Biology subjects

Ye, S.

Publications and source records attributed to Ye, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Homodimerized Arpins: Binding to Arp2/3 Complexes with Positive Synergy to Inhibit Lamellipodia-Dependent Tumor Metastasis

The Arp2/3 complex is a central regulator of actin polymerization dynamics and cancer cell motility, with its dysregulation implicated in metastasis and therapeutic resistance. Despite its therapeutic potential, targeting Arp2/3 remains challenging due to the lack of precise molecular insights into endogenous inhibitors. Arpin, a lamellipodia-localized Arp2/3 inhibitor, has emerged as a critical modulator of cancer migration; however, the structural and mechanistic basis of its inhibitory function remains unresolved. Here, we report the 1.65-[A] crystal structure of Arpins N-terminal globular domain, revealing a unique structural fold distinct from all known Arp2/3-binding factors. Structural and biophysical analyses demonstrate that Arpin forms homodimers via a conserved interface, which is essential for cooperative inhibition of Arp2/3-dependent actin polymerization. Functional studies in cancer models reveal that Arpin homodimerization potently suppresses lamellipodia-driven migration and invasion, effects further enhanced by engineered dimeric constructs or artificially designed dual-tailed peptides. These findings elucidate a structural basis for Arpin-mediated suppression of cancer cell motility and identify homodimeric cooperativity as a druggable mechanism for targeting metastatic progression. Our work provides a molecular framework for designing Arpin-inspired inhibitors to counteract therapeutic resistance and metastasis in cancers reliant on Arp2/3-driven actin dynamics.

cancer biology↗

bioRxiv2025

Frontoparietal functional dedifferentiation during naturalistic movie watching among older adults at risk of emotional vulnerability

Functional dedifferentiation, a hallmark of brain aging particularly evident within the frontoparietal network (FPN), has been extensively investigated in the context of cognitive decline, yet its implications for late-life mental health remain poorly understood. Leveraging naturalistic fMRI combined with gradient mapping techniques, the present study investigated FPN functional dedifferentiation--quantified by functional dispersion of FPN in the multidimension gradient manifold--during real-life emotional experiences and its link to affective outcomes. Here, we estimated functional dispersion during naturalistic movie watching in both younger (N=72, 34 female, 19-36 yrs) and older (N=68, 36 female, 65-82 yrs) adult groups with 7T MRI scanner and assessed their emotion regulation difficulties, anxiety, and depression symptoms as indicators of mental health status. The results demonstrated that greater FPN dispersion (i.e., more dissimilar connectivity) was linked to increased depressive symptoms in older adults and highlighted emotion regulation difficulties as a full mediator of this relationship. Moreover, FPN dispersion could distinguish emotionally resilient from vulnerable older individuals. These findings suggest that functional dedifferentiation of the FPN during ecologically valid emotional context constitutes a promising neural signature of affective vulnerability in older adults. By bridging age-related functional dedifferentiation to real-world emotional scenario, this work underscores the translational value of naturalistic paradigms in geriatric psychiatry and identifies potential intervention targets aimed at enhancing FPN specificity to promote mental health in aging population.

neuroscience↗

bioRxiv2025

Rainbow Nucleus Charts Dynamic Interactome of Membrane-less Organelles

Membrane-less organelles (MLOs) perform diverse cellular functions, but how they interact to coordinate these processes remains poorly understood. Here we constructed a "Rainbow Nucleus" cell line to simultaneously visualize five nuclear MLOs using multi-spectral live-cell imaging. We find that MLO interactions are not random: nuclear speckles serve as hubs, and functionally related MLOs interact more frequently than unrelated MLOs. While some interactions are stable, such as those between the histone locus bodies and Cajal bodies, others are transient, such as those between PML nuclear bodies and Cajal bodies. Single particle tracking revealed that stable contacts between Cajal bodies and nuclear speckles are functional, promoting the outward trafficking of small nuclear ribonucleoproteins from Cajal bodies. Finally, RNA Polymerase II-mediated transcription is required to organize the MLO interactome. Our study reveals a structured, transcription-dependent contact network among nuclear MLOs, laying the foundation for future cellular engineering efforts to modulate the MLO interactome.

