Biology subjects

Liu, X.

Publications and source records attributed to Liu, X..

At least 847 records · Page 47Linked to original sources

bioRxiv2024

Determination and characterization of papillomaviurs and parvovirus causing mass mortality of Chinese tongue sole (Cynoglossus semilaevis) in China

Chinese tongue sole (Cynoglossus semilaevis) is one of the representative species in flatfish aquaculture in China. In recent years, massive mortality of farmed Chinese tongue soles occurred in Tianjin, China. The causative pathogens were determined as Cynoglossus semilaevis papillomavirus (CsPaV) and parvovirus (CsPV) by electron microscopy, virus isolation, experimental challenge, histopathological analysis, genome sequencing, fluorescence In situ hybridization (FISH) and epidemiology investigation. Electron microscopy showed large numbers of spherical non-enveloped virus particles presenting in liver, kidney, spleen, gill and heart of the diseased fish. The viruses were isolated and propagated in flounder gill cells (FG) and induced a typical cytopathic effect (CPE). The cumulative mortality reached 100% at 8 dpi by intraperitoneal injection. The complete genome of CsPaV and CsPV was 5939 bp and 3663 bp in size respectively, and both viral genomes shared no nucleotide sequence similarity with other viruses. The CsPaV contained seven predicated protein coding regions (E1, E2, L2, L1a, L1b, sORF1 and sORF2) and CsPV contained three predicated protein coding regions (NS1, VP and ORF3). Phylogenetic analysis basing on L1 and NS1 protein sequences revealed that CsPaV and CsPV are novel members belonging to new genus in Papillomaviridae and Parvoviridae family. FISH results showed positive signals in spleen and kidney tissues from CsPaV and CsPV infected fish and the two viruses could co-infected one cell. Epidemiological investigation showed that the two viruses cocurrented in 82.9% sampled fish and they were proved to be the pathogenic agents of the emerging disease in farmed Chinese tongue soles in China. This study represents the first report of co-infection of papillomavirus and parvovirus in farmed fish and provides a basis for further studies on prevention and treatment of the emerging viral disease, and also represents clues to elucidate the the mechanisms of viruses co-infection and evolution of viruses. Author summaryChinese tongue sole is a valuable fish kept in marincultures. Outbreak of an emerging disease caused massive mortality and resulted in significant economic loss. The pathogenic agent remains unknown. In this study, we identified papillomavirus (CsPaV) and parvovirus (CsPV) from the diseased fish simultaneously, and they are proved to be novel members belonging to new genus in Papillomaviridae and Parvoviridae family. It was shown that the emerging disease was caused by co-infection with the two viruses. Viral co-infections are widespread in nature, however, studies and available data on viral co-infections in fish aquaculture are limited. Our findings represent new clues to elucidate the mechanisms of viruses co-infection and evolution of viruses, and moreover, the present study provide a solution for the control of emerging viral diseases in Chinese tongue sole.

microbiology↗

bioRxiv2024

Self-Supervised Electrocardiograph De-noising

The electrocardiogram (ECG) records heart-beats and is potentially life-saving. However, the ECG signals (e.g., recorded by the standard ECG monitoring system or the Holter ECG monitoring system) heavily suffered from the noises. Thus, the recorded signals involve meaningful cardiac deflections, other biological waves (e.g., caused by the muscle or electrode movements), and even some noises from the monitoring devices (e.g., the power cables). These noise sources would result in inaccurate analyses of cardiac diseases, thus requiring the ECG de-noising methods in data pre-processing phase before the diagnoses. Previous work provided various ECG de-noising approaches, typically based on some filter algorithms or some wave decomposition algorithms. Most of these approaches did not profoundly consider the ECG signals specific data structure, and were not adaptive to the signals recorded by various devices or different skin electrodes. Inspired by the ECG recording theory, we find it available to extract noise information from noisy ECG signals directly. We propose a new ECG de-noising method implemented by the neural network, which de-noise the ECG signals without the supervision of the clean signals. The procedure in the self-supervision is straightforward: we first estimate and simulate the noise signals according to the given noisy ECG signals, and then "subtract" the simulated noises to obtain the de-noised ECG signals by the neural network. Experiments on a public dataset verify that our approach is adaptive to ECG signals from different patients and devices. Also, it is proven that the classification on the ECG signals de-noised by the proposed de-noising methods outperforms those with the traditional de-noising methods.

