Biology subjects

Wu, Y.

Publications and source records attributed to Wu, Y..

At least 433 records · Page 24Linked to original sources

bioRxiv2024

Association analysis of PAEP, KRT10 and BMP7 Genes SNPs with reproductive traits in Kele pigs

The aims of this study were to investigate the effects of single nucleotide polymorphisms (SNPs) in progestogen-associated endometrial protein (PAEP), keratin 10 (KRT10), and bone morphogenetic protein 7 (BMP7) genes on reproductive traits (total number of piglets born, number of piglets born alive, litter birth weight, number of piglets weaned and litter weight weaned) in Kele pigs. We used a total of 255 multiparous Kele sow (2-4 parities) as research materials. SNPs were identified by PCR amplification instrument and sequence alignment software DANMAN. The population genetic characteristics of SNPs were analyzed using the SHEsis online software. Bioinformatics analysis of SNPs were conducted using RNAfold, SOPMA, SWISS-MODEL, and Swiss-PdbViewer programs. The associations between the SNPs and reproductive traits in Kele pigs were analyzed through SPSS 22.0 software. In this study, nine SNPs were identified in the three genes: g.1884992 T>C (exon 4), g.1885152 G>C (intron 4) and g.1887834 G>A (intron 4) in PAEP, g.21643703 C>T (intron 4), g.21643714 G>A (intron 4) and g.21643741 G>A (exon 5) in KRT10, and g.57647887 G>A (intron 3), g.57647990 C>T (intron 3) and g.57648145 C>G (intron 3) in BMP7. In SNPs g.1884992 T>C of PAEP, missense mutation eventuated structural changes in mRNA and proteins secondary structure. In SNPs g.21643741 G>A of KRT10, synonymous mutation led to alteration in mRNA secondary structure. For PAEP, the CC genotype in SNPs g.1885152 G>C and the AA genotype in SNPs g.1887834 G>A showed significantly higher values than other genotypes in all reproduction traits except for litter birth weight, preliminarily identified as favorable genotypes. For KRT10, the GG genotype in SNPs g.21648641 G>A showed significant superiority than AA genotype (P<0.05) in all aspects except for litter birth weight, and notably surpassed the GA genotype in total number of piglets born (P<0.05), preliminarily recognized as a favorable genotype. Regarding BMP7, the GA genotype in SNPs g.57647887 G>A and the CT genotype in SNPs g.57647990 C>T exhibited significantly higher number of piglets born alive and number of piglets born alive compared to other genotypes (P<0.05). And the GG genotype in SNPs g.57648145 C>G was significantly associated with higher litter birth weight (P<0.05). The result of diplotype analyses indicated that the H3H3 (CCGGGG) of PAEP and H3H3 (CCGGAA) of KRT10 had a significant effect on the five traits. For BMP7, the H4H4 (AATTGG) diplotype showed a significant influence on all genotypes except litter birth weight.

genetics↗

bioRxiv2024

STANCE: a unified statistical model to detect cell-type-specific spatially variable genes in spatial transcriptomics

A significant challenge in analyzing spatial transcriptomics data is the effective and efficient detection of spatially variable genes (SVGs), whose expression exhibits non-random spatial patterns in tissues. Many SVGs show spatial variation in expression that is highly correlated with cell type categories or compositions, leading to the concept of cell type-specific spatially variable genes (ctSVGs). Existing statistical methods for detecting ctSVGs treat cell type-specific spatial effects as fixed effects when modeling, resulting in a critical issue: the testing results are not invariant to the rotation of spatial coordinates. Additionally, an SVG may display random spatial patterns within a cell type, and a ctSVG may exhibit random spatial patterns from a general perspective, indicating that an SVG does not necessarily have to be a ctSVG, and vice versa. This poses challenges in real analysis when detecting SVGs or ctSVGs. To address these problems, we propose STANCE, a unified statistical model developed to detect both SVG and ctSVGs in spatial transcriptomics. By integrating gene expression, spatial location, and cell type composition through a linear mixed-effect model, STANCE enables the identification of both SVGs and ctSVGs in an initial stage, followed by a second stage test dedicated to ctSVG detection. Its design ensures robustness in complex scenarios and the results are spatial rotation invariant. We demonstrated the performance of STANCE through comprehensive simulations and analyses of three public datasets. The downstream analyses based on ctSVGs detected by STANCE suggest promising future applications of the model in spatial transcriptomics and various areas of genome biology. A software implementation of STANCE is available at https://github.com/Cui-STT-Lab/STANCE.

