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Biology subjects

Mai, Y.

Publications and source records attributed to Mai, Y..

At least 19 recordsLinked to original sources

Brief illumination of an optoGPCR elicits prolonged inhibition of Drosophila behavior

Light-actuated G protein-coupled receptors (optoGPCRs) are a class of opsins that act through intracellular signaling cascades. As optogenetic tools, bistable inhibitory optoGPCRs are attractive as they decouple the duration of silencing from the duration of illumination: brief light pulses drive prolonged signaling. Opsin3 from the mosquito Anopheles stephensi (MosOPN3) is a bistable Gi/o-coupled opsin that produces sustained inhibition in mammalian neurons and C. elegans, but its utility in vinegar flies, Drosophila melanogaster, remains untested. Here we tested three optoGPCRs in adult flies; MosOPN3 emerged as the most effective and was benchmarked against an established inhibitor, Guillardia theta anion channelrhodopsin 1 (GtACR1), in walking and memory assays. MosOPN3 inhibitory potency was comparable to that of GtACR1 across most neuronal classes tested, with substantially lower developmental toxicity. Rearing flies on all-trans-retinal-supplemented food throughout development improved both viability and inhibitory efficacy for both opsins. A single pulse of green light (as brief as 5 s) inhibited behavior for minutes, and was sufficient to ablate aversive olfactory learning over a one-minute training epoch. For flies, MosOPN3 is a low-toxicity optogenetic inhibitor for flies that yields minutes of silencing from brief light pulses--especially useful where continuous actuating light would be confounding. Key pointsO_LITo our knowledge, Anopheles stephensi Opsin3 (OPN3) is the first GPCR opsin that inhibits behavior in adult Drosophila melanogaster. C_LIO_LIOPN3 has inhibitory efficacy close to that of GtACR1, with superior viability. C_LIO_LIBrief light pulses drive sustained inhibition lasting minutes, eliminating the need for continuous illumination. C_LIO_LIFor both GtACR1 and OPN3, rearing flies on ATR-supplemented food enhances inhibition efficacy and improves developmental viability. C_LI

neuroscience↗

Long-Stokes-Shift mScarlet3 as a Structural Marker for Two-Photon Imaging

Two-photon imaging with genetically encoded sensors is widely used to monitor neurophysiology. An additional fluorescent protein can provide anatomical landmarks for cell-type identification and motion detection. However, monomeric red fluorescent proteins often require a dedicated excitation laser. We made transgenic Drosophila with a long-Stokes-shift mScarlet variant (LSSmScarlet3) to image alongside green sensors with a single 920-nm laser. We describe excitation and emission spectra of the expressed protein and show robust fluorescence at 920 nm in vitro and in vivo with minimal channel crosstalk. This approach can reduce equipment complexity and cost while placing functional calcium dynamics in their anatomical context.

neuroscience↗

Getting over ANOVA: Estimation graphics for multi-group comparisons

Data analysis in experimental science mainly relies on null-hypothesis significance testing, despite its well-known limitations. A powerful alternative is estimation statistics, which focuses on effect-size quantification. However, current estimation tools struggle with the complex, multi-group comparisons common in biological research. Here we introduce DABEST 2.0, an estimation framework for complex experimental designs, including shared-control, repeated-measures, two-way factorial experiments, and meta-analysis of replicates.

bioinformatics↗

Lateral plate mesoderm directs human amnion and ventral skin organoid formation

Summary ParagraphEngineering organoids that faithfully replicate the intricate architecture and region-specific features of bodily organs and extraembryonic tissues remains a significant scientific challenge. Previously, we demonstrated that craniofacial skin organoids (cSkOs)--containing epidermis, dermis, and hair--could be generated by co-developing epidermal progenitors with cranial mesenchyme. Building on this approach, we precisely adjusted cellular composition and signaling environments to generate ventral skin organoids (vSkOs) with lateral plate mesoderm (LPM) progenitors, successfully recapitulating features of abdominal or groin skin. Modulating early BMP and FGF signaling redirected these vSkOs toward an extraembryonic fate, producing human amnion-like tissues, termed Amnioids. Like native human amnion, Amnioids rapidly expanded into large, avascular, hairless cysts, in sharp contrast to the primitive vasculature and abundant hair follicles of vSkOs. Single-cell RNA sequencing identified divergent molecular signatures and developmental trajectories, highlighting key roles for NOTCH, WNT, and YAP/Hippo signaling pathways. Functional studies further underscored mesenchymal-epithelial interactions and mechanical forces as critical regulators of epithelial expansion. Together, these models provide potent tools to investigate human development at the embryonic-extraembryonic interface, offering critical insights into congenital skin and amniotic disorders and opening new avenues for precision regenerative therapies.

