Biology subjects

Nakamura, K.

Publications and source records attributed to Nakamura, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Hippocampal interferon-response, unfolded-protein-response and synaptic transcriptional signatures in RORγt-transgenic mice

Aim: ROR{gamma}t-transgenic mice provide a model of sustained T helper 17-cell bias, but the associated hippocampal transcriptional profile is incompletely characterized. We investigated gene-level and gene-set expression differences in this model. Methods: Bilateral hippocampal samples from 10-week-old male ROR{gamma}t-transgenic mice and wild-type littermates (n = 3 per genotype) underwent bulk RNA sequencing. Gene-level differential expression was evaluated using the Empirical Analysis of DGE tool in CLC Genomics Workbench. Preranked gene set enrichment analysis examined coordinated expression differences after expression filtering and exclusion of Rorc (13,813 genes). Results: Sixteen genes met a false discovery rate < 0.05 (nine higher and seven lower in transgenic mice), including Rorc, C4b, Xbp1, Nptx2 and Mt2. Of 212 candidates selected using unadjusted P < 0.05 and a twofold-change threshold, 155 (73.1%) had a mean expression below 0.5 reads per kilobase of transcript per million mapped reads. Hallmark interferon--response, interferon-{gamma}-response, and unfolded-protein-response gene sets showed positive enrichment. Thirteen Gene Ontology biological-process sets met a false discovery rate < 0.05, including negatively enriched sets related to excitatory postsynaptic potential, glutamatergic transmission, and calcineurin-mediated signaling. Il17a and Il17f had zero reported counts, and none of the displayed leukocyte or central nervous system cell-marker genes met false discovery rate < 0.05. Conclusion: This exploratory dataset identifies interferon-response, unfolded-protein-response and synaptic transcriptional signatures associated with the ROR{gamma}t-transgenic genotype. The cellular sources, causal mediators and functional consequences remain unresolved.

neuroscience↗

bioRxiv2026

Social isolation is associated with microRNA expression changes in the visual system of poison frog tadpoles

Brain microRNA (miRNA) expression can shift in response to the social environment, translating external cues into regulatory action that can influence brain structure, neural activity, and behavior. miRNAs are key drivers of behavioral flexibility, regulating gene networks involved in neuroplasticity. We manipulated social rearing conditions of brilliant-thighed poison frog tadpoles (Allobates femoralis) to test whether isolation-linked behavioral changes are associated with altered miRNA expression in the midbrain and eyes, tissues linked by the retinotectal tract, a known connection for trafficked precursor miRNAs. We asked whether isolation alters visually guided behavior using a light/dark preference assay and found that isolated tadpoles spent less of the trial on the dark side than did group-housed tadpoles. In a social place preference assay, group-housed tadpoles preferred a zone near a conspecific over an object control when provided with multimodal sensory access, but not when access was restricted to vision alone. We next tested whether social rearing conditions influenced miRNA expression and found that isolated tadpoles exhibited upregulation of miR-15-P1c_3p*, the canonically non-dominant arm of an understudied miRNA, in the midbrain and eyes. We detected a shift in arm dosing for miR-124, a miRNA with conserved roles in neural differentiation and plasticity. Finally, social isolation during development was associated with downregulation of parathyroid hormone 2 (pth2), a peptide associated with social isolation and mechanosensation in other aquatic larvae. This work contributes to a growing body of literature implicating miRNAs in developmental neuroplasticity, presenting precedented and novel signatures of the transcriptional and regulatory response to isolation.

neuroscience↗

bioRxiv2026

The CD112-TIGIT/PVRIG Axis Mediates NK Cell Evasion inDecitabine-Treated Acute Myeloid Leukemia Cells