cell biology↗

bioRxiv2025

Robust and Reliable de novo Protein Design: A Flow-Matching-Based Protein Generative Model Achieves Remarkably High Success Rates

Generative models have achieved significant progress in the field of protein design, particularly in the generation of tertiary structures. However, they still face several challenges, such as balancing the designability and diversity of the generated structures, generating specified structures under highly constrained conditions, and the most challenging aspect, direct functional design such as motifs and binders. We present OriginFlow, an efficient protein generative model that combines Stochastic Differential Equation (SDE) models and flow models based on flow matching. The generated structures exhibit state-of-the-art (SOTA) levels of designability, diversity, and novelty. Moreover, this model demonstrates outstanding performance in functional design aspects such as motifs, binders, and symmetric motif scaffolding. We performed binder design for multiple targets, and all results showed excellent affinity performance in AF3 complex predictions and MD experiments. Wet-lab validation was conducted on PD-L1, RBD, and VEGF targets, achieving 90% expression, solubility, and affinity. These results are significantly superior to all current AI binder design algorithms.

bioengineering↗

bioRxiv2025

Compression of functional gradients from rest to naturalistic processing: Moderation effect of age

The functional cortical hierarchy of the human brain, a fundamental principle of brain organization, has been extensively characterized during resting state for healthy younger adults. However, functional re-organization during naturalistic settings, such as movie-watching, and its alterations across the adult lifespan remains poorly understood. Using resting-state and movie fMRI data from two large datasets, Cam-CAN (N=416) and DyNAMiC (N=156), this study conducted a comprehensive comparison of brain organization across two states. We identified a robust reorganization with compression of functional gradients from rest to movie-watching states, which is mediated by changes in functional integration and segregation of brain networks. The extent of compression from rest to movie was significantly greater in older adults and predicted worse cognitive performance among the elderly population. Our findings provide novel insights into how macroscale brain hierarchy is reorganized during naturalistic processing, and how this reorganization during aging impacts cognitive processes, offering a deeper understanding of the neural basis of aging and cognition.

neuroscience↗

bioRxiv2025

Biosynthesis of modular signaling molecules requires functional diversification of carboxylesterases in Pristionchus pacificus

The model nematode Pristionchus pacificus produces four types of complex ascaroside pheromones named UBAS, DASC, NPAR, and PASC. However, the exact biosynthetic pathways of these modular signaling molecules remain enigmatic. We have previously identified a carboxylesterase Ppa-UAR-1 for the biosynthesis of UBAS, enabling the attachment of ureidoisobutyric acid at the 4-position of simple ascarosides. Here, we report three new carboxylesterases Ppa-UAR-5, Ppa-UAR-6 and Ppa-UAR-12 from P. pacificus. Ppa-UAR-5 functions downstream of Ppa-UAR-1 to furnish the biosynthesis of ubas#1 and ubas#2, whereas Ppa-UAR-12 specifically links two ascr#1 at the 4-position to synthesize dasc#1. Finally, Ppa-UAR-6 is essential for the biosynthesis of npar#1-3 and part#9. The expression patterns of Ppa-uar-6 and Ppa-uar-12 in the intestinal and epidermal cells suggest pheromone biosynthesis to be restricted to specific tissues. These findings indicate that the expansion and functional diversification of carboxylesterases plays a crucial role in the evolution of complex pheromones in nematodes. SIGNIFICANCEOur study identified three new carboxylesterase genes (Ppa-uar-5, Ppa-uar-12 and Ppa-uar-6) from P. pacificus. The encoded enzymes separately regulated the biosynthesis of three types of modular pheromones (UBAS, DASC, and NPAR-types) in worms intestinal cells and exhibited extremely high substrate-specificity. For example, we verified that Ppa-UAR-12 specifically linked one ascr#1 to the 4-position of another ascr#1 to finally furnish the biosynthesis of ascaroside dimer dasc#1. These new discoveries largely clarify the delicate biosynthetic mechanisms of how diversification of carboxylesterases functions in P. pacificus to build up enormous complexity of modular signaling molecules. Such a biosynthetic mechanism of nematode pheromones might be widely conserved in the phylum Nematoda.

