. During the transition from aquatic to terrestrial environments, land plants have acquired mechanisms to adapt to gravitational force on land. Thus, elucidating gravity responses of rhizoids in bryophytes, early diverging land plants, provides important insights into how gravity-response mechanisms were established during land plant evolution. Analyzing rhizoid morphology under microgravity, where gravitational effects are largely eliminated, provides an effective approach to examine the gravity-response mechanisms that evolved after terrestrialization. In this study, to elucidate microgravity effects on rhizoid growth of Physcomitrium patens, we analyzed 3D datasets obtained by refraction-contrast micro-CT using synchrotron radiation after fixation and embedding of samples from the Space Moss experiment conducted on the International Space Station. Because each CT volume contains numerous rhizoids, we optimized a WEKA-based machine-learning segmentation approach by improving preprocessing, training, and postprocessing steps, resulting in a significantly improved segmentation accuracy. Comparison of 3D morphological indices between manually segmented rhizoids and predicted results supported the validity of the proposed method for morphological analysis. Morphological analyses revealed that, compared with both ground and artificial 1 x g conditions, rhizoid elongation and gravitropic responses were suppressed under microgravity, leading to reduced vertical growth. These findings indicate that gravity plays a fundamental role in rhizoid morphogenesis, and their absence affects growth orientation and elongation. This study provides foundational data for research on the rooting systems of bryophytes in space.

plant biology↗

bioRxiv2026

Interferon Beta Drives Therapy Resistance in a Patient Derived Model of High Grade Serous Ovarian Cancer

Cancer cell-autonomous type 1 interferon (IFN-1) production and signaling is frequently activated in response to DNA damage and has been associated with the development of therapy resistance in several cancer types. However, its cell-autonomous role in driving resistance in high-grade serous ovarian cancer (HGSOC), a disease defined by near-universal exposure to genotoxic therapy as frontline treatment, remains unclear. Specifically, whether IFN-1 functions in HGSOC as only a response to genotoxic stress or can independently act in driving resistance phenotypes has not been studied. Utilizing a syngeneic patient-derived model of cisplatin-sensitive (SE) and -resistant (CR) HGSOC, we demonstrate that chronic cisplatin exposure is associated with enrichment of IFN-1 signaling and the interferon-related DNA damage resistance signature (IRDS). Acute cisplatin treatment elicited dynamic, temporal IFN-1 signaling and responses in both sensitive and resistant cells, indicating a conserved stress response in resistant cells. Chronic, low-level exposure to exogenous IFN{beta}, in the absence of a DNA-damaging agent, was sufficient to phenocopy several features of chronic cisplatin driven resistance, including reduced therapeutic sensitivity, cell cycle arrest, and decreased proliferation. Notably, IFN{beta} driven resistance occurred without sustained IRDS or canonical interferon stimulated gene (ISG) induction, revealing alternative mechanisms for IFN-1 mediated therapy resistance. Together, these findings identify IFN{beta} as a functional driver of the development of resistance-associated phenotypes and highlight cell-autonomous IFN-1 signaling as a potential biomarker for resistance and a therapeutic target in platinum-resistant disease.

cancer biology↗

bioRxiv2026

Epigenetic Programming of Macrophage Phenotypes by STING-IRF3 Drives Inflammation in Ascending Thoracic Aortic Dissection