developmental biology↗

A ratio-based framework using Quartet reference materials for integrating long- and short-read RNA-seq

Long-read RNA sequencing (lrRNA-seq) enables full-length transcript profiling but is confounded by technical batch effects that compromise quantification and prevent data integration across platforms, protocols, and laboratories. The lack of a transcriptome-wide biological ground truth has hindered objective benchmarking. To address these dual challenges, we leveraged certified Quartet reference materials to generate one of the largest multi-center lrRNA-seq resources to date: over one billion long reads from 144 libraries across four PacBio and Nanopore protocols in four independent laboratories. We first establish that ratio-based quantification against built-in reference samples effectively removes technical noise, revealing underlying biological signals. We then constructed the first ratio-based reference datasets for full-length transcripts-- comprising 10,218 isoforms and 6,032 alternative splicing (AS) events--and orthogonally validated them with RT-qPCR. Finally, a comprehensive benchmark using these ground truths reveals that a hybrid strategy integrating long- and short-read data (hybrid-seq) achieves the highest quantification accuracy for both isoforms and AS events. Our work provides a foundational framework and resource for evaluating lrRNA-seq technologies and accelerating the standardization of full-length transcriptomics for research and clinical applications.

genomics↗

A trade-off mechanism underpins the evolution of a young two-gene sex-determining system in plants

Sexual systems in animals and plants are remarkably diverse, with dioecy having evolved independently in numerous lineages. In plants, dioecy often evolved more recently than in the best-studied animal systems, making plants especially important for understanding how separate sexes evolved independently from functionally hermaphrodite ancestors. Despite long-standing theories of developmental trade-offs in sex allocation, the underlying genetic mechanisms remain elusive. Here, we show that the XY sex determination system in the dioecious plant species Eurycorymbus cavaleriei in Sapindaceae involves two Y-linked mutations that act jointly within the developmental male-female trade-off: YUN{Delta}, a truncated allele that lowers the dosage of the D-class MADS-box gene YUN, and SUNMAO, a novel sRNA locus that silences the X-linked SUN allele. In females, SUN stabilizes the HD-ZIP transcription factor KUN, which is a known sex determinant in another dioecious plant, thereby promoting femaleness by increasing YUN expression; loss of SUN expression, together with the effect of YUN{Delta}, shifts development toward males. Two interlocking regulatory loops in this "SKY" module (SUN-KUN-YUN) fine-tunes YUN dosage. This dioecious system in E. cavaleriei likely evolved by sequential mutations in genes acting in the predicted male-female trade-off system, with their close linkage reflecting a translocation, and later recombination-suppressing inversions.

plant biology↗

Entirely synthetic memory inception via dual optogenetic activation of sensory and dopaminergic neurons

Associative conditioning is a fundamental learning paradigm that links salient stimuli to appropriate behavior. The vinegar fly is an important memory model that can associate odors with rewarding or punishing reinforcement stimuli via distinct sets of dopaminergic neurons. While much is known about learning, a crucial question remains: is the simple co-activation of sensory and neuromodulatory dopaminergic neurons sufficient to induce memory formation? To address this, we systematically replaced natural stimuli, namely odor-evoked activity, punishment, and reward signals, with optogenetic activation of corresponding neurons, both individually and in combination. In all cases, including a full-substitution paradigm where both olfactory activity and reinforcement dopamine signals were replaced, optogenetic activation successfully implanted synthetic memories. These findings provide a clear answer: simple coincident, rectangular-pulse sensory and neuromodulatory stimulation can instruct associative memory formation. We conclude that associative memory does not have strict requirements for temporal or ensemble activity patterns in olfactory or dopaminergic neurons that are specific to natural stimuli (e.g. odorants, sugar, or pain); rather, simple coincidence is an effective driver of memory inception. These findings open new avenues for manipulating and studying memory formation with all-optical control.

