Biology subjects

Ju, H.

Publications and source records attributed to Ju, H..

9 recordsLinked to original sources

bioRxiv2025

The Rise and Fall of SARM1 Base-Exchange Inhibitors

The sterile alpha and TIR motif containing 1 (SARM1) enzyme is a key driver of axonal degeneration in response to injury, making it an attractive target for treating chemotherapy-induced peripheral neuropathy (CIPN) and other nervous system diseases. In this study, we identified and optimised a new class of base-exchange inhibitors (BEXi) targeting SARM1 and explored their molecular interactions and conformational effects using cryo-EM, HDX-MS and SAXS. Although BEXi produced robust inhibition across all biochemical and cellular assay formats, application at sub-inhibitory concentrations consistently led to paradoxical SARM1 activation, and in neuronal assays, accelerated neurite degeneration. Further analysis showed that BEXi only delayed, rather than prevented, neurite degeneration when applied to primary neuronal cells, even at exceedingly high inhibitor concentrations. These results prompted us to discontinue BEXi development in favour of alternative strategies, underscoring the complexity of SARM1 as a therapeutic target and the need for comprehensive, mechanistically informed screening cascades.

neuroscience↗

bioRxiv2024

OfWRKY33 binds to the key linalool synthase gene OfTPS7 to promote linalool synthesis in Osmanthus fragrans flowers

Volatile aroma compounds make significant contributions to human perception of flowers. Osmanthus fragrans is a famous aroma plant and linalool along with its oxides are proved to be the dominant aroma active compounds. Although some terpene synthases (TPSs) have been characterized, a comprehensive study of the hub metabolic gene and its transcriptional regulation remain to be revealed. Here, we selected a specific cultivar Boyeyingui (BBYG) with the highest content of linalool among 20 wide-cultivated cultivars for genome and transcriptome sequencings. Among the 25 new putative OfTPSs, only OfTPS6, OfTPS7 could exclusively produce linalool in planta. Biochemical analysis demonstrated that OfTPS6, OfTPS7 were able to catalyze geranyl diphosphate (GPP) into linalool and a small proportion of other monoterpenes in vitro. Spatial and temporal correlation analysis further confirmed the transcript level of OfTPS7 was closely associated with linalool content in diverse cultivars and different tissues, suggesting OfTPS7 was the essential linalool synthase gene. Combined with yeast one-hybrid screen and weighted correlation network analysis (WGCNA), a nucleus-localized transcriptional factor OfWRKY33 was considered as a potential modulator. Y1H, dual-luciferase assay and electrophoretic mobility shift assay (EMSA) demonstrated that OfWRKY33 directly bound to the W-box of OfTPS7 promoter to stimulate its transcription. OfWRKY33 could coordinately induce the expressions of OfTPS7, 1-deoxy-d-xylulose 1 (OfDXS1), thereby promoting the linalool formation. The results first revealed the hub linalool synthase gene OfTPS7 and a novel TF participating in the complex transcriptional regulation of linalool biosynthesis in O. fragrans flowers.

biochemistry↗

bioRxiv2024

Remote ischemic conditioning attenuates transneuronal degeneration and promotes stroke recovery via CD36-mediated efferocytosis.