Both drug resistance and immune evasion are considered to contribute to the persistence of residual AML cells and disease relapse. Natural killer (NK) cells play an important role in antileukemic immune surveillance and represent a key component of antitumor immunity in AML. Here, we investigated whether antileukemic drugs alter the susceptibility of surviving AML cells to natural killer (NK) cell-mediated cytotoxicity. AML cells surviving decitabine treatment became resistant to NK-92-mediated killing and showed marked upregulation of CD112. CD112 overexpression reduced NK-92-mediated cytotoxicity, whereas deletion of CD112 in AML cells or deletion of either TIGIT or PVRIG, two inhibitory receptors for CD112, in NK-92 cells restored cytotoxicity. Mechanistically, decitabine induced demethylation of two enhancer regions within the CD112 locus. Deletion of either enhancer attenuated CD112 upregulation, suggesting that enhancer demethylation contributes to decitabine-induced CD112 expression. Furthermore, antibody-mediated blockade of CD112 or combined blockade of TIGIT and PVRIG enhanced cytotoxicity against decitabine-treated AML cells. CD112 upregulation was also observed following azacitidine or cytarabine treatment, although the magnitude of induction varied across drugs and cell lines. These findings identify CD112 upregulation, which is associated with enhancer demethylation, as a mechanism of drug-induced immune evasion in AML and provide a rationale for combining hypomethylating agents with blockade of the CD112-TIGIT/PVRIG axis to enhance NK cell-mediated antileukemic activity.

cancer biology↗

bioRxiv2026

A quantitative proteomics dataset for assessment and prediction of low dose X-ray radiation exposure in mice.

Ionizing radiation induces molecular responses that may be used to estimate exposure when physical dosimeters are unavailable. Here we present two large-scale proteomics datasets generated from mouse dorsal skin punch samples collected following controlled X-ray exposures spanning multiple doses, dose rates, and post-exposure time points. Experiment 1 comprised 96 samples (including 16 reference samples) collected 6 days after exposure to 0-75 cGy delivered at either 30 or 300 cGy/min. Experiment 2 comprised 936 samples (including 236 reference samples) exposed to 0-100 cGy at either 3 or 28 cGy/min dose rates and harvested between 7 and 150 days post-exposure. All samples were processed using a standardized workflow involving automated bead-based digestion and data-independent acquisition mass spectrometry. The datasets include multiple pooled reference sample types, process controls, and system suitability standards ensuring high quality data. All data presented are available via ProteomeXchange at several levels of processing, from raw files through normalized peptide- and protein-level abundance matrices suitable for biomarker discovery and machine learning applications. This dataset will facilitate generation of new insights into the biological changes and molecular signatures resulting from X-ray exposure in mice and may also help inform future studies in humans.

biochemistry↗

bioRxiv2026

Ectopic hAMH-driven SOX17 expression induces hyperplastic Sertoli valve formation in mouse testes

In the terminal segment of the seminiferous tubules, SOX17 expression in the rete testis (RT) epithelium plays a crucial role in the formation of the Sertoli valve (SV), as revealed by phenotypic analyses of RT-specific Sox17 conditional knockout (cKO) mouse testes. In these RT-specific Sox17 cKO testes, SV disruption leads to the backflow of RT fluid into the seminiferous tubules, resulting in defective spermiogenesis and male infertility. Although valve deformation in the Sox17 cKO testes is likely caused indirectly by impaired downstream actions of Sox17 in the RT, the mechanisms by which SOX17 in RT influences SV formation in the seminiferous tubules remain unclear. To address this, we generated a novel AMH-Sox17 transgenic (Tg) mouse line carrying a human AMH promoter-driven Sox17 cDNA cassette. We analyzed the phenotypes of the Sertoli valve and spermatogenesis in AMH-Sox17 Tg mice, as well as in RT-specific Sox17 cKO; AMH-Sox17 Tg double mutant mice. Ectopic SOX17 (SOX17+) expression in Sertoli cells resulted in excessive Sertoli valve structures with acetylated tubulin bundles in the terminal segment of the AMH-Sox17 Tg testes, along with enhanced WNT4/RSPO1 signaling, suggesting the enhanced valve formation of ectopic SOX17+ Sertoli cells by themselves. Moreover, the AMH-Sox17 Tg could partially rescue the SV deformation and infertility in RT-specific Sox17 cKO mice, leading to proper SV formation, normal spermiogenesis and a partial recovery of male fertility in AMH-Sox17 Tg; RT-specific Sox17 cKO double mutant mice. These findings genetically demonstrate that ectopic SOX17+ Sertoli cells can compensate for SOX17 paracrine signaling in the RT, underscoring a key shared downstream pathway between RT and SV. Summary statementThe paracrine actions downstream of ectopic SOX17 expression in the Sertoli cells not only promote the valve formation, but also partially rescue the defective spermiogenesis of the rete testis-specific Sox17-null mice.