bioengineering↗

bioRxiv2024

Single-Nuclei RNA Sequencing Identifies Type C Low-Threshold Mechanoreceptors as Key Players in Paclitaxel-Induced Peripheral Neuropathy

Neuropathic pain triggered by chemotherapy poses a significant clinical challenge. Investigating cell type-specific alterations through single-cell transcriptome analysis holds promise in understanding symptom development and pathogenesis. In this study, we performed single nuclei RNA (snRNA) sequencing of dorsal root ganglions (DRG) to explore the molecular mechanism underlying paclitaxel-induced neuropathic pain. Mouse exposed to repeated paclitaxel doses developed persistent pain hypersensitivity lasting at least 21 days. The snRNA sequencing unveiled seven major cell types within DRGs, with neurons further subdivided into 12 distinct subclusters using known markers. Notably, type C low-threshold mechanoreceptors (C_LTMR) exhibited the most pronounced transcriptomic changes post-paclitaxel administration. Differential gene expression and Gene Ontology (GO) analysis highlighted suppressed potassium-related currents, microtubule transport, and mitochondrial functions in C_LTMR following paclitaxel treatment. Meanwhile, Gene Set Enrichment Analysis (GSEA) suggested increased Interleukin 17 production in C_LTMR after paclitaxel exposure. Pseudo-time analysis uncovered nine distinct states (state 1 to 9) of C_LTMR. State 1 exhibits higher prevalence in paclitaxel-treated mice and altered neurotransmission properties, likely contributing to paclitaxel-induced pain hypersensitivity. This comprehensive exploration sheds light on the molecular mechanisms driving paclitaxel-induced neuropathic pain, offering potential avenues for therapeutic intervention.

neuroscience↗

bioRxiv2024

Hunting for peptide binders of specific targets with data-centric generative language models

Bioactive peptides have become strong candidates for a variety of clinical therapies due to their diverse advantages, which promotes the development of deep generative models for peptide design. Considering that existing methods cannot effectively deal with the conformational flexibility of peptides and are difficult to capture accurate residue-to-residue interaction dependencies, we propose a unified weakly order-dependent autoregressive language modeling architecture (PepGenWOA) for bioactive peptide generative design with tolerating out-of-order input as inductive bias. The superiority of PepGenWOA is demonstrated by generating three classes of therapeutic peptides, including antimicrobial peptides, anticancer peptides, and peptide binders. For antimicrobial and anticancer peptide generation, PepGenWOA not only comprehensively outperforms state-of-the-art baseline models, but also exhibits a significant propensity to incorporate specific types of residues that are beneficial for antimicrobial or anticancer bioactivity. For characteristic-guided peptide binder generation, the pretrained PepGenWOA is fine-tuned with Mixture-of-Experts-style plugins with lifelong learning paradigm, thereby achieving the best trade-off between memory stability for world knowledge and learning plasticity for new downstream tasks. The subsequent structure-based virtual screening anchors the 7 most promising candidates from the mega-scale synthetic sequence space, reducing the number of candidates for in vitro experimental validation by 5 orders of magnitude. A target binding rate of 28.6% with binding specificity further confirms the effectiveness of the fine-tuning strategy. Overall, PepGenWOA is a unified architecture for peptide generative design that can be flexibly customized for different task requirements, thereby harnessing generative language models to reach the "dark space" of biological language.

bioinformatics↗

bioRxiv2023

Structure of the minor spliceosomal U11 snRNP

The minor spliceosome catalyses the excision of U12-dependent introns from pre-mRNAs. These introns are rare, but their removal is critical for cell viability. We obtained a cryo-EM reconstruction of the 13-subunit U11 snRNP complex, revealing structures of U11 snRNA and five minor spliceosome-specific factors. U11 snRNP appears strikingly different from the equivalent major spliceosome U1 snRNP. SNRNP25 and SNRNP35 form a dimer, which specifically recognises U11 snRNA. PDCD7 forms extended helices, which bridge SNRNP25 and SNRNP48, located at the distal ends of the particle. SNRNP48 forms multiple interfaces with U11 snRNP and, together with ZMAT5, are positioned near the 5-end of the U11 snRNA and likely stabilise the binding of the incoming 5SS. Our structure provides mechanistic insights into U12-dependent intron recognition and the evolution of the splicing machinery.

biochemistry↗

bioRxiv2023

Mapping the bioimaging marker of Alzheimer's disease based on pupillary light response-driven brain-wide fMRI in awake mice