biochemistry↗

bioRxiv2025

Dynamic and Biphasic Regulation of Cell Migration by Ras

Ras has traditionally been regarded as a positive regulator and therapeutic target due to its role in cell proliferation, but recent findings indicate a more nuanced role in cell migration, where suppressed Ras activity can unexpectedly promote migration. To clarify this complexity, we systematically modulate Ras activity using various RasGEF and RasGAP proteins and assess their effects on migration dynamics. Leveraging optogenetics, we assess the immediate, non-transcriptional effects of Ras signaling on migration. Local RasGEF recruitment to the plasma membrane induces protrusions and new fronts to effectively guide migration, even in the absence of GPCR/G-protein signaling whereas global recruitment causes immediate cell spreading halting cell migration. Local RasGAP recruitment suppresses protrusions, generates new backs, and repels cells whereas global relocation either eliminates all protrusions to inhibit migration or preserves a single protrusion to maintain polarity. Consistent local and global increases or decreases in signal transduction and cytoskeletal activities accompany these morphological changes. Additionally, we performed cortical tension measurements and found that RasGEFs generally increase cortical tension while RasGAPs decrease it. Our results reveal a biphasic relationship between Ras activity and cellular dynamics, reinforcing our previous findings that optimal Ras activity and cortical tension are critical for efficient migration. SignificanceThis study challenges the traditional view of Ras as solely a positive regulator of cell functions by controlling of gene expression. Using optogenetics to rapidly modulate Ras activity in Dictyostelium, we demonstrate a biphasic relationship between Ras activity and migration: both excessive and insufficient Ras activity impair cell movement. Importantly, these effects occur rapidly, independent of transcriptional changes, revealing the mechanism by which Ras controls cell migration. The findings suggest that optimal Ras activity and cortical tension are crucial for efficient migration, and that targeting Ras in cancer therapy should consider the cells initial state, aiming to push Ras activity outside the optimal range for migration. This nuanced understanding of the role of Ras in migration has significant implications for developing more effective cancer treatments, as simply inhibiting Ras might inadvertently promote metastasis in certain contexts.

cell biology↗

bioRxiv2025

HMG box-containing protein 1 (HBP1) prevents pancreatic injury in experimental pancreatitis but accelerates pancreatic neoplasia progression

Background & AimsPancreatitis is an inflammatory disease of the exocrine pancreas and a known risk factor for pancreatic ductal adenocarcinoma (PDAC). Previously, we identified HMG- box transcription factor 1 (HBP1) as a potential master transcription factor (TF) in the early progression of PDAC, with its expression associated with poor patient survival, underscoring its significance in pancreatic disease. However, the functional role of HBP1 in the onset and progression of acute pancreatitis (AP) remains unknown. MethodsWe examined HBP1 expression in human pancreatitis samples and a cerulein-induced AP mouse model. Pancreatic-specific conditional HBP1 knockout mice, with or without an oncogenic Kras mutation, were generated and compared to their littermate controls. Spatial transcriptomics and multiplexed protein assays, histological analysis, and immunostaining were utilized to characterize pathological changes. Findings from mouse models were validated using inducible HBP1-overexpressing human pancreatic ductal epithelial cells. ResultsHBP1 was upregulated in pancreatic exocrine cells in human chronic pancreatitis and mouse acute pancreatitis, with its expression in human chronic pancreatitis correlating with cancer presence. Pancreatic HBP1 ablation disrupted acinar homeostasis by impairing autophagic flux and exacerbating inflammation following injury. In the presence of oncogenic KRAS, HBP1 ablation delayed the formation of pancreatic intraepithelial neoplasia (PanIN), the precursor to PDAC, and slowed its progression to higher-grade lesions. ConclusionsHBP1 upregulation in pancreatitis mitigates pancreatic inflammatory injury; however, in the presence of oncogenic KRAS, it facilitates PanIN progression. Thus, HBP1 serves as a critical regulator in both pancreatitis and early pancreatic neoplasia, representing a potential therapeutic target for intervening pancreatitis and PanIN progression.