bioinformatics↗

bioRxiv2024

Hydrogels with Independently Controlled Adhesion Ligand Mobility and Viscoelasticity Increase Cell Adhesion and Spreading

A primary objective in designing hydrogels for cell culture is recreating the cell-matrix interactions found within human tissues. Identifying the most important biomaterial features for these interactions is challenging because it is difficult to independently adjust variables such as matrix stiffness, stress relaxation, the mobility of adhesion ligands and the ability of these ligands to support cellular forces. In this work we designed a hydrogel platform consisting of interpenetrating polymer networks of covalently crosslinked poly(ethylene glycol) (PEG) and self-assembled peptide amphiphiles (PA). We can tailor the storage modulus of the hydrogel by altering the concentration and composition of each network, and we can tune the stress relaxation half-life through the non-covalent bonding in the PA network. Ligand mobility can be adjusted independently of the matrix mechanical properties by attaching the RGD cell adhesion ligand to either the covalent PEG network, the dynamic PA network, or both networks at once. Interestingly, our findings show that endothelial cell adhesion formation and spreading is maximized in soft, viscoelastic gels in which RGD adhesion ligands are present on both the covalent PEG and non-covalent PA networks. The dynamic nature of cell adhesion domains, coupled with their ability to exert substantial forces on the matrix, suggests that having different presentations of RGD ligands which are either mobile or are capable of withstanding significant forces are needed mimic different aspects of complex cell-matrix adhesions. By demonstrating how different presentations of RGD ligands affect cell behavior independently of viscoelastic properties, these results contribute to the rational design of hydrogels that facilitate desired cell-matrix interactions, with the potential of improving in vitro models and regenerative therapies.

bioengineering↗

bioRxiv2024

Distinct Neural Representations of Hunger and Thirst in Neonatal Mice before the Emergence of Food- and Water-seeking Behaviors

Hunger and thirst are two fundamental drives for maintaining homeostasis and elicit distinct food- and water-seeking behaviors essential for survival. For neonatal mammals, however, both hunger and thirst are sated by consuming milk from their mother. While distinct neural circuits underlying hunger and thirst drives in the adult brain have been characterized, it is unclear when these distinctions emerge in neonates and what processes may affect their development. Here we show that hypothalamic hunger and thirst regions already exhibit specific responses to starvation and dehydration well before a neonatal mouse can seek food and water separately. At this early age, hunger neurons drive feeding behaviors more than do thirst neurons. In vivo Neuropixels recordings in dehydrated and starved neonatal mice revealed that maternal presentation leads to a relative increase in activity which is suppressed by feeding on short timescales, particularly in hypothalamic and thalamic neurons. Changes in activity become more heterogeneous on longer timescales. Lastly, within neonatal regions that respond to both hunger and thirst, subpopulations of neurons respond distinctly to one or the other need. Combining food and water into a liquid diet throughout the animals life does not alter the distinct representations of hunger and thirst in the adult brain. Thus, neural representations of hunger and thirst in mice become distinct before food- and water-seeking behaviors mature and are robust to environmental changes in food and water sources.