Pupil dynamics has emerged as a critical non-invasive indicator of brain state changes. In particular, pupillary-light-responses (PLR) in Alzheimers disease (AD) patients may be used as biomarkers of brain degeneration. To characterize AD-specific PLR and its underlying neuromodulatory sources, we combined high-resolution awake mouse fMRI with real-time pupillometry to map brain-wide event-related correlation patterns based on illumination-driven pupil constriction (Pc) and post-illumination pupil dilation recovery (amplitude, Pd, and time, T). The Pc-driven differential analysis revealed altered visual signal processing coupled with reduced thalamocortical activation in AD mice compared with the wild-type normal mice. In contrast, the post-illumination pupil dilation recovery-based fMRI highlighted multiple brain areas related to AD brain degeneration, including the cingulate cortex, hippocampus, septal area of the basal forebrain, medial raphe nucleus, and pontine reticular nuclei (PRN). Also, brain-wide functional connectivity analysis highlighted the most significant changes in PRN of AD mice, which serves as the major subcortical relay nuclei underlying oculomotor function. This work combined non-invasive pupil-fMRI measurements in preclinical models to identify pupillary biomarkers based on neuromodulatory dysfunction coupled with AD brain degeneration.

neuroscience↗

bioRxiv2023

LLPS condensates of Fha initiate the inside-out assembly of the type VI secretion system

The type VI secretion system (T6SS) is one of the most powerful nanomachines employed by Gram-negative pathogens for penetrating diverse cell envelopes, including bacteria and fungi, to deliver potent effectors into target cells. While the membrane-anchored contractile tubular structure of the T6SS is well characterized, the assembly process remains poorly understood. The prevailing model suggests that the assembly of T6SS initiates from its outer-membrane component. Here, we report a distinct model that the cytoplasmic protein Fha initiates T6SS assembly in Acidovorax citrulli, an important plant pathogen. Fha dictates the formation of the inner-membrane complex and the baseplate, and directly interacts with these key components. Importantly, imaging and biochemical assays reveal that Fha undergoes liquid-liquid phase separation (LLPS), forming condensates that selectively recruit essential T6SS proteins, which are otherwise dispersed in cells. Fha also exhibited conserved functions in human pathogens Vibrio cholerae and Pseudomonas aeruginosa. These findings unveil an inside-first LLPS-driven model for T6SS assembly and suggest LLPS might be broadly involved in mediating the assembly of bacterial macromolecular complexes and facilitating interspecies interactions and pathogenesis. Significance statementThe T6SS plays a pivotal role in interspecies competition and host-microbe interactions by delivering toxins to various prokaryotes and eukaryotes. Its crucial function relies on a membrane-anchored macromolecular structure comprising at least 13 conserved components. However, the mechanisms governing the efficient assembly of its diverse cytosolic and membrane-bound components remain elusive. Here, we identify Fha, a conserved cytosolic protein, as a key initiator of T6SS assembly. Fha recruits multiple structural and effector components, forming LLPS condensates. Fha homologs of plant and human pathogens exhibit conserved functions. Our findings not only unveil an inside-first assembly model for the T6SS, initiating from inner-membrane and baseplate components, but also suggest LLPS may have a broader impact on bacterial physiology beyond intracellular activities.

microbiology↗

bioRxiv2023

Distinct roles of H3K27me3 and H3K36me3 in vernalization response, maintenance and resetting in winter wheat