developmental biology↗

bioRxiv2026

Explicit representation of germline and non-germline residues improves antibody language modeling

Antibodies originate from germline templates and are diversified by somatic hypermutation, producing sequences in which conserved germline residues scaffold structure while rare non-germline (NGL) substitutions refine antigen binding. Current antibody language models (ALMs) treat all residues equivalently and inherit a germline bias that systematically down-weights functionally critical NGL mutations as statistical noise. We introduce PRISM, a germline-aware ALM that explicitly represents germline and nongermline residues as distinct token types over a factorized 53-token vocabulary. PRISM achieves state-of-the-art pseudo-perplexity in hypervariable CDRs and is uniquely positively correlated with experimental binding affinity across three deep mutational scanning landscapes on which all compared ALMs anti-correlate. The dual-vocabulary further enables property-specific controllable generation previously unattainable with entangled ALMs. NGL-directed sampling improves physics-based binding scores while GL-directed sampling preserves stability and solubility. These results establish disentangled germline/non-germline representation as a substantive advance in antibody language modeling.

immunology↗

bioRxiv2026

Reprogramming of Lipid Metabolism by FLASH Radiotherapy Selectively Protects Radiosensitive Normal Tissues

FLASH radiotherapy, delivered at ultra-high dose rates exceeding 100 Gy/s, spares normal tissues while maintaining tumor control, yet the molecular mechanisms underlying this differential response remain poorly understood. Here we employed spatial and bulk multi-omics to investigate lipid and protein remodeling in tongue tissue and Mouse oral carcinoma 2 (MOC2) tumors at two weeks post-irradiation with FLASH or conventional dose-rate (CONV) proton radiotherapy. Bulk lipidomics revealed that CONV irradiation induced marked triglyceride (TG) depletion in tongue tissue, whereas FLASH attenuated this depletion. Spatial lipidomics using MALDI-MSI demonstrated that this TG loss was spatially restricted to minor salivary glands, identifying these radiosensitive structures as focal points of radiation-induced lipid damage. Additionally, FLASH irradiation uniquely promoted increases in membrane phospholipids and their lysophospholipid intermediates, consistent with active phospholipid turnover rather than passive damage avoidance. Proteomics revealed divergent metabolic programs: CONV activated a destructive cascade characterized by Ces1d depletion, Acox1-mediated peroxisomal {beta}-oxidation, and Acot7-driven fatty acid overflow, collectively defining a lipid droplet collapse; whereas FLASH engaged a protective program featuring Mgll suppression, Apoe-mediated triglyceride redistribution, and Lypla2-mediated lysophospholipid clearance. We propose a lipid metabolic reprogramming hypothesis in which FLASH not only minimizes acute oxidative damage but actively reprograms lipid metabolism to preserve lipid droplet stores and promote membrane remodeling. These findings provide a putative molecular foundation for the FLASH effect and support published data on the protection of normal tissues.

cancer biology↗

bioRxiv2026

Neural correlates of licking behavior modulated by target position in the striatal matrix compartment