animal behavior and cognition↗

EasyMultiProfiler: An Efficient Multi-Omics Data Integration and Analysis Workflow for Microbiome Research

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/649266v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@14dd0b1org.highwire.dtl.DTLVardef@1c04a79org.highwire.dtl.DTLVardef@159894dorg.highwire.dtl.DTLVardef@1454a01_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG HighlightsO_LIEasyMultiProfiler provides unified integration of microbial multi-omics data C_LIO_LIEasyMultiProfiler enables natural language-style analytical workflows C_LIO_LIEasyMultiProfiler solves key challenges in standardization and reproducibility C_LIO_LIEasyMultiProfiler extracts meaningful biological insights efficiently C_LI Host-microbiome interactions are crucial in maintaining physiological homeostasis and influencing disease progression. While traditional microbiome research, focused on microbial diversity and abundance, provided essential frameworks, the integration of multi-omics approaches established a far more comprehensive, systems-level understanding of microbiome functionality. However, significant methodological challenges in multi-omics data integration remain, including inconsistent sample coverage, heterogeneous data formats, and complex downstream analytical workflows. These challenges impact the reproducibility and reliability of results and underscore the critical requirement for developing standardized, systematic workflows. Thus, we developed the EasyMultiProfiler (EMP) workflow, a streamlined and efficient analytical framework for multi-omics data analysis. EMP provides a comprehensive infrastructure based on the SummarizedExperiment and MultiAssayExperiment classes, creating a unified framework for storing and analyzing omics data. The frameworks architecture comprises five interconnected functional modules: data extraction, preparation, support, analysis, and visualization. These modules are smoothly integrated into natural language-style analytical workflows, offering users an efficient and standardized solution for multi-omics analysis. EMP addresses critical challenges in multi-omics data analysis, including data integration, workflow standardization, and result reproducibility. The platforms modular architecture and intuitive interface provide researchers and clinicians with a robust, flexible workflow to systematically extract biologically relevant insights from complex multi-omics datasets.

bioinformatics↗

Spatial confinement induces reciprocating migration of epidermal keratinocytes and forms triphasic epithelia

Epithelial cells undergo epithelial-mesenchymal transition (EMT) during migration and regain their epithelial phenotype in the post-migration phase (mesenchymal-epithelial transition; MET). We established an experimental system that reproduces a three-compartment epithelial structure comprising the original epithelium, its EMT state, and its MET state. Keratinocytes (KCs), skin epithelial cells, placed on a microporous membrane migrated through 3.0-{micro}m or larger micropores. The 3.0-{micro}m-pored membrane induced an epithelial structure with three distinct states: stratified KCs above the membrane, KCs showing EMT within the micropores, and a new stratified epithelium under the membrane. The membrane with larger micropores failed to maintain the three-compartment epithelial structure. Live imaging revealed that KCs moved in an oscillatory manner, with actin-rich filopodia-like structures extending into and out of the 3.0-{micro}m micropores, while the cells migrated unidirectionally into larger micropores. Piezo1 and keratin 6 were identified as negative modulators of KC entry into and exit from the 3.0-{micro}m micropores. These results demonstrate that non-cancerous epithelial cells migrate through confined spaces in an oscillatory manner, which might contribute to the formation of a three-compartment epithelial structure that recapitulates key aspects of wound healing.

cell biology↗

Identification of Intrinsic Features for Cortical Separability of Human and Mouse Neurons