cell biology↗

bioRxiv2025

Revealing the diversity of light-harvesting antenna of in vivo photosystem I

The photosynthetic reaction is driven by the cooperation of two light-excited pigment-protein supercomplexes: photosystem II (PSII) and photosystem I (PSI). The efficiency of the excitation of the two PSs relies on the exquisite organization of their light-harvesting antenna under environmental fluctuations. However, since the antenna-protein composition within cells remains elusive, the in vivo events arising from antenna variations cannot be accurately explored. Here, we implemented the single-pixel excitation-emission spectroscopy of Chlamydomonas cells under 80 K using a cryogenic optical microscope. The antenna variations of in vivo PSI can be exclusively evaluated via this low-temperature spectro-imaging method. The simultaneous acquisition of two types of fluorescence spectra enables the analysis of the intracellular correlation between the PSII/PSI intensity ratio and the chlorophyll-b/a (Chl-b/a) concentration ratio. We found that the Chl-b/a ratio hardly correlated with the PSII/PSI intensity ratio in most cases, suggesting that the in vivo PSI intensity ratio reflects the relative PSI stoichiometry rather than their antenna sizes. More importantly, the analysis of the PSI antenna-related Chl-b concentration within cells reveals a mega-antenna system that is much larger than the antenna sizes of the PSI supercomplexes whose structures have been resolved so far. Such PSI megacomplexes tended to be enriched in the region surrounding the pyrenoids of Chlamydomonas cells. We anticipate the present investigation to be a starting point for directly estimating the arrangements of antenna systems of photosystems at the single-cell scale, which is necessary for a deeper understanding of dynamic in vivo events related to the photosynthetic light-harvesting process.

biophysics↗

bioRxiv2024

Age-related Increase in Locus Coeruleus Activity and Connectivity with Prefrontal Cortex during Ambiguity Processing

Interpreting ambiguous environmental cues, like facial expressions, becomes increasingly challenging with age, especially as cognitive resources decline. Managing these challenges requires adaptive neural mechanisms that are essential for maintaining mental well-being. The locus coeruleus (LC), the brains main norepinephrine source, regulates attention, arousal, and stress response. With extensive cortical connections, the LC supports adapting to cognitive demands and resolving conflicting cues from environment, particularly in later life. Previous research suggests that LC interacts with the prefrontal cortex (PFC) during high-conflict tasks. However, whether LC activity and its connectivity with the PFC support emotional ambiguity processing and contributes to emotional well-being in healthy aging remains unclear. To address this gap, we used 7T-MRI to examine LC function in 75 younger (25.8 {+/-} 4.02years, 35females) and 69 older adults (71.3 {+/-} 4.1 years, 35females) during facial-emotion-recognition task morphed with varying ambiguity: anchor (unambiguous happy or fearful), intermediate-ambiguity (30%happy-70%fearful and 40%happy-60%fearful expressions), and absolute-ambiguity (50%happy-fearful). Behaviorally, participants had longer response times and lower confidence during the absolute-ambiguity condition, while older adults perceived ambiguous faces as happy more frequently than younger adults. Neuroimaging results revealed older adults exhibited greater LC activity and enhanced connectivity with dorsolateral PFC (dlPFC) during absolute-ambiguity compared to younger adults. This heightened connectivity in older adults was linked to better task-independent self-reported mental well-being questionnaires and greater emotional resilience scores derived from principal component analysis. Overall, these findings suggest that greater LC activity supports managing cognitively demanding tasks, while enhanced LC-dlPFC connectivity promotes emotional well-being, highlighting this neural pathways role in healthy aging. Significance StatementUnderstanding how the brain adapts to cognitive and emotional demands with age is key to promoting healthy aging. This study examined whether the locus coeruleus (LC), a brain region critical for regulating attention and arousal, undergoes adaptive changes with age, especially during emotional ambiguity task. Using ultra-high-field imaging, we explored younger and older adults recognize facial expressions with varying ambiguity levels. Our findings indicated that compared to young, older adults showed heightened LC activity and LC-dorsolateral prefrontal cortex (dlPFC) connectivity when processing absolute-ambiguous facial expressions, with enhanced connectivity linked to improved mental well-being. These results suggest higher LC activity supports cognitive demands of ambiguity processing with LC-dlPFC connectivity promoting emotional well-being and resilience, offering insights into mechanisms underlying healthy aging.