The striatum is a major cortical input site of the basal ganglia and plays a critical role in the control of orofacial movements such as licking. However, how striatal activity relates to the spatial features of licking behavior remains unclear. In this study, we examined whether neural activity in the striatal matrix and striosomal compartments is associated with the spatial position of a licking target during an operant task. Head-fixed mice performed a licking task in which the target positions were varied across three spatial dimensions. Using fiber photometry in Calb1-IRES-Cre and Pdyn-IRES-Cre mice, we recorded calcium signals from matrix and striosomal neurons. Associations between neural activity, target position, and behavioral variables were quantified using linear mixed-effects modeling with cross-validation. Matrix activity prior to licking onset was primarily associated with the dorsal-ventral target position and reaction time. During licking, matrix activity was modulated by anterior-posterior and medial-lateral positions, independent of reaction time and lick count. In contrast, striosomal activity during licking was predominantly associated with the dorsal-ventral position. These findings demonstrate that neural matrix activity is systematically associated with spatial features of licking behavior, with distinct contributions before and during movement. Our results suggest that striatal matrix circuits provide task-relevant spatial signals for the control of orofacial actions. Significant StatementWe show that neural activity in the striatal matrix is associated with the three-dimensional position of a licking target during an operant task. Activity prior to licking onset reflects dorsal-ventral position, whereas activity during licking is modulated by the anterior-posterior and medial-lateral positions. These findings indicate that matrix activity represents spatial aspects of licking behavior, supporting a role for the striatum in integrating motor execution with task-specific spatial information and pointing to the matrix compartment as a substrate for transforming spatial coordinates into action-specific motor commands.

neuroscience↗

bioRxiv2026

Requirement for oxidation of neuronal ketone bodies in aging andneurodegeneration

Glucose is the brains primary fuel, but the brain can also use alternative energy substrates, especially during development or starvation. Emerging evidence suggests ketone metabolism may help the brain adapt to energy stress in neurodegenerative diseases such as Alzheimers disease, although its role in constitutive brain function in normal aging is poorly understood. Using iPSC-derived human neurons and adult-inducible, neuron-specific Bdh1 knockout mice, we show that ketone body metabolism is essential for maximum energy production, neuronal function, and mouse survival--even under normal nutritional conditions. Mechanistically, phenotypes of Bdh1 knockout neurons are mitigated by provision of acetoacetate, a downstream energy metabolite. Moreover, loss of neuronal ketone oxidation markedly increases mortality and memory deficits in Alzheimers disease model mice. These findings identify ketones as critical neuronal fuels, with particular importance during neurodegeneration. While non-energetic activities of ketone bodies are increasingly appreciated, oxidation for energy provision is an essential mechanism for normal function in neurons and mice. Targeting the energetic function of ketones may thus offer new therapeutic strategies for both aging and neurodegenerative diseases such as Alzheimers.

neuroscience↗

bioRxiv2026

Acute Milk-Protein Intake Enhances Pupil-Linked Executive Function and Esports Performance During Prolonged Play

Prolonged esports play induces cognitive fatigue that is not fully captured by subjective awareness, motivating practical, non-stimulant nutritional strategies supported by objective physiological markers. We here tested whether acute milk protein intake attenuates fatigue-related physiological responses during prolonged esports play and supports subjective state, executive control, and in-game performance. In a randomized, single-blind (assessor-blind), energy-matched controlled crossover study, 15 healthy young adults with esports experience completed two sessions in which they consumed either a milk protein drink or an energy-matched apple juice control before a 3-h virtual soccer task. Physiological measures included pupillometry during gameplay, salivary cortisol, continuous interstitial glucose monitoring, and heart rate. Subjective ratings (VAS) and executive function (flanker task) were assessed across post-ingestion time points, and in-game performance metrics were aggregated within hourly gameplay blocks. Milk protein intake was associated with a coherent pattern of physiological advantages, including larger pupil diameter during gameplay, smoother interstitial glucose dynamics, and lower salivary cortisol, while heart rate showed time-dependent changes without a clear condition effect. These physiological changes co-occurred with higher enjoyment and lower hunger, improved flanker performance, and condition-dependent improvements in in-game performance, most notably higher shot success rate. Additionally, pupil diameter during gameplay was associated with inhibitory-control efficiency on the flanker task. These findings suggest that acute milk protein intake may serve as a practical, non-stimulant nutritional strategy to sustain physiological state and cognitive-behavioral performance during prolonged esports (virtual soccer) play. Highlights- Prolonged esports play models modern digital cognitive activity and cognitive fatigue. - Acute milk protein intake increases pupil diameter during prolonged esports play. - Interstitial glucose dynamics are smoother and salivary cortisol is lower with milk protein. - Enjoyment increases and hunger decreases during 3 h of virtual soccer play. - Executive function and in-game performance improve, most notably shot success rate.

neuroscience↗

bioRxiv2026

Genome-wide CRISPRi screen identifies basigin loss as protective in cardiac hypoxia