neuroscience↗

bioRxiv2024

Unsaturated lipids as key control points for caveola formation and disassembly

Caveolae are specialized plasma membrane domains with a unique lipid composition. Recent work has implicated lipid peroxidation in triggering caveola disassembly, releasing caveolar proteins to regulate the cellular response to oxidative stress. Here we investigated the role of specific lipid species in caveola formation and response to oxidative stress. Systematic screening of lipid enzymes identified ACSL4, a critical enzyme in the synthesis of polyunsaturated fatty acid-containing lipids, and enzymes involved in the biosynthesis of pro-ferroptotic ether lipids, as key regulators of caveola formation. Omega-6 fatty acids promoted efficient caveola formation, while their oxidation or displacement by omega-3 or monounsaturated fatty acids disrupted this process. Moreover, we found that omega-6 fatty acid-containing membrane lipids were required for oxidative stress-induced caveola disassembly. These findings unveil a new model for caveola formation, highlighting specific unsaturated lipids as essential caveolar components and key control points for caveola disassembly in response to an oxidizing environment.

cell biology↗

bioRxiv2024

A brain-body feedback loop driving HPA-axis dysfunction in breast cancer

Breast cancer patients often exhibit disrupted circadian rhythms in circulating glucocorticoids (GCs), such as cortisol. This disruption correlates with reduced quality of life and higher cancer mortality1-3. The exact cause of this phenomenon -- whether due to treatments, stress, age, co-morbidities, lifestyle factors, or the cancer itself remains unclear. Here, we demonstrate that primary breast cancer alone blunts host GC rhythms by disinhibiting neurons in the hypothalamus, and that circadian phase-specific neuromodulation of these neurons can attenuate tumor growth by enhancing anti-tumor immunity. We find that mice with mammary tumors exhibit blunted GC rhythms before tumors are palpable, alongside increased activity in paraventricular hypothalamic neurons expressing corticotropin-releasing hormone (i.e., PVNCRH neurons). Tumor-bearing mice have fewer inhibitory synapses contacting PVNCRH neurons and reduced miniature inhibitory post-synaptic current (mIPSC) frequency, leading to net excitation. Tumor-bearing mice experience impaired negative feedback on GC production, but adrenal and pituitary gland functions are largely unaffected, indicating that alterations in PVNCRH neuronal activity are likely a primary cause of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in breast cancer. Using chemogenetics (hM3Dq) to stimulate PVNCRH neurons at different circadian phases, we show that stimulation just before the light-to-dark transition restores normal GC rhythms and reduces tumor progression. These mice have significantly more effector T cells (CD8+) within the tumor than non-stimulated controls, and the anti-tumor effect of PVNCRH neuronal stimulation is absent in mice lacking CD8+ T cells. Our findings demonstrate that breast cancer distally regulates neurons in the hypothalamus that control output of the HPA axis and provide evidence that therapeutic targeting of these neurons could mitigate tumor progression.

neuroscience↗

bioRxiv2024

Towards genuine three-dimensional diffusion imaging with physiological motion compensation

PurposeWe aim to implement a 3D DWI sequence and show its usage on patients with new ischemic lesions. Materials and MethodsThe proposed 3D DWI sequence was implemented by integrating second-order gradient moment nulling (M2) and cardiac motion synchronization (Sync). All data were acquired on a 3T MAGNETOM Prisma scanner (Siemens Healthcare, Erlangen, Germany) using a 64 channel head and neck coil. 21 healthy volunteers underwent 3D DWI scans at 0.9 mm isotropic resolution using four motion compensation methods for comparison: no compensation (M0), M2 only, Sync only and the proposed M2+Sync method. 2D phase variation maps with different motion compensation methods were also acquired for one subject to illustrate the mechanism of the proposed method. A ghost-to-signal ratio (GSR) and blurring index was defined and compared among the four methods with repeated measures ANOVA and Tukeys test. 3D DWI was compared with 2D DWI for ADC quantification. Image quality and ischemic lesion conspicuity were evaluated with 12 patients after endovascular treatment. >ResultsWhole brain 3D DWI was achieved at 0.9 mm isotropic resolution within 5 minutes using the proposed sequence. M2+Sync achieved the lowest level of GSR and blurring along the slice direction. ADC quantification showed no statistically significant difference between M2+Sync compared to 2D DWI. 3D DWI showed similar image quality, higher lesion conspicuity and counts compared to 2D DWI. ConclusionDirect 3D DWI can be achieved by the combination of second order gradient moment nulling and cardiac synchronization.