This work introduces a novel framework for holistic comparative analysis of cortical regions in mouse and human brains at single-neuron resolution, with a primary focus on the morphological and molecular characteristics of neurons. To do so, we generated one of the largest dendritic reconstruction datasets of cortical neurons to date, comprising 2,363 human neurons and 16,011 mouse neurons from the frontal, parietal, and temporal lobes, followed by establishing a rigorous procedure to identify anatomically and functionally corresponding brain regions with minimal variability in brain mapping. Additionally, we leveraged single nucleus/cell transcriptomic data from independent groups to validate the molecular correspondence of the brain regions identified in this study. The significance of these anatomically, functionally, and molecularly corresponding mouse-human region pairs is highlighted by examining the intrinsic features of their respective cortical regions. Our findings reveal that human neuron branching patterns differ dramatically from those in mouse brains, particularly in terms of dendritic branching frequency and normalized dendritic branching intervals. This difference is pronounced in the frontal and temporal lobes, underscoring the distinct neuronal architectures between the two species. At the single-neuron level, we found that neurons from the human frontal and parietal lobes are six times more separable than those from the same regions in mouse brains. This heightened separability is also observed between the frontal and temporal lobes, as well as between the parietal and temporal lobes in humans. We thoroughly explored the entire morphological feature space, along with its characteristic subspaces, and consistently found this distinct separability. Remarkably, this neuronal separability can be partially recapitulated when examining the global functional states of these brain lobes--using newly acquired Electroencephalography (EEG) and Magnetoencephalography (MEG) signals as physiological measures--as well as their global metabolic states, molecular profiles, and cortical geometry. These findings suggest that our comparative analysis of single-neuron intrinsic features could serve as a valuable foundation for future comprehensive studies of cross-species brain structures and functions.

neuroscience↗

Uncovering Individualized Cerebellar Atrophy Pattern and Behavioral Links in Children with Brainstem Tumor

Background and PurposeBrainstem tumors are rare but cause enduring behavioral issues, challenging patients and surgeons. Research on cerebellar changes in these patients limited, despite symptoms similar to cerebellar injuries. This study aims to investigate cerebellar damage pattern resulting from brainstem tumors and its association with behavioral disorders. MethodsIn this study, a U-Net-based segmentation algorithm was used to divide the cerebellum into 26 lobules, which were then used to build a normative model for assessing individual structural deviations. Furthermore, a behavior prediction model was developed using the total outlier count (tOC) index and brain volume as predictive features. ResultsMost patients were found to have negative deviations in cerebellar regions, particularly in anterior lobules like Left V. Higher tOC was significantly associated with severe social problems (r = 0.31, p = 0.001) and withdrawal behavior (r = 0.28, p = 0.001). Smaller size of cerebellar regions strongly correlated with more pronounced social problems (r = 0.27, p = 0.007) and withdrawal behavior (r = 0.25, p = 0.015). Notably, lobules Right X, V, IV, VIIB, Left IX, VIII, and X influenced social problems, while Left V, Right IV, Vermis VI, and VIII impacted withdrawal behavior. ConclusionsOur study revealed cerebellar damage patterns in patients with brainstem tumors, emphasizing the role of both anterior and posterior cerebellar lobes in social problems and withdrawal behavior. This research sheds light on the brain mechanisms underlying complex behavioral disorders in brainstem tumor patients.

neuroscience↗

Normative Growth Modeling of Cortical Thickness Identify Neuroanatomical Variability and Distinct Subtypes in Brainstem Tumor Patients

BackgroundBrainstem tumors can cause structural brain changes, but the resulting heterogeneity within wholebrain structure is not well-studied. This study examines cortical thickness to identify patterns of structural alterations and explore underlying biological subtypes and their associations with clinical factors. Materials and MethodsThis study involved 124 pediatric brainstem tumor patients, aged 4-18 years. Cortical thickness was measured using CAT12 segmentation of 3D T1-weighted structural MRI. A normative model was established using data from 849 healthy children. Deviations in cortical thickness were estimated, and patients were classified into two subtypes using spectral clustering. Clinical statistical analyses were conducted with SPSS 26.0. ResultsThe normative model revealed significant heterogeneity in cortical thickness deviations, which correlated with tumor size and growth patterns. Focal tumors primarily caused negative deviations (t = 3.14, p = 0.02). There was a significant positive correlation between extreme positive deviations and tumor volume (r = 0.214, p = 0.010), and between extreme negative deviations and progression-free survival (r = 0.39, p = 0.008). Two subtypes were identified: Subtype 1, consisting of diffuse tumors with extreme positive deviations, and Subtype 2, consisting of focal tumors with extreme negative deviations. Subtype and tumor growth pattern significantly influenced duration (p < 0.01). The Kaplan-Meier survival curves for Subtype 1 and Subtype 2 demonstrated a significant difference in survival probabilities over time (p = 0.03). ConclusionOverall, this study identifies two major patterns of cortical thickness changes in brainstem tumor patients, enhancing our understanding of their relationship with cortical morphology. The findings suggest that cortical thickness alterations could serve as valuable biomarkers for predicting progression-free survival, which is crucial for clinical assessment and personalized treatment strategies. This research provides new insights into the physiological mechanisms by which brainstem tumors affect brain structure, supporting more precise clinical interventions and efficacy monitoring in the future.