Winter plants rely on vernalization, a vital process for adapting to cold and ensuring successful reproduction. However, understanding the role of histone modifications in guiding the vernalization process in winter wheat is limited. In this study, we investigate the transcriptome and chromatin dynamics in the shoot apex throughout the life cycle of winter wheat in the field. Two core histone modifications, H3K27me3 and H3K36me3, exhibit opposite pattern on the key vernalization gene VERNALIZATION1 (VRN1), correlated with its induction during cold exposure. Additionally, H3K36me3 remains high at VRN1 after cold exposure, maintaining its active state. Mutations in FERTILIZATION-INDEPENDENT ENDOSPERM (TaFIE) and SET DOMAIN GROUP 8 (TaSDG8), writer complex components of H3K27me3 and H3K36me3, respectively, affect flowering time. Interestingly, VRN1 loses its high expression after cold exposure memory in the absence of H3K36me3. During embryo development, VRN1 is silenced with the removal of H3K36me3 in both winter and spring alleles. H3K27me3 is selectively added to the winter allele, influencing the cold exposure requirement for the next generation. Integrating gene expression with H3K27me3 and H3K36me3 patterns identified potential regulators of flowering. This study reveals distinct roles of H3K27me3 and H3K36me3 in controlling vernalization response, maintenance, and resetting in winter wheat. Significance StatementVernalization, initially observed in cereals, lacks a comprehensive understanding of its underlying mechanism, particularly regarding chromatin-mediated transcriptional regulation in winter wheat. By delving into the transcriptome and chromatin dynamics in the shoot apex throughout winter wheats life cycle, we pinpointed two crucial histone modifications, H3K27me3 and H3K36me3, each playing distinct roles at different vernalization stages. H3K27me3 is implicated in establishing and resetting the extended cold exposure requirement for winter wheat, gradually diminishing during vernalization. On the other hand, H3K36me3 is crucial for maintaining VRN1s active state post-cold exposure, contributing to the memory of the vernalization treatment. Additionally, the integration of transcriptome and histone modification profiles unveiled potential novel regulators of flowering in winter wheat.

plant biology↗

bioRxiv2023

Substrate identification and specificity profiling of deubiquitylases against endogenously-generatedubiquitin-protein conjugates

Deubiquitylating enzymes (DUBs) remove ubiquitin from proteins thereby regulating their stability or activity. Our understanding of DUB-substrate specificity is limited because DUBs are typically not compared to each other against many physiological substrates. By broadly inhibiting DUBs in Xenopus egg extract, we generated hundreds of ubiquitylated proteins and compared the ability of 30 DUBs to deubiquitylate them using quantitative proteomics. We identified five high impact DUBs (USP7, USP9X, USP36, USP15 and USP24) that each reduced ubiquitylation of over ten percent of the isolated proteins. Candidate substrates of high impact DUBs showed substantial overlap and were enriched for disordered regions, suggesting this feature may promote substrate recognition. Other DUBs showed lower impact and non-overlapping specificity, targeting distinct non-disordered proteins including complexes such as the ribosome or the proteasome. Altogether our study identifies candidate DUB substrates and defines patterns of functional redundancy and specificity, revealing substrate characteristics that may influence DUB-substrate recognition.

biochemistry↗

bioRxiv2023

The E3 ubiquitin ligase RNF220 maintains hindbrain Hox expression patterns through regulation of WDR5 stability

The spatial and temporal linear expression of Hox genes establishes a regional Hox code, which is crucial for the antero-posterior (A-P) patterning, segmentation, and neuronal circuit development of the hindbrain. RNF220, an E3 ubiquitin ligase, is widely involved in neural development via targeting of multiple substrates. Here, we found that the expression of Hox genes in the pons was markedly up-regulated at the late developmental stage (post-embryonic day E15.5) in Rnf220-/- and Rnf220+/-mouse embryos. Single-nucleus RNA-seq analysis revealed different Hox de-repression profiles in different groups of neurons, including the pontine nuclei (PN). The Hox pattern was disrupted and the neural circuits were affected in the PN of Rnf220+/- mice. We showed that this phenomenon was mediated by WDR5, a key component of the TrxG complex, which can be polyubiquitinated and degraded by RNF220. Intrauterine injection of WDR5 inhibitor (WDR5-IN-4) and genetic ablation of Wdr5 in Rnf220+/- mice largely recovered the de-repressed Hox expression pattern in the hindbrain. In P19 embryonal carcinoma cells, the retinoic acid induced Hox expression was further stimulated by Rnf220 knockdown, which can also be rescued by Wdr5 knockdown. In short, our data suggest a new role of RNF220/WDR5 in Hox pattern maintenance and pons development in mice.

developmental biology↗

bioRxiv2023

The Horizontal Ladder Test (HLT) protocol: A novel, optimized, and reliable means of assessing motor coordination in Sus scrofa domesticus