bioengineering↗

bioRxiv2024

Cytoplasmic ribosomes hitchhike on mitochondria to dendrites

Neurons rely on local protein synthesis to rapidly modify the proteome of neurites distant from the cell body. A prerequisite for local protein synthesis is the presence of ribosomes in the neurite, but the mechanisms of ribosome transport in neurons remain poorly defined. Here, we find that ribosomes hitchhike on mitochondria for their delivery to the dendrite of a sensory neuron in C. elegans. Ribosomes co-transport with dendritic mitochondria, and their association requires the atypical Rho GTPase MIRO-1. Disrupting mitochondrial transport prevents ribosomes from reaching the dendrite, whereas ectopic re-localization of mitochondria results in a concomitant re-localization of ribosomes, demonstrating that mitochondria are required and sufficient for instructing ribosome distribution in dendrites. Endolysosomal organelles that are involved in mRNA transport and translation can associate with mitochondria and ribosomes but do not play a significant role in ribosome transport. These results reveal a mechanism for dendritic ribosome delivery, which is a critical upstream requirement for local protein synthesis.

cell biology↗

bioRxiv2024

Structure-Based Computational Analysis of Interactions between Insulin Receptor and Insulin Inhibitory Receptor

The recently discovered insulin inhibitory receptor (inceptor) plays a crucial role in insulin resistance and diabetes by reducing the insulin receptor count on cell membranes, resulting in higher blood glucose levels and decreased insulin sensitivity. Therefore, understanding the mechanism of how the inceptor insulin receptor complex interacts is exceedingly important. This study uses computational drug discovery to inhibit this interaction. Initially, we employed AlphaFold-Multimer to model the inceptor-insulin receptor protein complex and subsequently identified specific inceptor residues likely involved in binding to the insulin receptor. Through virtual screening, thousands of potential small molecules were found to bind to the inceptor, and 10 with the highest probability were chosen for docking. Beta-L-fucose, beta-D-fucose, and alpha-L-fucose showed the most promising binding energies, meaning these three small molecules can effectively interrupt the binding between the complex. We also computationally mutated the binding site of the insulin receptor and calculated the change in binding energy of the inceptor insulin receptor complex, the most dramatic being a 0.4 kcal mol^-1 change when Arginine mutated to Tryptophan at residue 926. Our study suggests that the mutations led to disease primarily due to the change in interactions of the inceptor insulin receptor complex.

bioinformatics↗

bioRxiv2024

Biomolecular condensation of ERC1 recruits ATG8 and NBR1 to drive autophagosome formation for plant heat tolerance

Macroautophagy (hereafter autophagy) is essential for cells to respond to nutrient stress by delivering cytosolic contents to vacuoles for degradation via the formation of a multi-layer vesicle named autophagosome. A set of autophagy-related (ATG) regulators are recruited to the phagophore assembly site for the initiation of phagophore, as well as its expansion and closure and subsequent delivery into the vacuole. However, it remains elusive that how the phagophore assembly is regulated under different stress conditions. Here, we described an unknown Arabidopsis (Arabidopsis thaliana) cytosolic ATG8-interaction protein family (ERC1/2), that binds ATG8 and NBR1 to promote autophagy. ERC1 proteins translocate to the phagophore membrane and develop into classical ring-like autophagosomes upon autophagic induction. However, ERC1 proteins form large droplets together with ATG8e proteins when in the absence of ATG8 lipidation activity. We described the property of these structures as phase-separated membraneless condensates by solving the in vivo organization with spatial and temporal resolution. Moreover, ERC1 condensates elicits a strong recruitment of the autophagic receptor NBR1. Loss of ERC1 suppressed NBR1 turnover and attenuated plant tolerance to heat stress condition. This work provides novel insights into the mechanical principle of phagophore initiation via an unreported ERC1-mediated biomolecular condensation for heat tolerance in Arabidopsis.

plant biology↗

bioRxiv2024

Wnt5a and Notum Influence the Temporal Dynamics of Cartilaginous Mesenchymal Condensations in Developing Trachea.