neuroscience↗

Molecular basis of enhanced GLP-1 signaling mediated by GLP-1(9-36) in conjunction with LSN3318839

Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) is essential for glucose metabolism and energy balance. It is primarily activated by the endogenous hormone GLP-1(7-36) and its weaker metabolite GLP-1(9-36). Although GLP-1(9-36) was previously considered biologically inactive, emerging evidence indicate that it exerts cardioprotective and insulinotropic actions. Here, we present cryo-electron microscopy structures showing that GLP-1(9-36) binds to an atypical site composed of the upper halves of transmembrane helices 1 (TM1) and 2 (TM2), extracellular loop 1, and the extracellular domain, distinct from the binding site of GLP-1(7-36). Meanwhile, LSN3318839, an orally effective positive allosteric modulator selective for GLP-1(9-36), anchors in the TM1-TM2 cleft and repositions GLP-1(9-36) to adopt a binding pose like GLP-1(7-36), thereby enhancing GLP-1R-mediated signal transduction. Mutagenesis and molecular dynamics simulations confirmed the crucial interactions and structural adjustments involved in this modulation. Our study uncovers a novel binding mode of GLP-1 metabolite and allosteric modulation that augments GLP-1R signaling, both are potentially insightful to unveil the physiological role of GLP-1(9-36) and design better small molecule therapeutics targeting GLP-1R.

molecular biology↗

Cell-cell adhesion drives patterning in stratified epithelia

Epithelia consist of proliferating and differentiating cells that often display patterned arrangements. However, the mechanism regulating these spatial arrangements remains unclear. Here, we show that cell-cell adhesion dictates multicellular patterning in stratified epithelia. When cultured keratinocytes, a type of epithelial cell in the skin, are subjected to starvation, they spontaneously develop a pattern characterized by areas of high and low cell density. Pharmacological and knockout experiments show that adherens junctions are essential for patterning, whereas mathematical modeling indicates that cell-cell adhesion alone is sufficient to form regions with high/low cell density. This phenomenon, called cell-cell adhesion-induced patterning (CAIP), influences cell differentiation and proliferation through Yes-associated protein modulation. Starvation, which induces CAIP, enhances the stratification of the epithelia. These findings highlight the intrinsic self-organizing property of epithelial cells and indicate that CAIP modulation might promote wound healing in clinical settings.

cell biology↗

Long noncoding RNA Hottip maintained skeletal homeostasis via suppressing the enhancer of zeste homolog 2 (Ezh2)/histone methylation regulatory axis

Recent evidence suggests that long noncoding RNAs (lncRNAs) play a crucial role in regulating bone remodeling and skeletal homeostasis by coordinating the development of osteoblasts and osteoclasts. Several lncRNAs have been identified to participate in bone formation and resorption processes. Among them, the well-known oncogenic lncRNA, Hottip, has been reported to be involved in osteogenesis regulation. However, the specific function and underlying mechanisms remain poorly understood. In this study, we investigated the role of lncRNA Hottip in bone remodeling and skeletal homeostasis. Hottip knockout mice exhibited disrupted bone metabolism, abnormal bone tissue, and compromised bone quality, resulting in delayed fracture healing. In vitro experiments demonstrated that Hottip knockdown inhibited osteoblast differentiation while promoting osteoclast differentiation, with the opposite effect observed upon Hottip overexpression. Mechanistically, Hottip physically interacted with EZH2, leading to its degradation and facilitating the transcription of osteogenic genes by suppressing H3K9me3 and H3K27me3. In vivo experiments further validated the potential of Hottip overexpression to promote bone regeneration and accelerate fracture healing. In conclusion, our study reveals Hottip as a critical regulator in the differentiation of osteoblasts and osteoclasts, crucial for maintaining skeletal homeostasis. This lncRNA shows potential as a promising therapeutic target for bone regeneration.