Pigs can be an important model for preclinical biological research, including neurological diseases such as Alcohol Use Disorder. Such research often involves longitudinal assessment of changes in motor coordination as the disease or disorder progresses. Current motor coordination tests in pigs are derived from behavioral assessments in rodents and lack critical aspects of face and construct validity. While such tests may permit for the comparison of experimental results to rodents, a lack of validation studies of such tests in the pig itself may preclude the drawing of meaningful conclusions. Here, we present a novel, optimized, and reliable horizontal ladder test (HLT) test protocol for evaluating motor coordination in pigs and an initial validation of its construct validity using voluntary alcohol consumption as an experimental manipulation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/571517v2_ufig1.gif" ALT="Figure 1"> View larger version (101K): org.highwire.dtl.DTLVardef@167924eorg.highwire.dtl.DTLVardef@b674f2org.highwire.dtl.DTLVardef@b7c369org.highwire.dtl.DTLVardef@7e5a42_HPS_FORMAT_FIGEXP M_FIG C_FIG

animal behavior and cognition↗

bioRxiv2023

ARHGAP32 as a novel RhoGAP interacting with desmoplakin is required for desmosomal organization and assembly

Desmosomes are specialized cell-cell junctions that play a critical role in maintaining tissue barrier integrity, particularly in mechanically stressed tissues. The assembly of desmosomes is regulated by the cytoskeleton and its regulators, and desmosomes also function as a central hub for regulating F-actin. However, the specific mechanisms underlying the crosstalk between desmosomes and F-actin, particularly involving RhoGAP or RhoGEF proteins, remain unclear. In our study, we identified that ARHGAP32, a Rho GTPase-activating protein, is located in desmosomes through its interaction with DSP via its GAB2-interacting domain. Using CRISPR-Cas9 gene knockout system, we confirmed that ARHGAP32 is required for proper desmosomal organization, maturation, and length regulation. Notably, the loss of ARHGAP32 resulted in increased formation of F-actin stress fibers and phosphorylation of MYOSIN at T18/S19, indicating enhanced actomyosin contractility. Furthermore, inhibition of ROCK1 kinase activity using Y27632 effectively restored desmosomal organization. Moreover, we demonstrated that the regulation of desmosomes by ARHGAP32 is crucial for maintaining the integrity of epithelial cell sheets. Collectively, our study unveils ARHGAP32 as a RhoGAP present at desmosomes, potentially facilitating the crosstalk between desmosomes and F-actin. Its presence is indispensable for desmosomal assembly and the preservation of epithelial cell sheet integrity by regulating actomyosin contractility.

cell biology↗

bioRxiv2023

Comparison of chronic aerosol inhalation with combustible cigarette and e-cigarette on the psychiatric behaviors and neuroimmune profile in mice

With the worldwide use of electronic cigarettes (e-cigarettes) as a substitution for tobacco, the effects of e-cigarette vapor exposure on human health have been investigated. However, the comparison of long-term effects of aerosol inhalation with combustible cigarette and e-cigarette on the psychiatric behaviors has not been fully revealed. The present study examines the distinct effects of combustible cigarette and e-cigarette on anxiety, depression, cognition, and social behaviors. Here we found that the combustible cigarette induced the higher level of anxiety after long-term inhalation compared to the e-cigarettes with or without the tobacco flavor. Since the mechanism of action on the psychiatric behaviors entails the alterations on the neuroimmune-sensors and principal regulators such as glial cells, we further profiled the alterations of microglia and astrocytes by chronic inhalation of combustible tobacco cigarette, specifically the negative correlations between the IBA-1 level in the locus coeruleus (LC) and the latency to nest in VLT; as well as the GFAP level in LC and the open arm time in EPM were observed. Our current data provided an insight into the less impact of e-cigarettes on the anxiety-like behaviors and neuroimmune activation compared to combustible tobacco cigarettes which is not related to the flavor in e-cigarette, and the modulation on the neuroimmune signals in LC could be a therapeutic target for smoking-related anxiety.

animal behavior and cognition↗

bioRxiv2023

Ultrasound programmable hydrogen-bonded organic frameworks for sono-chemogenetics