Cardiac function depends on continuous oxidative metabolism, rendering cardiomyocytes highly vulnerable to oxygen deprivation. Here, we performed a genome-wide CRISPR interference (CRISPRi) screen in human iPSC-derived cardiomyocytes to identify genes that modulate survival during chronic hypoxia. This screen revealed that knockdown of basigin (BSG), a chaperone for the monocarboxylate transporters MCT1 and MCT4, confers robust protection. Canonically, hypoxic cells suppress pyruvate dehydrogenase (PDH) activity to reduce the oxidation of major fuel sources, thereby limiting TCA cycle flux, lowering oxygen consumption, and minimizing reactive oxygen species generated by an overly reduced electron transport chain (ETC). In contrast, we found that BSG inhibition reverses this response, prioritizing ATP maintenance during hypoxia and enhancing cardiomyocyte survival. Mechanistically, BSG loss restricts lactate efflux, leading to decreased PDH phosphorylation and increased glucose uptake for oxidation. Consistent with this, ETC subunits are more essential under hypoxia, highlighting cardiomyocytes unusual reliance on aerobic ATP production even when oxygen is limited. These findings challenge prevailing models of hypoxic adaptation by revealing cardiomyocyte-specific bioenergetic requirements and motivating future therapeutic efforts.

cell biology↗

bioRxiv2025

Quantitative analysis of synaptic zinc in the brain by covalent chemistry-based semisynthetic biosensors

Labile zinc ions (Zn{superscript 2}) are stored in glutamatergic vesicles at specific excitatory synapses in the central nervous system and released into synaptic clefts in an activity-dependent manner. Although Zn{superscript 2} is suggested to modulate various neuroreceptor functions, its precise roles remain unclear due to a lack of tools capable of quantitatively analyzing Zn{superscript 2} with synapse-level spatial resolution. Here, we developed neuroreceptor-based semisynthetic sensors that record synaptic Zn{superscript 2} dynamics by covalent chemistry in the living mouse brain. Using a chemical knock-in strategy, we introduced activity-based Zn2+-probes with distinct affinities into endogenous -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid or {gamma}-aminobutyric acid type A receptors. These in-brain-constructed Zn{superscript 2} sensors enabled, to our knowledge, for the first time, quantitative, region-specific mapping of Zn{superscript 2} released into synaptic clefts. Imaging-based analyses revealed differences in Zn{superscript 2} concentrations at excitatory and inhibitory synapses across hippocampal regions during kainate-induced seizures, providing new insights into the physiological and pathological functions of synaptic Zn{superscript 2}.

neuroscience↗

bioRxiv2025

Genetic regulators of neuronal survival across metabolic environments

Cellular energy metabolism and oxygen availability shape neuronal function and vulnerability, yet the genetic regulators of these metabolic processes in human neurons remain incompletely understood. Here, we performed CRISPR interference (CRISPRi) screens in human induced pluripotent stem cell (iPSC)-derived neurons across four distinct metabolic conditions and at three physiologically relevant oxygen tensions. This combinatorial approach enabled systematic interrogation of gene-environment interactions that govern neuronal metabolic adaptation. We identified genes--including genes associated with Leigh syndrome and autism spectrum disorder--whose importance for cell survival is highly sensitive to environmental context, revealing potential mechanisms underlying metabolic specification and selective neuronal vulnerability in neurological disorders. Our screens also uncovered regulators of neuronal glycolysis, including KIAA1429 and MAPT among others, which are previously uncharacterized modulators of neuronal glucose utilization and metabolic flexibility. Our work nominates candidate metabolic interventions and gene targets for enhancing neuronal resilience under hypoxic or nutrient-limited conditions.

systems biology↗

bioRxiv2025

Mechanosensitive Stanniocalcin-1 Attenuates Pulmonary Arterial Hypertension by Suppressing Smooth Muscle Cell Proliferation