The trachea is essential for proper airflow to the lungs for gas exchange. Frequent congenital tracheal malformations affect the cartilage, causing the collapse of the central airway during the respiratory cycle. We have shown that Notum, a Wnt ligand de-acylase that attenuates the canonical branch of the Wnt signaling pathway, is necessary for cartilaginous mesenchymal condensations. In Notum deficient tracheas, chondrogenesis is delayed, and the tracheal lumen is narrowed. It is unknown if Notum attenuates non-canonical Wnt signaling. We observed premature tracheal chondrogenesis after mesenchymal deletion of the non-canonical Wnt5a ligand. We hypothesize that Notum and Wnt5a are required to mediate the timely formation of mesenchymal condensations, giving rise to the tracheal cartilage. Ex vivo culture of tracheal tissue shows that chemical inhibition of the Wnt non-canonical pathway promotes earlier condensations, while Notum inhibition presents delayed condensations. Furthermore, non- canonical Wnt induction prevents the formation of cartilaginous mesenchymal condensations. On the other hand, cell-cell interactions among chondroblasts increase in the absence of mesenchymal Wnt5a. By performing an unbiased analysis of the gene expression in Wnt5a and Notum deficient tracheas, we detect that by E11.5, mRNA of genes essential for chondrogenesis and extracellular matrix formation are upregulated in Wnt5a mutants. The expression profile supports the premature and delayed chondrogenesis observed in Wnt5a and Notum deficient tracheas, respectively. We conclude that Notum and Wnt5a are necessary for proper tracheal cartilage patterning by coordinating timely chondrogenesis. Thus, these studies shed light on molecular mechanisms underlying congenital anomalies of the trachea.

developmental biology↗

bioRxiv2024

Repeat Ascaris challenge reduces worm intensity through gastric cellular reprograming

Ascariasis (roundworm) is the most prevalent parasitic nematode infection worldwide, impacting approximately 500 million people predominantly in low- and middle-income countries (LMICs). While people of all ages are infected with Ascaris, infection intensity (defined by worm burden) paradoxically peaks in pre-school and school aged children but then declines with age. The cause of age-dependent Ascaris worm intensity is not well understood but may be dependent on cellular changes in mucosal barrier sites. We have previously found that the gastric mucosa is a critical barrier site for Ascaris infection. Following oral ingestion of Ascaris eggs, larvae use AMCase secreted by gastric chief cells and acid secreted by gastric parietal cells to hatch. Once hatched, larvae translocate across the gastric mucosa to initiate the larval migratory cycle. However, inducing mucosal injury with administration of Tamoxifen induces mucosa cellular changes that impairs Ascaris hatching and reduces larval translocation across the gastric mucosa. In this study we established a repeated Ascaris suum challenge mouse model and evaluated if repeated Ascaris challenge also lead to cellular changes in the gastric mucosal barrier. We found that repeated Ascaris challenge caused cellular changes in the gastric mucosa which reduced worm intensity in the liver independent of the adaptive immune response. Thus, in endemic regions, where individuals experience recurrent infection throughout their lives, gastric cellular changes may be a key mechanism leading to the observed age-dependent Ascaris worm intensity changes from childhood to adulthood.

microbiology↗

bioRxiv2024

SynPull: a novel method for studying neurodegeneration-related aggregates in synaptosomes using super-resolution microscopy