BACKGROUNDRemote ischemic limb conditioning (RIC) has been implicated in cross-organ protection in cerebrovascular disease, including stroke. However, the lack of a consensus protocol and controversy over the clinical therapeutic outcomes of RIC suggest inadequate mechanistic understanding of RIC. The current study identifies RIC-induced molecular and cellular events in the blood that enhance long-term functional recovery in experimental cerebral ischemia METHODSNaive mice or mice subjected to transient ischemic stroke were randomly selected to receive sham conditioning or RIC in the hind limb at 2 h post-stroke. At 3d post-stroke, monocyte composition in the blood was analyzed, and brain tissue was examined for monocyte-derived macrophages (M{varphi}), levels of efferocytosis, and CD36 expression. Mouse with conditional deletion of CD36 in M{varphi} (cKOMM{varphi}) was used to establish the role of CD36 in RIC-mediated modulation of efferocytosis, transneuronal degeneration, and recovery following stroke. RESULTSRIC applied 2h after stroke increased entry of monocytes into the injured brain. In the post-ischemic brain, M{varphi} had increased levels of CD36 expression and efferocytosis. These changes in brain M{varphi} were derived from RIC-induced changes in circulating monocytes. In the blood, RIC increased CD36 expression in circulating monocytes and shifted monocytes to a proinflammatory LY6CHigh state. Conditional deletion of CD36 in M{varphi} abrogated the RIC-induced monocyte shift in the blood and efferocytosis in the brain. During the recovery phase of stroke, RIC rescued the loss of the volume and of tyrosine hydroxylase+ neurons in substantia nigra (SN) as well as behavioral deficits in WT mice, but not in cKOMM{varphi} mice. CONCLUSIONSRIC induces a shift in monocytes to a proinflammatory state with elevated CD36 levels, and this is associated with CD36-dependent efferocytosis in M{varphi}s that rescues delayed transneuronal degeneration in the post-ischemic brain and promotes stroke recovery. Together, these findings provide novel insight into our mechanistic understanding of how RIC improves in post-stroke recovery. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIInfiltrated monocyte-derived macrophages (M{varphi}) into the post-ischemic brain cause neural inflammation, but they also engage in efferocytosis that promotes tissue repair in the injured CNS. C_LIO_LIRemote ischemic limb conditioning (RIC) changes monocyte composition and enhances functional recovery in experimental brain ischemia. C_LIO_LIThe application of RIC is safe, feasible, and tolerable in stroke patients, but clinical outcomes remain inconsistent. C_LI What New Information Does This Article Contribute?O_LIWe provide experimental evidence that RIC modifies peripheral monocyte composition and molecular expression, and leads to favorable changes in debris clearance, structure integrity, transneuronal degeneration, and behavior following stroke. C_LIO_LIProtective effects of RIC disappear in the absence of CD36 in M{varphi}, suggesting an essential mechanistic role for CD36 in RIC-induced endogenous protective outcomes. C_LIO_LIThe current study demonstrates that immune-mediated RIC mechanisms facilitate inflammatory and recovery processes in the injured CNS. Given the challenges in directly manipulating the brain after stroke, the study suggests that RIC is a promising alternative strategy by inducing changes in peripheral monocytes that can influence injury progression and recovery. Moreover, RIC-induced peripheral changes uncovered by this study may serve as biomarkers to establish an optimal RIC protocol. C_LI

neuroscience↗

bioRxiv2024

The Class III peroxidase OsPrx20 is a key regulator of stress response and growth in rice

In plants, reactive oxygen species maintain strictly low intracellular levels that is prerequisite for their function as second messengers. However, abiotic and biotic stresses are also long-term processes, requiring rapid scavenging of excess intracellular ROS. Plant Class III peroxidases, as multifunctional enzymes, are core enzymes in regulating intracellular ROS homeostasis and are key to regulating the complicated signaling network. Here, we found a rice Class III peroxidase OsPrx20 maintains intracellular ROS homeostasis in different conditions. OsPrx20 is a target of Ca2+/calmodulin-dependent protein kinase (OsDMI3) and phosphorylates its Thr-244 site by OsDMI3. Overexpression of OsPrx20 enhances osmotic stress tolerance but reduces blast resistance, while lack of OsPrx20 is opposite, suggesting OsPrx20 positively regulates osmotic stress tolerance but negatively regulates blast resistance in rice. Meanwhile, overexpression of OsPrx20 enlarges spike size and grain fullness, whereas lack of OsPrx20 leads to dwarfism and smaller spike. In ABA signaling, OsPrx20 Thr-244 phosphorylation is specifically dependent on OsDMI3 to reduce the sensitivity of ABA to seed germination and root growth and to enhance osmotic stress tolerance without affecting spike and grain development. Our study reveals an essential regulatory mechanism that directly activates OsPrx20 in ABA signaling, highlighting the multi-functionality of OsPrx20 in different biological processes.

plant biology↗

bioRxiv2024

Machine learning-guided reconstruction of cytoskeleton network from Live-cell AFM Images

How actin filaments (F-actins) are dynamically reorganized in motile cells at the level of individual filaments is an open question. To this end, we developed a high-speed atomic force microscopy (HS-AFM) to live-imagine intracellular dynamics of the individual F-actins. However, noise and low resolution made it difficult to fully recognize individual F-actins in the HS-AFM images. To tackle this problem, we developed a new machine learning method that quantitatively recognizes individual F-actins. The method estimates F-actin orientation from the image while improving the resolution. We found that F-actins were oriented at {+/-}35{degrees} toward the membrane in the lamellipodia, which is consistent with Arp2/3 complex-induced branching. Furthermore, in the cell cortex our results showed non-random orientation at four specific angles, suggesting a new mechanism for F-actin organization demonstrating the potential of our newly developed method to fundamentally improve our understanding of the structural dynamics of F-actin networks.

biophysics↗

bioRxiv2021

Differential effects of Wnt-β-catenin signaling in Purkinje cells and Bergmann glia in SCA1