BackgroundIdiopathic pulmonary arterial hypertension (IPAH) is driven by progressive pulmonary vascular remodeling, particularly pulmonary arterial smooth muscle cell (PASMC) proliferation. Current combination vasodilator therapies have markedly improved outcomes; however, prognosis remains poor in subgroups such as patients with respiratory comorbidities, highlighting the need for novel therapies. Elevation of intravascular hydrostatic pressure is a hallmark of IPAH, yet its direct role in PASMC pathobiology remains largely unexplored. We developed a cyclic hydrostatic pressurization culture system to model hypertensive hemodynamic stress in vitro and identify pressure-responsive mediators. MethodsPASMCs from 4 patients with IPAH were exposed to high hydrostatic pressure (70/40 mmHg, 60 bpm). Transcriptomic profiling identified differentially expressed genes, validated by qPCR. Functional studies included piezo-type mechanosensitive ion channel component 1 (PIEZO1) modulation, recombinant human stanniocalcin-1 (rhSTC1) treatment, bromodeoxyuridine (BrdU) incorporation, and western blotting for cell-cycle regulators. In vivo, chronic hypoxia-induced pulmonary hypertension was assessed in wild-type and Stc1-/- mice by hemodynamic and histological analyses, with or without intratracheal rhSTC1 administration. ResultsRNA sequencing revealed STC1 as a robustly pressure-induced gene in IPAH PASMCs. PIEZO1 activation upregulated STC1, whereas knockdown blunted this response. Elevated STC1 expression was observed in PASMCs of IPAH lung tissues, and rhSTC1 reduced PASMC proliferation and increased p-p53, p21, and p27 expression. In the chronic hypoxia model, Stc1-/- mice exhibited higher right ventricular systolic pressure (RVSP) (43.7 {+/-} 1.3 vs. 30.6 {+/-} 0.9 mmHg) and greater pulmonary arterial medial thickness (39.1 {+/-} 2.5% vs. 26.5 {+/-} 1.3%) than wild-type mice. CD68-positive macrophages were increased in Stc1-/- mice under normoxia and further elevated with hypoxia. In wild-type and Stc1-/- PAH models, intratracheal administration of rhSTC1 markedly reduced medial thickening, CD68-positive macrophage accumulation, and RVSP in both wild-type and Stc1-/- mice. ConclusionsWe demonstrate that elevated hydrostatic pressure drives STC1 expression via PIEZO1, conferring potent anti-remodeling effects in IPAH. STC1 supplementation represents a potential therapeutic strategy that addresses an urgent medical need not fulfilled by conventional therapies. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIWe established a novel hydrostatic pressurization system to recapitulate idiopathic pulmonary arterial hypertension (IPAH) hemodynamic conditions in vitro. C_LIO_LIStanniocalcin-1 (STC1) is a hydrostatic pressure-responsive gene in pulmonary arterial smooth muscle cells (PASMCs) from IPAH patients, induced via the mechanosensitive receptor piezo type mechanosensitive ion channel component 1 (PIEZO1). C_LIO_LIExogenous STC1 suppresses PASMC proliferation and attenuates pulmonary vascular remodeling in chronic hypoxia-induced PAH models. C_LI What Are the Clinical Implications?O_LISTC1 supplementation represents a potential therapeutic strategy for IPAH, acting through a non-vasodilatory mechanism. C_LIO_LISTC1 supplementation may offer benefit in patients with limited response to current vasodilator therapies or with comorbid respiratory disease. C_LIO_LITargeting mechanotransduction pathways could expand treatment options for pulmonary hypertension. C_LI

molecular biology↗

bioRxiv2025

Selective innervation of subpopulations of striatal neurons by distinct sets of neurons of the external globus pallidus

The striatum, the primary input nucleus of the basal ganglia, contains diverse populations of projection neurons and interneurons, each with distinct roles in motor processing. The external globus pallidus contains distinct populations of inhibitory neurons that are highly interconnected with other regions of the basal ganglia. How pallidal neurons innervate different populations of striatal neurons is critical for our understanding of their role in motor processing. Here we use monosynaptic viral tracing in transgenic mice to quantitively define the organization of pallidostriatal connectivity. We show that FoxP2-expressing arkypallidal neurons provide the greatest input to the striatum, primarily targeting indirect pathway spiny projection neurons and cholinergic interneurons. In contrast, prototypic pallidal neurons, defined by Nkx2-1 expression, preferentially innervate parvalbumin- and somatostatin-expressing interneurons. These data reveal a structured and selective organization of pallidostriatal projections, suggesting that distinct classes of pallidal neurons modulate striatal circuits through complementary pathways. Mapping these connections is key to understanding how basal ganglia networks coordinate motor control.