Synaptic dysfunction is one of the primary hallmarks of both Alzheimers and Parkinsons disease, leading to cognitive and behavioural decline. While alpha-synuclein, beta-amyloid, and tau are involved in the physiological functioning of synapses, their pathological aggregation has been linked to synaptic dysfunction. However, the methodology for studying the small (sub-diffraction limit) and soluble aggregates -often called oligomers, formed by these proteins is limited. Here we describe SynPull, a novel method combining single-molecule pulldown, super-resolution microscopy, and advanced computational analyses, in order to reliably study the quantity and morphology of the oligomeric alpha-synuclein, beta-amyloid, and AT8-positive tau aggregates in synaptosomes harvested from post-mortem human brain samples and mouse models. Using SynPull, we show that AT8-positive tau is the predominant aggregate type in AD, with significantly more aggregates compared to the control samples, yet the aggregate size does not differ between disease and control samples. Meanwhile, the relatively smaller amount of alpha-synuclein and beta-amyloid aggregates found in the synapses are larger than the extra-synaptic ones. Collectively, these results show the utility of SynPull to study pathological aggregates in dementia, which can help further understand the disease mechanisms causing synaptic dysfunction. O_FIG O_LINKSMALLFIG WIDTH=140 HEIGHT=200 SRC="FIGDIR/small/609517v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@d53d06org.highwire.dtl.DTLVardef@1995971org.highwire.dtl.DTLVardef@bf3edaorg.highwire.dtl.DTLVardef@1b75ca5_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO Human post-mortem orbitofrontal cortex samples from subjects with neuropathological diagnosis of Alzheimers and Parkinsons disease, as well as age-matched controls cut into [~]300 mg sections, and MI2, APPNL-G-F, P301S, and C57Bl/6J mouse brains were first homogenised in synaptosome buffer using a Dounce homogeniser and then filtered and centrifuged to separate nuclei and organelles from the synaptic fragments. Then, the isolated synaptosomes were incubated on the SiMPull surface with anti-neurexin antibody overnight, followed by fixation and permeabilisation. Imaging antibodies against beta-amyloid, alpha-synuclein, and AT8-positive tau were added to the samples and dSTORM imaging was performed to super-resolve the aggregates. C_FIG

neuroscience↗

bioRxiv2024

A modular encapsulation system for precision delivery of proteins, nucleic acids and therapeutics

Targeted nanoparticles have the potential to revolutionize therapeutics for medical applications. Here, we demonstrate the utility of a flexible precision nanovesicle delivery system for functional delivery of DNA, RNA, proteins and drugs into target cells. Nanovesicles generated by the membrane sculpting protein caveolin, termed caveospheres, can be loaded with RNA, DNA, proteins or drugs post-synthesis or incorporate genetically-encoded cargo proteins during production without the need for protein purification. Functionalized fluorescently-labeled caveospheres form a modular system that shows high stability in biological fluids, specific uptake by target-positive cells, and can deliver proteins, drugs, DNA, and mRNA directly to the cytoplasm and nuclei of only the target cells. The negligible level of off-target transduction and uniform levels of targeted expression demonstrates advantages of the system over lipid-mediated gene delivery. Caveospheres can also be engineered to mimic viral particles by displaying the SARS-CoV-2-RBD protein, enabling targeted delivery to human bronchial epithelial cells. We demonstrate their application as a targeted transfection system for cells in culture, and critically, their efficacy in precision tumor killing in vivo.

bioengineering↗

bioRxiv2024

Solving the "Blind men and the elephant problem": Additive deep learning of complex high dimensional models from partial faceted datasets

Biological systems are complex networks involving tens of thousands of interacting molecular components, and measurable biological functions are emerging properties of these complex networks. Many quantitative studies in biology attempt to connect biological function with molecular components and genes, in the process developing mechanistic understanding. However, it is challenging to quantify the contribution of all components to the biological function simultaneously, especially at the single cell level. Instead, in typical experiments, only a subset of the variables (or facet) is measured. This makes it difficult to obtain a complete and unbiased understanding of the network and how different components of the network cooperatively contribute to the biological function. In this paper, we explore a machine learning approach to combine different facets of data and obtain a complete picture of the biological system based on conditional distributions from faceted data subsets. Both a polynomial regression approach and a neural network approach are developed and examined with two set of concrete examples: A mechanical spring network system deforming under external forces and a small (8-dimensions) biological network including the cellular senescence marker P53. In the later example, single cell data is collected to validate the machine learning approach. We find that the full system is successfully reconstructed from faceted data in both examples. We further discuss the additive property of the model, where the model predictive accuracy increases with increasing number of simultaneously measured variables (dimension of subsets). Our model provides a systematic and novel approach to integrate different pieces of experimental information to reconstruct complex high dimensional systems, arriving at an unbiased and wholistic model of biological function.