BackgroundAscending thoracic aortic dissection (ATAD) is characterized by extensive macrophage (M{Phi}) accumulation and profound inflammation; however, the mechanisms sustaining pro-inflammatory M{Phi} activation remain incompletely defined. Emerging evidence indicates that epigenetically generated immune memory drives innate immune cells toward persistent inflammatory states. In this study, we investigated whether epigenetic reprogramming governs M{Phi} phenotypic fate and contributes to ATAD pathogenesis. MethodsWe performed single-cell RNA sequencing of human ascending aortic tissues from controls, patients with ascending thoracic aortic aneurysm (ATAA), and patients with acute ascending thoracic aortic dissection (ATAD). We also performed integrated single-cell RNA sequencing, single-cell ATAC sequencing, and spatial transcriptomics in an angiotensin II (Ang II)-infused mouse model. The role of the STING-IRF3 signaling axis in M{Phi} epigenetic programming was examined using M{Phi}-Sting -/- and M{Phi}-Irf3-/- mice. ResultsIn human and mouse aortic tissues, we identified multiple functional M{Phi} populations including pro-inflammatory, phagocytic/anti-inflammatory, proliferative, and reparative/healing M{Phi}s. Aortic M{Phi}s in both sporadic ATAD patients and Ang II-induced ATAD mice exhibited a pronounced pro-inflammatory bias with enhanced differentiation toward pro-inflammatory M{Phi}s and impaired differentiation toward phagocytic/anti-inflammatory states. Pro-inflammatory M{Phi}s were particularly abundant in dissection sites, whereas phagocytic M{Phi}s were enriched in discrete adventitial niches. Origin analyses revealed a substantial increase in CCR2 recruited M{Phi}s within the aortic wall, which preferentially differentiated into pro-inflammatory M{Phi}s. In contrast, LYVE1 resident M{Phi}s-- predominantly biased toward phagocytic phenotypes--were markedly depleted in ATAD. Single-cell ATAC sequencing identified coordinated chromatin remodeling with increased accessibility at pro-inflammatory gene loci and decreased accessibility at phagocytic gene loci. Among candidate transcriptional regulators identified, IRF family TFs, including IRF3 emerged as unique factors capable of simultaneously promoting pro-inflammatory gene programs while suppressing phagocytic gene expression. Mechanistically, STING-IRF3 signaling orchestrates this biased transcriptional state, likely through coordinated BRG1-dependent chromatin opening at pro-inflammatory gene loci and chromatin closing at phagocytic/anti-inflammatory gene loci. M{Phi} specific Sting -/- and Irf3-/- mice exhibited attenuated inflammatory reprogramming and reduced aortic destruction and dissection. ConclusionsThese findings identify STING-IRF3-mediated epigenetic programming of M{Phi}s as a fundamental mechanism driving aortic inflammation and ATAD development. Targeting M{Phi} epigenetic programming may represent a promising therapeutic strategy to prevent aortic dissection. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/701198v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@c97bcdorg.highwire.dtl.DTLVardef@1df0ca8org.highwire.dtl.DTLVardef@b7fd04org.highwire.dtl.DTLVardef@1443e16_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

CaMKIIα holoenzymes self-organize into worm-like mesoscale clusters

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is highly enriched in dendritic spines at concentrations comparable to those of cytoskeletal proteins and plays a central role in synaptic plasticity. During long-term potentiation (LTP), CaMKII further accumulates in spines. However, the mechanisms governing its higher-order organization remain poorly understood. Here, we use high-speed atomic force microscopy to visualize inter-holoenzyme interaction of CaMKII at mesoscopic scales (5-500 nm). Under freely diffusible conditions, CaMKII holoenzymes do not form stable clusters. In contrast, when spatially confined, they assemble into worm-like chain clusters mediated by kinase-domain interactions. These clusters expand upon activation, concomitant with the dissociation of the regulatory segment. Notably, the CaMKII P212L mutant associated with neurodevelopmental disorders, forms extensive clusters even in the basal state. Together, our findings demonstrate that CaMKII-CaMKII interactions drive mesoscale cluster formation and that precise regulation of cluster size and activation-dependent growth might be critical for synaptic signaling.

neuroscience↗

bioRxiv2026

The circadian clock gates lateral root development

Lateral root (LR) formation remodels root architecture, yet how temporal information integrates with hormonal cues remains unclear. We show that the circadian clock component EARLY FLOWERING 3 (ELF3) acts as a temporal gatekeeper of root organogenesis in Arabidopsis thaliana. Time-resolved transcriptomics, imaging, and genetics reveal that ELF3 restrains hormone-induced pericycle proliferation by maintaining rhythmic expression of key regulators under callus-inducing conditions. Loss of ELF3 disrupts rhythmic gene expression, enhancing callus growth and accelerating LR development. ELF3 functions through its target LNK1 to regulate the MADS-box genes AGL14 and AGL20. Notably, callus-inducing signals partially restore rhythmicity in elf3 mutants, revealing feedback from hormonal signaling to the circadian system. These findings identify ELF3 as an integrator of circadian and hormonal inputs that temporally constrains root developmental plasticity.