neuroscience↗

bioRxiv2025

Synaptic and potential fluctuations drive representational drift with differential effects on discrimination learning

Large-scale neuronal measurements have revealed continual drift of neural representations without explicit learning, raising fundamental questions about how the brain maintains reliable perception. While representational drift has been studied both experimentally and theoretically, the underlying mechanisms and computational consequences remain unclear. Here, we systematically compare two drift mechanisms--fluctuations in synaptic weights versus membrane potential--using an analytically tractable neural network model with aligned drift magnitude and timescale. We found that both mechanisms preserve representational structure across time regardless of the drift magnitude. However, only synaptic fluctuations maintain discriminability between representations under large drift magnitude. We use a selectivity space to explain how these similar and differential effects on representational drift emerge from the dynamics of individual neuronal tuning. We further examine functional consequences of drift using reversal learning tasks where stimulus-reward associations switch. Both mechanisms enhance single stimulus learning by gradually removing the old associations, but only synaptic fluctuations substantially improved learning of multiple stimuli by preserving the representational structure during drift. Our results reveal distinct computations performed by specific fluctuation mechanisms and explain how representational drift can support both stable and adaptive behavior.

neuroscience↗

bioRxiv2025

Live-cell imaging reveals nutrient-dependent dynamics of ER-mitochondria contact formation via PDZD8

Cells adapt to changes in nutrient conditions by reorganizing organelle activities. Mitochondria-endoplasmic reticulum contact sites (MERCS) have been proposed to play an essential role in this adaptive response. However, the lack of suitable tools for detecting these contact sites in living cells has hindered the studies of the mechanisms regulating MERCS in response to nutritional changes. Here, we establish a novel cell line, MERCdRED, which expresses a ddFP-based fluorescent MERCS sensor. Using correlative light-electron microscopy, we show that the MERCdRED signal accurately labels the contact sites as defined by electron microscopy. Live imaging of MERCdRED cells revealed that large MERCS are more stable than smaller ones. Furthermore, in combination with knockout of the ER-mitochondria tethering protein PDZD8, we revealed that nutrient deprivation reduces MERCS area in a PDZD8-dependent manner. This new tool, together with our findings, will contribute to a better understanding of the molecular basis of cellular metabolism. Summary StatementWe established a novel cell line enabling live imaging of MERCS, which revealed their dynamic nature and demonstrated nutrient deprivation-induced MERCS reduction along with its underlying mechanisms.

cell biology↗

bioRxiv2025

Metabolic cell death of labile iron deficiency as a vulnerability of head and neck squamous cancer cells evaded by BACH1

Head and neck squamous cell carcinoma (HNSCC) remains difficult to treat due to the lack of molecularly targeted drugs with high anti-tumor efficacy and safety. To investigate the involvement of the transcription factor BACH1, which is known to promote the metastasis of various cancers, in the malignant properties of HNSCC cells, we examined the effects of BACH1 depletion with short interfering RNAs in human HNSCC cell lines. We found that knockdown of BACH1 induced cell death due to depletion of intracellular labile iron which is not tightly bound to protein. Mitochodrial electron transfer chain activity was severely reduced but efficiently resuced with supplementation of iron in the medium. By combining chromatin immunoprecipitation-sequence and RNA-sequence analyses, we found that BACH1 represses ferritin genes in HNSCC cells. BACH1 knockdown was found to enhance the effect of tipifarnib, a selective inhibitor of farnesyltransferase required for HRAS activation, resulting in efficient inhibition of proliferation of HNSCC cell lines in vitro. These results indicate that BACH1 is essential for maintaining the amount of labile iron in HNSCC cells to evade metabolic cell death of iron deficiency and to proliferate. BACH1 can be a target for conferring Tipifarnib sensitivity to HNSCC cells.

cancer biology↗