bioinformatics↗

bioRxiv2024

GPT-4V shows human-like social perceptual capabilities at phenomenological and neural levels

Humans navigate the social world by rapidly perceiving social features from other people and their interaction. Recently, large-language models (LLMs) have achieved high-level visual capabilities for detailed object and scene content recognition and description. This raises the question whether LLMs can infer complex social information from images and videos, and whether the high-dimensional structure of the feature annotations aligns with that of humans. We collected evaluations for 138 social features from GPT-4V for images (N=468) and videos (N=234) that are derived from social movie scenes. These evaluations were compared with human evaluations (N=2254). The comparisons established that GPT-4V can achieve human-like capabilities at annotating individual social features. The GPT-4V social feature annotations also express similar structural representation compared to the human social perceptual structure (i.e., similar correlation matrix over all social feature annotations). Finally, we modeled hemodynamic responses (N=97) to viewing socioemotional movie clips with feature annotations by human observers and GPT-4V. These results demonstrated that GPT-4V based stimulus models can also reveal the social perceptual network in the human brain highly similar to the stimulus models based on human annotations. These human-like annotation capabilities of LLMs could have wide range of real-life applications ranging from health care to business and would open exciting new avenues for phycological and neuroscientific research.

neuroscience↗

bioRxiv2024

Bio-macromolecular assembly machine for human limb lengthening

Growth plate (GP) is the critical cartilaginous structure for longitudinal bone growth. Herein, employing high-resolution analytical techniques, we explore the intricate mechanisms that govern the polarized mineralization patterns within GP. The GP-epiphysis interface displays a sharp transition in tissue modulus, acting as a "protective shell" for the underlying GP, whereas the GP-metaphysis interface exhibits a gradual modulus increase, enabling efficient load redistribution to metaphysis. The unique mechanical environments at these two interfaces contribute to polarized CaP mineralization patterns, which are regulated by a complex protein-based molecular machinery. The mineralization inhibitors SPP1 and AHSG enriched at the GP-epiphysis interface could act as a line of defence against mineralization. When these two proteins coexisted with the mineralization-promoting ENPP1 and ALPL at the GP-metaphysis interface, a sequential event of precise nucleation and programmable assembly of CaP minerals occur, forming "mineralization waves" to guide bone elongation. By replicating such specific macromolecular environment at GP-metaphysis interface, a hypertable amorphous calcium phosphate (ACP) phase is well-retained in vitro, demonstrating the possibility for precise and gentle control of ACP-hydroxyapatite (HAp) transformation under physiological conditions. Our study defines a novel concept of "mineralization waves" that govern the velocity and amplitude of GP-guided mineralization process.

bioengineering↗

bioRxiv2024

A novel role for Neurog2 in MYCN driven neuroendocrine plasticity of prostate cancer

Neuroendocrine prostate cancer (NEPC) presents a formidable clinical challenge owing to its aggressive progression and resistance to conventional therapies. A key driver of NEPC is the overexpression of MYCN, a well-established oncogene associated with neuroendocrine tumors. However, efforts to directly inhibit the N-Myc protein encoded by this gene have resulted in limited success, thereby hindering therapeutic advancements. To overcome this obstacle, we conducted unbiased genome-wide screening using isogenic prostate cancer cell lines to identify the synthetic vulnerabilities of MYCN. Among the identified candidates, NEUROG2 emerged as a significant candidate. Neurog2 is a proneural transcription factor (PTF) known for its role in developmental processes and trans-differentiation of adult cells. Our findings demonstrate that Neurog2 depletion does not affect non-malignant cells, but significantly suppresses the growth of MYCN-overexpressing cells and tumors in orthotopic NEPC models. Furthermore, our observations indicate that the Neurog2-mediated regulation of PTFs can facilitate NEPC development. Thus, targeting Neurog2 holds promise as an effective therapeutic strategy for MYCN-overexpressing NEPC.

cancer biology↗