neuroscience↗

bioRxiv2024

RIG-I and MDA5 cooperatively recognize the DENV replicative-form dsRNA to activate innate immunity

RIG-I like receptors (RLRs) are a family of cytosolic RNA sensors that sense RNA virus infection to activate innate immune response. It is generally believed that different RNA viruses are recognized by either RIG-I or MDA5, two important RLR members, depending on the nature of pathogen-associated molecular patterns (PAMPs) that are generated by RNA virus replication. Dengue virus (DENV) is an important RNA virus causing serious human diseases. Despite extensive investigations, the molecular basis of the DENV PAMP recognized by the host RLR has been poorly defined, and which RLR is involved in sensing the DENV PAMP remains controversial. Here, we demonstrated that the DENV infection-induced interferon response is dependent upon both RIG-I and MDA5, with RIG-I playing a predominant role. Next we purified the DENV PAMP RNA from the DENV-infected cells, and demonstrated that the purified DENV PAMP is viral full-length double-stranded RNA bearing 5ppp modifications, likely representing the viral replicative-form RNA. Finally, we confirmed the nature of the DENV PAMP by reconstituting the viral replicative-form RNA from in vitro synthesized DENV genomic RNA. In conclusion, our work not only defined the molecular basis of the RLR-PAMP interaction during DENV infection, but also revealed the previously underappreciated recognition of the distinct moiety of same PAMP by different RLRs in innate immunity against RNA viruses. ImportanceThe molecular interaction between PAMPs and RLRs plays a crucial role in innate immune response against the RNA virus infection. To our knowledge, the exact molecular basis of the DENV PAMPs and which RLR member (RIG-I or MDA5) is involved in this recognition remain controversial. In this study, we demonstrated that the DENV PAMP is likely DENV replicative-form RNA, a double-stranded RNA. RIG-I and MDA5 can sense different moieties of this DENV PAMP to active innate immune response. Our work not only clarified which RLR and what viral PAMP are involved in innate immune sensing of DENV infection, but also revealed previously underappreciated recognition of the same PAMPs by different RLRs in innate immunity against RNA viruses.

microbiology↗

bioRxiv2024

Time- Space Resolved Fluorescence Spectroscopy in Live Chlamydomonas Cells under Light-Harvesting Regulation