plant biology↗

bioRxiv2025

Molecular signature of COVID-19 prior to its exacerbation by multi-omics survey

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic due to its high transmissibility and ability to evade innate immune responses. Comprehensive characterization of the disease is essential for elucidating its pathophysiology and clinical progression. In this study, we performed multi-omics analyses of plasma samples collected from SARS-CoV-2-positive patients prior to clinical deterioration of coronavirus disease 2019 (COVID-19). These samples revealed the potential of previously reported clinical parameters, including CRP and neutrophil level, to predict COVID-19 exacerbation in the early stage. Our analysis identified a novel panel of molecules that precede the clinical manifestations associated with COVID-19 progression. These candidate biomarkers exhibited strong correlations with previously reported clinical and immunological parameters. Notably, several inflammation-related markers showed inverse associations with specific interferon subtypes, including IFN-6 and IFN-8, potentially reflecting mechanisms of SARS-CoV-2-mediated immune evasion. Our findings contribute to the understanding of virus-induced acute exacerbation and offer a valuable foundation for future pandemic research.

microbiology↗

bioRxiv2025

A thermodynamic chromatin polymer model characterizes the epigenetic conditions for Hox collinearity.

Hox genes consist of four clusters, A, B, C, and D, each containing up to 13 paralogous genes. They are linearly arrayed on cluster regions in the same order as their expression timings along the anterior-posterior (A-P) axis development. This correspondence is known as temporal collinearity, and when the expression order of Hox genes is disrupted, the A-P axis is not accurately established. Although essential molecules and genomic regulatory elements for Hox collinearity have been identified, it remains unclear whether they act on individual genes or instead coordinate the cluster-wide sequential activation along the genomic order. To address this question, we developed a theoretical framework based on the statistical thermodynamics of chromatin modeled as a polymer, interpreting collinearity as a sequential opening of nucleosomes along the gene cluster. The model incorporates interactions between nucleosomes and DNA-binding factors, including transcription factors, represented by energy terms for binding and chromatin bridging. This formulation links the thermodynamic stability of chromatin states with the sequential opening process along the Hox clusters. Our model characterized key quantities that determine the order of chromatin opening and revealed intrinsic constraints that limit sequential opening of chromatin, underlying Hox collinearity. Significance statementHox collinearity, a remarkable correspondence between the genomic order and expression timing of Hox genes, provides cells with positional information on the anterior-posterior axis during development. Although essential molecules and genomic regulatory elements have been identified, the mechanism of sequential activation along the genomic order remains elusive. To address this question, we theoretically investigated the epigenetic states of chromatin using a chromatin polymer model in statistical thermodynamics. Our model provides a possible explanation for the sequential activation of the chromatin underlying Hox collinearity. This work bridges developmental genetics and statistical thermodynamics, offering a quantitative framework for understanding gene activation order along the genome.

biophysics↗

bioRxiv2025

Adaptation of an herbivorous arthropod to green tea plants by overcoming catechin defenses

Green tea catechins are known antioxidants that benefit human health and protect tea plants from biotic stressors. However, some herbivores can counteract catechin defenses and can use tea plants as a host. Among herbivorous mites, an extreme generalist Tetranychus urticae has not been reported as a tea pest. Instead, T. kanzawai, another generalist, has some populations that thrive on tea plants. Here, we investigated the mechanism of the adaptation of these mites to tea plants. Comparative study of the intra- and inter-specific variations in mite performances uncovered differences in their behavioral and xenobiotic responsiveness to green tea catechins. We showed that green tea catechins exert complex defensive roles. They were repellent and toxic to T. urticae and tea non-adapted T. kanzawai mites. In addition, they had an antifeedant effect on tea non-adapted T. kanzawai mites. Matching the catechin structure, we identified an intradiol ring-cleavage dioxygenase DOG15, a gene horizontally transferred from fungi, as one required for the adaptation of T. kanzawai mites to tea plants. The DOG15 gene has an enhanced inducible expression in tea-adapted T. kanzawai mites, with mRNA and protein levels up to 31.6 and 12.1 times higher than in T. urticae mites fed on tea plants. Furthermore, we identified two amino acid substitutions in DOG15 between Tetranychus species leading to the increased efficacy of the T. kanzawai encoded enzyme toward cleavage of green tea catechins. Thus, we showed that mite adaptation to tea plants occurred in a two-step process. The amino acid substitutions in DOG15 predispose T. kanzawai but not T. urticae for the adaptation to tea plants. Further increased expression of modified DOG15 enables T. kanzawai mites to efficiently detoxify green tea catechins, leading to intra- and inter-specific differences in mites ability to use tea plants as a host. Our findings reveal how a horizontally transferred gene can be co-opted through structural and regulatory changes to overcome plant chemical defenses, with implications for herbivore host adaptation and tea pest management.