cell biology↗

Distinct eLPB ChAT projections for methamphetamine anxiety and relapse

Choline acetyltransferase-positive neurons in the external lateral parabrachial nucleus (eLPBChAT) send projections to PKC{delta}-positive (PKC{delta}+) neurons in lateral portion of central nucleus of amygdala (lCeAPKC{delta}) and oval portion of bed nucleus of the stria terminalis (ovBNSTPKC{delta}), forming eLPBChAT-lCeAPKC{delta} and eLPBChAT-ovBNSTPKC{delta} pathways. At least in part, the eLPBChAT neurons positively innervate lCeAPKC{delta} and ovBNSTPKC{delta} through regulating synaptic elements of presynaptic acetylcholine (Ach) release and postsynaptic nicotinic acetylcholine receptors (nAChRs). Methamphetamine (METH) withdrawal anxiety and METH-primed reinstatement of conditioned place preference (CPP) recruit eLPBChAT-lCeAPKC{delta} pathway and eLPBChAT-ovBNSTPKC{delta} pathway in male METH-exposed mice, respectively.

neuroscience↗

Functionally dissecting claustrum along anterior-posterior axis in anxiety and higher sensitivity to cocaine

Adolescent cocaine exposure (ACE) induce anxiety and higher sensitivity to drug addiction during adulthood. Here, we show that the claustrum is crucial for control of these two distinct psychiatric disorders in ACE mice. In the process of anxiety test, the CaMKII-positive neurons in median portion of claustrum (MClaustrum) were obviously triggered, and chemogenetic suppressing these neurons efficiently reduced ACE-induced anxiety in adulthood. While, the CaMKII-positive neurons in anterior portion of claustrum (AClaustrum) were obviously activated in response to cocaine-induced conditioned place preference (CPP), and chemogenetic suppressing these neurons efficiently blocked cocaine CPP in ACE mice during adulthood. Our findings dissociating specific sub-portions of claustrum for drug-related anxiety and susceptibility of addiction, extending our understanding to diverse functions of claustrum subregions.

neuroscience↗

SapBase (Sapinaceae Genomic DataBase): a central portal for functional and comparative genomics of Sapindaceae species

Sapindaceae is a family of flowering plants, also known as the soapberry family, comprising 141 genera and about 1900 species (Pedro et al., 2010). Most of them are distributed in tropical and subtropical regions, including trees, shrubs, also woody or herbaceous vines. Some are dioecious, while others are monoecious. Many Sapindaceae species possess great economic value; some furnish delicious fruits, like lychee (Litchi chinensis), longan (Dimocarpus longan), rambutan (Nephelium lappaceum); and ackee (Blighia sapida) - the national fruit of Jamaica; some produce abundance secondary metabolites, like saponin from soapberry (Sapindus mukorossi), and seed oil from yellowhorn (Xanthoceras sorbifolium); some yield valuable timber including maple (Acer spp.) and buckeye (Aesculus glabra); and some are of great herbal medicinal value, like balloon-vine (Cardiospermum halicacabum). In the last decade, with the rocketing of next generation sequencing (NGS) and genomic technologies, the full genome sequences of several Sapindaceae plants have been resolved (Lin et al., 2017; Liang et al., 2019; Yang et al., 2019; Zhang et al., 2021; Hu et al., 2022; Xue et al., 2022). Among them, our recent publication of the lychee genome attracted broad attention (Edger, 2022; Hu et al., 2022; Lyu, 2022). Now the post-genome era arrives for Sapindaceae, however, there is no public genomic database available for any Sapindaceae species, let alone an integrative database for the whole Sapindaceae family. A unified data platform is in urgent need to collect, manage and share relevant data resources. Therefore, we integrated our home-brew NGS data with all publicly available data for seven Sapindaceae plants and constructed the Sapinaceae Genomic DataBase, named SapBase (www.sapindaceae.com), in order to provide genomic resources and an online powerful analytic platform for scientific research on Sapinaceae species and comparative studies with other plants.

genomics↗