We report here a technical advancement that enables time-resolved fluorescence spectroscopy in spatially resolved domains of a living cell at low temperatures. The technique is based on a combination of the self-developed cryo-confocal microscope system and the streak-camera technology. An instrumental response time of ca. 24 ps was achieved. This technique was applied to reveal the light-harvesting dynamics in local domains within single Chlamydomonas reinhardtii cells. Organisms performing oxygenic photosynthesis, like Chlamydomonas, have evolved a regulation mechanism called state transitions (ST), which maintains the excitation balance between PSI and PSII. ST relies on the shuttling of light-harvesting chlorophyll protein complex II (LHCII) between the two PSs. In the present experiment, cells were induced either to state1, where LHCII is bound to PSII, or state2, where LHCII moved and is bound to PSI. After the induction of ST, cells were immediately cooled to ca. 80 K, where PSI and PSII show clearly separated fluorescence emission bands, enabling the visualization of these components separately. Based on kinetic analyses of the time-resolved fluorescence spectra in both PSI-rich and PSII-rich local domains, we concluded that (1) the intracellular inhomogeneity in the PSII/PSI fluorescence ratio comes from that in the PSII/PSI stoichiometry, not from that in the antenna sizes of the PSs, and (2) the antenna size of PSI in state2 cells may larger in intact cells than that of the isolated PSI-LHCI-LHCII super-complex reported so far.

biophysics↗

bioRxiv2024

Single-cell Landscape of Immune Cells in Blood and Skin in Psoriasis

BackgroundPsoriasis is a systemic inflammatory disease for which there is currently no cure, in part due to an incomplete understanding of its pathophysiology. MethodsTo better understand the immune response in psoriasis, we performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) and on lesional and non-lesional skin samples from a cohort of 11 psoriasis patients and 8 healthy controls. Additionally, we conducted flow cytometry on PBMCs from a separate cohort of 13 psoriasis patients and 11 ankylosing spondylitis. FindingsOur study revealed altered immune signatures of specific myeloid and lymphocyte subsets in blood and skin, both in terms of cell numbers and gene expression. Specifically, we discovered elevated proportions of circulating CD14++ monocytes, increased expression of major histocompatibility complex (MHC) class II molecule by circulating CD16+ monocytes, as well as increased expression of genes related to skin homing and to pro-inflammatory responses in psoriasis by circulating plasmacytoid dendritic cells (pDCs). Circulating CD8+ T effector memory cells in psoriasis patients exhibited reduced abundance but increased skin-homing potential. In psoriatic lesions, we observed a hyperinflammatory myeloid-cell state and enrichment of IL17-producing cells with a tissue-resident memory T-cell signature. InterpretationThe changes in immune cell numbers and gene expression indicate a significant alteration in the immune landscape of psoriasis patients. This suggests that the immune system in psoriasis is reprogrammed, affecting both innate and adaptive branches. These findings provide new insights into the aberrant immune-cell signatures in the circulation and skin lesions in psoriasis, and thereby help to understand its pathophysiology. FundingThis study was financially supported by the National Natural Science Foundation of China (U23A6012), Science and Technology Planning Project of Guangzhou (2024A03J0055, 202206080005), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202204).

systems biology↗

bioRxiv2024

Tanshinone IIA potentiates the therapeutic efficacy of glucocorticoid in lipopolysaccharide-treated HEI-OC1 cells through modulation of Foxp3/Nrf2 signaling pathway