evolutionary biology↗

bioRxiv2025

NADPH phosphatase activity of Mesh1 controls sleep in Drosophila

Recent findings have shown that metazoans accumulate the bacterial second messenger guanosine tetraphosphate (ppGpp) and possess Mesh1, a gene encoding a ppGpp hydrolase domain. Mesh1 deficiency affects sleep behavior and eclosion under starvation in Drosopila, and ferroptosis in human cells. However, human Mesh1 also exhibits NADPH/NADP+ phosphatase activity in vitro, making it unclear whether these phenotypes result from loss of ppGpp hydrolysis, NADPH/NADP+ dephosphorylation, or both. To address this, we performed biochemical and genetic analysis of Drosophila Mesh1. We first found that Drosophila Mesh1 dephosphorylates NADPH, but not NADP+, in vitro. We subsequently sought to generate Drosophila Mesh1 point mutants specifically impaired in NADPH phosphatase activity. Based on structural data, we mutated W138 and R142, residues that are predicted to interact with NADPH but not ppGpp. W138 was replaced with phenylalanine results in complete loss of NADPH phosphatase activity with retained ppGpp hydrolase activity. Flies carrying the W138F mutation, introduced via genome editing, exhibited shortened total sleep and increased sleep fragmentation in behavioral assays, without changes in intracellular ppGpp levels. These results indicate that the NADPH phosphatase activity of Mesh1, and specifically the W138 residue, is essential for normal sleep regulation in Drosophila.

molecular biology↗

bioRxiv2025

Gait transition mechanism from quadrupedal to bipedal locomotion in the Japanese macaque based on inverted pendulum

The ability of non-human primates to transition from quadrupedal to bipedal locomotion offers critical insights into both the evolution of human bipedalism and the principles of complex motor control. While quadrupedal and bipedal gaits in non-human primates have been studied, the dynamic mechanisms underlying the transition between these gaits remain poorly understood. Japanese macaques trained to walk bipedally have been reported to utilize inverted pendulum dynamics to achieve efficient bipedal locomotion. Given the intrinsic instability of inverted pendulum systems, which can induce large changes in movement with minimal control input, we hypothesized that this mechanism also contributes to the gait transition. To test this, we developed a neuromusculoskeletal model of the Japanese macaque that integrates a detailed musculoskeletal structure with a physiologically inspired motor control system. Through forward dynamics simulations, we generated a variety of movement patterns by systematically parameterizing motor commands, including failed transitions that are difficult to capture experimentally. We then applied dynamical systems analysis using on an inverted pendulum model to examine the underlying principles of the transition process. Our results demonstrate that successful gait transitions depend on generating an inverted pendulum motion through appropriate control of the forward step length of one hindlimb. These findings provide mechanistic insights into how Japanese macaques coordinate their complex musculoskeletal systems to perform skilled, full-body movements in the gait transition, offering a deeper understanding of both advanced motor control and the evolution of human bipedalism.

neuroscience↗

bioRxiv2025

Revisiting the in vivo Functions of Coilin in Mice

Cajal bodies (CBs), first identified in the early 20th century, are classic nuclear structures organized primarily by the protein coilin. Although CBs have long been implicated in snRNA modification and maturation, their precise roles in mice remain unclear. Here, we revisit the functions of CBs by using genome editing to generate mice that lack nearly the entire coilin protein, retaining only the first seven amino acids. Mass-spectrometry analyses showed reduced 2'-O-methylation of U2 snRNA in coilin mutant liver; however, these reductions had minimal impact on overall gene expression and pre-mRNA splicing patterns. Additionally, detailed analysis recapitulated previously reported testicular size reductions and newly revealed decreased proportions of high-quality sperm. We also identified novel coilin-containing condensates distinct from genuine CBs in the nuclear pocket of elongating spermatids. Our findings implicate that coilin orchestrates membraneless organelles in various compartments, playing multifunctional roles beyond classical CB formation.

molecular biology↗