The precise control of mechanochemical activation within deep tissues via non-invasive ultrasound holds profound implications for advancing our understanding of fundamental biomedical sciences and revolutionizing disease treatments. However, a theory-guided mechanoresponsive materials system with well-defined ultrasound activation has yet to be explored. Here we present the concept of using porous hydrogen-bonded organic frameworks (HOFs) as toolkits for focused ultrasound programmably triggered drug activation to control specific cellular events in the deep brain, through on-demand scission of the supramolecular interactions. A theoretical model is developed to visualize the mechanochemical scission and ultrasound mechanics, providing valuable guidelines for the rational design of mechanoresponsive materials at the molecular level to achieve programmable and spatiotemporal activation control. To demonstrate the practicality of this approach, we encapsulate designer drug clozapine N-oxide (CNO) into the optimal HOF nanoparticles for FUS gated release to activate engineered G-protein-coupled receptors in the mice and rat ventral tegmental area (VTA), and hence achieved targeted neural circuits modulation even at depth 9 mm with a latency of seconds. This work demonstrates the capability of ultrasound to precisely control molecular interaction and develops ultrasound programmable HOFs to minimally invasive and spatiotemporally control cellular events, thereby facilitating the establishment of precise molecular therapeutic possibilities. We anticipate that this research could serve as a source of inspiration for precise and non-invasive molecular manipulation techniques, potentially applicable in programming molecular robots to achieve sophisticated control over cellular events in deep tissues.

bioengineering↗

bioRxiv2023

High-resolution awake mouse fMRI at 14 Tesla

High-resolution awake mouse fMRI remains challenging despite extensive efforts to address motion-induced artifacts and stress. This study introduces an implantable radiofrequency (RF) surface coil design that minimizes image distortion caused by the air/tissue interface of mouse brains while simultaneously serving as a headpost for fixation during scanning. Furthermore, this study provides a thorough acclimation method used to accustom animals to the MRI environment minimizing motion induced artifacts. Using a 14T scanner, high-resolution fMRI enabled brain- wide functional mapping of visual and vibrissa stimulation at 100x100x200{micro}m resolution with a 2s per frame sampling rate. Besides activated ascending visual and vibrissa pathways, robust BOLD responses were detected in the anterior cingulate cortex upon visual stimulation and spread through the ventral retrosplenial area (VRA) with vibrissa air-puff stimulation, demonstrating higher-order sensory processing in association cortices of awake mice. In particular, the rapid hemodynamic responses in VRA upon vibrissa stimulation showed a strong correlation with the hippocampus, thalamus, and prefrontal cortical areas. Cross-correlation analysis with designated VRA responses revealed early positive BOLD signals at the contralateral barrel cortex (BC) occurring 2 seconds prior to the air-puff in awake mice with repetitive stimulation, which was not detected using a randomized stimulation paradigm. This early BC activation indicated a learned anticipation through the vibrissa system and association cortices in awake mice under continuous training of repetitive air-puff stimulation. This work establishes a high-resolution awake mouse fMRI platform, enabling brain-wide functional mapping of sensory signal processing in higher association cortical areas. Significance StatementThis awake mouse fMRI platform was developed by implementing an advanced implantable radiofrequency (RF) coil scheme, which simultaneously served as a headpost to secure the mouse head during scanning. A thorough acclimation method was used to accustom animals to the MRI environment minimizing motion induced artifacts. The ultra-high spatial resolution (100x100x200{micro}m) BOLD fMRI enabled the brain-wide mapping of activated visual and vibrissa systems during sensory stimulation in awake mice, including association cortices, e.g. anterior cingulate cortex and retrosplenial cortex, for high order sensory processing. Also, the activation of barrel cortex at 2 s prior to the air-puff indicated a learned anticipation of awake mice under continuous training of the repetitive vibrissa stimulation.

neuroscience↗

bioRxiv2023

In vivo proximity proteomics uncovers palmdelphin (PALMD) as a Z-line-associated mitigator of isoproterenol-induced cardiac injury

Z-lines are core ultrastructural organizers of cardiomyocytes that modulate many facets of cardiac pathogenesis. Yet a comprehensive proteomic atlas of Z-line-associated components remain incomplete. Here, we established an adeno-associated virus (AAV)-delivered, cardiomyocyte-specific, proximity-labeling approach to characterize the Z-line proteome in vivo. We found palmdelphin (PALMD) as a novel Z-line-associated protein in both adult murine cardiomyocytes and human pluripotent stem cell-derived cardiomyocytes. Germline and cardiomyocyte-specific palmd knockout mice were grossly normal at baseline but exhibited compromised cardiac hypertrophy and aggravated cardiac injury upon long-term isoproterenol treatment. By contrast, cardiomyocyte-specific PALMD overexpression was sufficient to mitigate isoproterenol-induced cardiac injury. PALMD ablation perturbed transverse tubules (T-tubules) and their association with sarcoplasmic reticulum, which formed the Z-line-associated junctional membrane complex (JMC) essential for calcium handling and cardiac function. These phenotypes were associated with disrupted localization of T-tubule markers caveolin-3 (CAV3) and junctophilin-2 (JPH2) and the reduction of nexilin (NEXN) protein, a crucial Z-line-associated protein that is essential for both Z-line and JMC structures and functions. PALMD was found to interact with NEXN and enhance its protein stability while the Nexn mRNA level was not affected. Together, this study discovered PALMD as a potential target for myocardial protection and highlighted in vivo proximity proteomics as a powerful approach to nominate novel players regulating cardiac pathogenesis. HighlightsO_LIIn vivo proximity proteomics uncover novel Z-line components that are undetected in in vitro proximity proteomics in cardiomyocytes. C_LIO_LIPALMD is a novel Z-line-associated protein that is dispensable for baseline cardiomyocyte function in vivo. C_LIO_LIPALMD mitigates cardiac dysfunction and myocardial injury after repeated isoproterenol insults. C_LIO_LIPALMD stabilizes NEXN, an essential Z-line-associated regulator of the junctional membrane complex and cardiac systolic function. C_LI