Glucocorticoids (GC) are commonly used to treat sudden sensorineural hearing loss (SSNHL), although some patients show resistance to this therapeutic approach. Clinical studies demonstrate the efficacy of tanshinone IIA (TA) in combination with GC for managing various human ailments. However, it remains unclear whether TA can mitigate GC resistance in SSNHL. Aim of the studyOur aim is to elucidate the role of NRF2-induced transcriptional regulation of HDAC2 in influencing GC resistance and investigate the involvement of TA-related molecular pathways in GC resistance. Materials and MethodsHEI-OC1 cells are treated with lipopolysaccharide (LPS) to establish an in vitro model for SSNHL. Subsequently, the cells are treated with dexamethasone (DXE) or DXE+TA. RT-qPCR and western blot analyses are employed to measure mRNA and protein levels of Forkhead box P3 (FOXP3), nuclear factor erythroid 2-related factor 2 (NRF2), and histone deacetylase 2 (HDAC2). Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2-deoxyuridine (EdU) assays are conducted to assess cell proliferation. Flow cytometry analysis is performed for apoptosis evaluation. Mechanistic studies involve Chromatin immunoprecipitation (ChIP), luciferase reporter, and DNA pull-down assays. ResultsTreatment with TA+DEX significantly enhances proliferation and suppresses apoptosis in LPS-treated HEI OC1 cells. TA upregulates HDAC2 expression by activating NRF2-mediated transcription of HDAC2, with the NRF2-HDAC2 binding site located at bases 419-429 (ATGACACTCCA) in the promoter sequence of HDAC2. Furthermore, TA upregulates FOXP3 expression to activate NRF2 transcription, with the predicted FOXP3-binding site located at bases 864-870 (GCAAACA) in the promoter sequence of NRF2. ConclusionThis studys findings suggest that TA enhances the therapeutic effects of GC on proliferation and apoptosis in HEI OC1 cells by up-regulating FOXP3/Nrf2 expression. These results indicate that TA may be promising in ameliorating GC resistance in patients with SSNHL.

pharmacology and toxicology↗

bioRxiv2024

High-resolution chromosome-level genome provides molecular insights into adaptive evolution in crabs

Crabs thrive in diverse ecosystems, from coral reefs to hydrothermal vents and terrestrial habitats. Here, we report a comprehensive genomic analysis of the mud crab using ultralong sequencing technologies, achieving a high-quality chromosome-level assembly. The refined 1.21 Gb genome, with an impressive contig N50 of 11.45 Mb, offers a valuable genomic resource. Gene family analysis shows expansion in development-related pathways and contraction in metabolic pathways, indicating niche adaptations. Notably, Investigation into Hox gene regulation sheds light on their role in pleopod development, with the Abd-A gene identified as a linchpin. Posttranscriptional regulation involving novel-miR1317 negatively regulates Abd-A levels. Furthermore, the fru genes potential role in ovarian development and the identification of novel-miRNA-35 as a regulator of Spfru2 add complexity to gene regulatory networks. Comparative functional analysis across Decapoda species reveals neofunctionalization of the elovl6 gene in the synthesis of long-chain polyunsaturated fatty acids (LC-PUFA), suggesting its importance in environmental adaptation. These findings contribute significantly to our understanding of crab adaptability and evolutionary dynamics, offering a robust foundation for future investigations.

genomics↗

bioRxiv2024

Transcranial Direct Current Stimulation over the Posterior Parietal Cortex Increases Non-target Retrieval during Visual Working Memory

Accurate visual working memory (VWM) requires precise content-context binding. Previous studies have revealed a close relationship between the posterior parietal cortex (PPC) and feature binding during VWM, this study further examined their causal relationship through three transcranial direct current stimulation (tDCS) experiments. In Experiment 1 (N = 57), participants underwent three sessions of tDCS separately, including PPC stimulation, occipital cortex stimulation, and sham stimulation, and completed a series of delayed estimation tasks for orientations before and after stimulation. Results showed that tDCS over PPC selectively prolonged recall response time (RT) and increased the probability of non-target responses (a.k.a. failure of feature binding). In Experiment 2 (N = 29), combining metacognition estimation during the task, we further investigated whether the effects of PPC stimulation on RT and increased probability of non-target responses were attributed to more mis-binding (i.e., participants self-reported "remembered" in non-target responses) or informed guessing (participants self-reported "forgotten" in non-target responses). We replicated the main findings in Experiment 1, and we also observed greater tDCS effects of PPC on RT in informed guessing trials than mis-binding trials while comparable effects on non-target response rates in these two types of trials. In Experiment 3 (N = 28), we then examined whether the effects of tDCS over PPC specifically influenced the memory retrieval process by using a change detection task. We found that PPC stimulation did not influence the recognition RT or accuracy. Together, this study provides causal evidence supporting the involvement of PPC in feature binding during VWM retrieval. Significance StatementVisual working memory (VWM) enables humans to temporarily store and process visual information, which requires accurate binding of items to their unique context. Accumulating studies posited that the posterior parietal cortex (PPC) is closely related to this binding process, the current study further examined their causal relationship. Through three strictly within-subject well-designed non-invasive neural stimulation experiments, we found that PPC stimulation selectively increased response time (RT) and binding error during VWM. Moreover, we found these changes were modulated by individual metacognition and only occurred during memory recall instead of recognition. Together, our results provided strong evidence that PPC is causally involved in the binding process during visual working memory retrieval.