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease characterized by progressive ataxia and degeneration of specific neuronal populations, including Purkinje cells (PCs) in the cerebellum. Previous studies have demonstrated a critical role for various evolutionarily conserved signaling pathways in cerebellar patterning, such as the Wnt-{beta}-catenin pathway; however, the roles of these pathways in adult cerebellar function and cerebellar neurodegeneration are largely unknown. In this study, we found that Wnt-{beta}-catenin activity was progressively enhanced in multiple cell types in the adult SCA1 mouse cerebellum, and that activation of this signaling occurs in an ataxin-1 polyglutamine (polyQ) expansion-dependent manner. Genetic manipulation of the Wnt-{beta}-catenin signaling pathway in specific cerebellar cell populations revealed that activation of Wnt-{beta}-catenin signaling in PCs alone was not sufficient to induce SCA1-like phenotypes, while its activation in astrocytes including Bergmann glia (BG) resulted in gliosis and disrupted BG localization, which was replicated in SCA1 mouse models. Our studies identify a novel mechanism in which polyQ-expanded ataxin-1 positively regulates Wnt-{beta}-catenin signaling, and demonstrate that different cell types have distinct responses to the enhanced Wnt-{beta}-catenin signaling in the SCA1 cerebellum, underscoring an important role of BG in SCA1 pathogenesis. Significance statementThe mechanisms underlying the degeneration of specific cellular populations in various neurodegenerative disorders remain unknown. Here, we show that the polyQ expansion of ataxin-1 activates the Wnt-{beta}-catenin signaling pathway in various cell types, including Purkinje cells and Bergmann glia, in the cerebellum of SCA1 mouse models. We used conditional mouse genetics to activate and silence this pathway in different cell types and found elevated activity of this signaling pathway impacted Bergmann glia and Purkinje cell populations differently. This study highlights the important role of Wnt-{beta}-catenin signaling pathway in glial cell types for SCA1 pathogenesis.

neuroscience↗

bioRxiv2021

A global dataset for the projected impacts of climate change on four major crops

Reliable estimates of the impacts of climate change on crop production are critical for assessing the sustainability of food systems. Global, regional, and site-specific crop simulation studies have been conducted for nearly four decades, representing valuable sources of information for climate change impact assessments. However, the wealth of data produced by these studies has not been made publicly available. Here, we develop a global dataset by consolidating previously published meta-analyses and data collected through a new literature search covering recent crop simulations. The new global dataset builds on 8314 simulations from 203 studies published between 1984 and 2020. It contains projected yields of four major crops (maize, rice, soybean, and wheat) in 91 countries under major emission scenarios for the 21st century, with and without adaptation measures, along with geographical coordinates, current temperatures, local and global warming levels. This dataset provides a basis for a comprehensive understanding of the impacts of climate change on crop production and will facilitate the rapidly developing data-driven machine learning applications.

plant biology↗

bioRxiv2020

Reduction of Nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration

Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding TDP-43, account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS (fALS)-causing mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimers disease, and Parkinsons disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a novel function of Nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and lifespan deficits in two distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared along the autophagy-lysosome axis, targeted reduction of Nlk represents a viable approach to therapy development for multiple neurodegenerative disorders.

neuroscience↗

bioRxiv2018

Network topology of neural systems supporting avalanche dynamics predicts stimulus propagation and recovery

Many neural systems display avalanche behavior characterized by uninterrupted sequences of neuronal firing whose distributions of size and durations are heavy-tailed. Theoretical models of such systems suggest that these dynamics support optimal information transmission and storage. However, the unknown role of network structure precludes an understanding of how variations in network topology manifest in neural dynamics and either support or impinge upon information processing. Here, using a generalized spiking model, we develop a mechanistic understanding of how network topology supports information processing through network dynamics. First, we show how network topology determines network dynamics by analytically and numerically demonstrating that network topology can be designed to propagate stimulus patterns for long durations. We then identify strongly connected cycles as empirically observable network motifs that are prevalent in such networks. Next, we show that within a network, mathematical intuitions from network control theory are tightly linked with dynamics initiated by node-specific stimulation and can identify stimuli that promote long-lasting cascades. Finally, we use these network-based metrics and control-based stimuli to demonstrate that long-lasting cascade dynamics facilitate delayed recovery of stimulus patterns from network activity, as measured by mutual information. Collectively, our results provide evidence that cortical networks are structured with architectural motifs that support long-lasting propagation and recovery of a few crucial patterns of stimulation, especially those consisting of activity in highly controllable neurons. Broadly, our results imply that avalanching neural networks could contribute to cognitive faculties that require persistent activation of neuronal patterns, such as working memory or attention.

neuroscience↗