molecular biology↗

bioRxiv2023

Flexible and Controllable Protein Design by Prefix-tuning Large-Scale Protein Language Models

The design of novel proteins with tailored functionalities, particularly in drug discovery and vaccine development, presents a transformative approach to addressing pressing biomedical challenges. Inspired by the remarkable success of pre-trained language models in natural language processing (NLP), protein language models (ProtLMs) have emerged as powerful tools in advancing protein science. While NLP leverages flexible text-based control tags to prompt language model generation, the restricted amino acid space (limited to 20 residues) imposes inherent constraints on achieving analogous controllability. In this study, we propose PrefixProt, a framework for controllable protein design that employs prefix tuning to learn virtual tokens as control tags. These virtual tokens are adaptively tailored to diverse protein properties through a data-driven manner and can be combinatorially integrated to enable multi-objective control over protein generation. The effectiveness of PrefixProt was validated through extensive experiments encompassing both protein structure design (e.g. alpha-helix or beta-sheet topologies) and protein function design (e.g. antimicrobial or anticancer peptide activities). Benchmark results demonstrate that prefix virtual tokens efficiently guide the pre-trained ProtLM by optimizing a smaller number of trainable parameters, out-performing other parameter-efficient fine-tuning methods and text-guided ProtLMs, particularly in scenarios with limited data availability. More importantly, the compositional flexibility of virtual tokens facilitates the generation of proteins with multiple target properties, substantially expanding the scope of design possibilities. By harmonizing controllability, efficiency and generalizability, PrefixProt establishes a robust framework for de novo protein design, with promising applications in drug discovery and biomedicine. Availability and implementationThe models and code are available at: https://github.com/chen-bioinfo/PrefixProt

bioinformatics↗

bioRxiv2023

Stereopy: modeling comparative and spatiotemporal cellular heterogeneity via multi-sample spatial transcriptomics

Tracing cellular dynamic changes across conditions, time, and space is crucial for understanding the molecular mechanisms underlying complex biological systems. However, integrating multi-sample data in a unified and flexible way to explore cellular heterogeneity remains a major challenge. Here, we present Stereopy, a flexible and versatile framework for modeling and dissecting comparative and spatiotemporal patterns in multi-sample spatial transcriptomics with interactive data visualization. To optimize this flexible framework, we have developed three key components: a multi-sample tailored data container, a scope controller, and an analysis transformer. Furthermore, Stereopy showcases three transformative applications supported by pivotal algorithms. Firstly, the multi-sample cell community detection (CCD) algorithm introduces an innovative capability to detect specific cell communities and identify genes responsible for pathological changes in comparable datasets. Secondly, the spatially resolved temporal gene pattern inference (TGPI) algorithm represents a notable advancement in detecting important spatiotemporal gene patterns while concurrently considering spatial and temporal features, which enhances the identification of important genes, domains and regulatory factors closely associated with temporal datasets. Finally, the 3D niche-based regulation inference tool, named NicheReg3D, reconstructs the 3D cell niches to enable the inference of cell-gene interaction network within the spatial texture, thus bridging intercellular communications and intracellular regulations to unravel the intricate regulatory mechanisms that govern cellular behavior. Overall, Stereopy serves as both a bioinformatics toolbox and an extensible framework that provides researchers with enhanced data interpretation abilities and new perspectives for mining multi-sample spatial transcriptomics data.

bioinformatics↗