neuroscience↗

bioRxiv2024

Mass Generation and Long-term Expansion of Hepatobiliary Organoids from Adult Primary Human Hepatocytes

Adult primary human hepatocytes (PHHs) are the gold standard in ex vivo toxicological studies and possess the clinical potential to treat patients with liver disease as advanced therapy medicinal products (ATMPs). However, the utility of this valuable cell type has been limited by short-term functionality and limited expansion potential in vitro. While notable advances have been made in the long-term maintenance of primary hepatocytes, there has been limited success in driving the efficient generation and expansion of adult PHH-derived organoids which recapitulate both liver tissue architecture and function, hampering in vitro studies and regenerative medicine applications. Here we describe the mass generation and long-term expansion of hepatobiliary organoids with functionally interconnected hepatic and biliary-like structures from adult primary human hepatocytes. Hepatobiliary organoids retain the expression of lineage and functional markers, closely resembling PHH, while also acquiring the expression of regeneration, fetal and biliary markers. Organoids perform key hepatocyte functions while proliferating and can be matured to enhance their functionality. As a proof-of-principle, we demonstrate that hepatobiliary organoids can recapitulate hallmarks of cholestasis and steatosis in vitro. Moreover, we show that hepatocytes can be transfected, transduced and gene edited in 3D prior to organoid generation, facilitating a wide range of applications. Our novel hepatobiliary organoid system bridges the gap between short-term functionality of primary human hepatocytes and the need for scalable, long-term organoid models of the adult liver, offering immense potential for drug testing, disease modeling, and advanced therapeutic applications.

cell biology↗

bioRxiv2024

Tap into non-symbiotic carbon? Exogenous myristate fuels the growth of symbiotic arbuscular mycorrhizal fungi but disrupts their carbon-phosphorus exchange with host plants

Arbuscular mycorrhizal fungi (AMF) are obligate biotrophs that rely on symbiotic carbohydrates and, in particular, lipids derived from their host plants. However, it remains unclear whether symbiotic AMF can access exogenous non-symbiotic lipids in the presence of plant-derived carbon, complicating our understanding of their relationship with host plants. Here, we investigated the direct uptake of exogenous 13C1-labeled myristate by three symbiotic AMF species (Rhizophagus irregularis, R. intraradices, and R. diaphanous) and assessed their growth responses using AMF-carrot hairy root co-culture systems. Furthermore, we explored the environmental distribution of myristate, and evaluated the impact of exogenous myristate on the carbon-phosphorus exchange between R. irregularis and alfalfa or rice in a greenhouse experiment. Our results showed that symbiotic AMF can absorb exogenous myristate, as evidenced by 13C enrichment and transcriptional activation of fatty acid transport and metabolism genes in AMF extraradical hyphae. Myristate is commonly present in various soil and plant environments, and its application increased both intraradical and extraradical fungal biomass, possibly linked to suppressed mycorrhizal-activated defense responses in host roots. Unexpectedly, exogenous myristate reduced the mycorrhizal phosphorus benefits for both alfalfa and rice and decreased their symbiotic carbon allocation to root-colonizing AMF, suggesting that the application of exogenous myristate may not be a promising strategy to enhance AM symbiosis. These findings provide new insights into understanding and manipulating the nutritional interactions between AMF and host plants.

ecology↗