Biology subjects

Liu, Q.

Publications and source records attributed to Liu, Q..

At least 271 records · Page 15Linked to original sources

bioRxiv2024

GeneLLM: A Large cfRNA Language Model for Cancer Screening from Raw Reads

We present GeneLLM, a novel large language model that offers a transformative approach to non-invasive cancer detection and biomarker discovery by directly interpreting plasma cell-free RNA (cfRNA) sequences. Unlike traditional annotation-dependent methods, GeneLLM operates without prior knowledge, achieving significantly improved multi-cancer detection accuracy. Critically, GeneLLM identifies novel cfRNAs ( pseudo-biomarkers) originating from previously unannotated genomic regions-overlooked by existing methods-offering new therapeutic targets and insights into intercellular communication. This innovative, cost-effective approach bypasses traditional bioinformatics tools, generating novel pseudo-biomarkers that outperform existing methods even with low-depth sequencing data. Consequently, GeneLLM opens new avenues for biomarker discovery and expands our understanding of the extracellular transcriptomes role in cancer development.

bioinformatics↗

bioRxiv2024

InterLabelGO+: Unraveling label correlations in protein function prediction

MotivationAccurate protein function prediction is crucial for understanding biological processes and advancing biomedical research. However, the rapid growth of protein sequences far outpaces the experimental characterization of their functions, necessitating the development of automated computational methods. ResultsWe present InterLabelGO+, a hybrid approach that integrates a deep learning-based method with an alignment-based method for improved protein function prediction. InterLabelGO+ incorporates a novel loss function that addresses label dependency and imbalance and further enhances performance through dynamic weighting of the alignment-based component. A preliminary version of InterLabelGO+ achieved a strong performance in the CAFA5 challenge, ranking 6th out of 1,625 participating teams. Comprehensive evaluations on large-scale protein function prediction tasks demonstrate InterLabelGO+s ability to accurately predict Gene Ontology terms across various functional categories and evaluation metrics. Availability and ImplementationThe source code and datasets for InterLabelGO+ are freely available on GitHub at https://github.com/QuanEvans/InterLabelGO. The software is implemented in Python and PyTorch, and is supported on Linux and macOS. Contactlydsf@umich.edu (LF) and zcx@umich.edu (CZ)

bioinformatics↗

bioRxiv2024

Photoactivated SOPP3 enables APEX2-mediated proximity labeling with high spatio-temporal resolution in live cells

Protein interactome characterized via proximity labeling (PL) and proteomic analysis is important for mechanism study in biomedical research. However, exogenous H2O2 required for engineered peroxidase, like APEX2, is cytotoxic, while biotin ligases-based PL have poor temporal resolution. Here, we showed that SOPP3, an engineered photosensitizer, could trigger APEX2 mediated PL within seconds under blue light illumination, without exogenous H2O2 or cytotoxicity. We demonstrated that APEX2 plus photoactivated SOPP3 could catalyze spatially restricted biotinylation at endoplasmic reticulum-mitochondria contact sites and cell-cell interface. Through fusing APEX2 and SOPP3 as a chimeric probe, we showed that APEX2-SOPP3 also works well in multiple subcellular locations, including cell surface. Notably, either APEX2 plus SOPP3, or chimeric APEX2-SOPP3 requires 10 folds lower illumination power, compared to that for light-oxygen-voltage protein alone mediated PL, and has better response to illumination in terms of PL in time course with little cytotoxicity. Thus, this new PL technology paves an avenue to characterize molecular dynamics of key biomedical events with high spatial-temporal resolution, efficiency, and flexible applicability.

molecular biology↗

bioRxiv2024

Human tau promotes Warburg effect-like glycolytic metabolism under acute hyperglycemia conditions through modulating the homeostasis of protein-membrane association

The neurofilaments formed by hyperphosphorylated tau is a hallmark of tau-related neurodegenerative disease, including Alzheimers disease, tau related FTDP-17, Picks disease, et al. However, the biological functions of tau and the physiological significance of its phosphorylation are still not fully understood. By using human tau (441 a.a.) transgenic (hTau) mice in which murine tau has been deleted simultaneously, murine tau knockout (Tau KO) mice and C57BL/6J (C57) mice, unexpectedly, we found that under acute hyperglycemia conditions, JNK but not previously reported GSK-3{beta} mediated tau phosphorylation. Moreover, Akt, the upstream GSK-3{beta} inhibitory kinase, was activated in a tau dependent manner. By comparing the membrane-associated proteome, we found that human tau influenced the homeostasis of protein-membrane association under acute hyperglycemia conditions. Of note, with respect to WT and Tau KO mice, the membrane-association of Krts, TFAM, TRAP1, mTOR et al, were strengthened by human tau. Whereas, the membrane-association of ribosomal proteins Rpls, proteasome proteins Psmds, and mitochondrial proteins, such as COXs, Ndufa1, Mtnt4, et al, were impeded by human tau. In vitro study showed that aerobic glycolysis was promoted in the presence of human tau, which maintained NAD+/NADH ratio. On the other hand, it restricted oxidative phosphorylation level, modulated the activity of SDH, and reduced ROS production upon challenging by high glucose. Furthermore, under acute high glucose conditions, the presence of human tau significantly augmented Akt activation, but inhibited 4EBP phosphorylation simultaneously, indicating that human tau is also involved in regulating the alternative activation of mTORC1/2. In summary, the current study revealed that human tau played an important role in regulating glycolytic metabolism under acute high hyperglycemia conditions, which is similar with the Warburg-effect, through influencing the homeostasis of protein-membrane association.

molecular biology↗

bioRxiv2024

Proteasome inhibition induces DNA methylation alteration by attenuating the synthesis of DNA methyltransferase 1 and 3B in colorectal cancer

Proteasome is an essential organelle in guarding cellular protein homeostasis. Here, we report that inhibition of proteasome leads to alterations in DNA methylation patterns in colorectal cancer (CRC) by surpressing the synthesis of DNA methyltransferases (DNMTs). We found that treating CRC cells with proteasome inhibitors results in attenuated translation of DNMT1 and DNMT3B, mediated by the inactivation of AKT and mammalian target of rapamycin (mTOR), which is dependent on the accumulation of p300, an acetyltransferase that inhibits AKT through acetylation modification. Furthermore, we demonstrated that downregulation of DNMT1 and DNMT3B confers protection against proteasome inhibitor treatment, potentially through reprogramming the transcriptome of CRC cells, highlighting the significant role of DNMTs in response to disruptions in protein homeostasis. Interestingly, the proteasome inhibitor-induced downregulation of DNMT1 and DNMT3B appears to be CRC specific, notwithstanding the underlying mechanism remains unclear. Altogether, our findings reveal an epigenetic effect of proteasome on DNA methylation in CRC through its regulation of DNA methyltransferase synthesis.

cancer biology↗

bioRxiv2024

Embracing Uncertainty Reshapes the ETHYLENE INSENSITIVE2-Activated Ethylene Signaling Framework

Signal transduction of the gaseous plant hormone ethylene by ETHYLENE INSENSITIVE2 (EIN2) is proposed to be regulated at multiple levels. EIN2 is phosphorylated by CONSTITUTIVE TRIPLE-RESPONSE1 (CTR1), subject to the F-Box proteins [EIN2-TARGETING PROTEIN1 (ETP1) and ETP2]-mediated degradation, and cannot activate ethylene signaling. Ethylene prevents EIN2 phosphorylation and degradation, and EIN2 accumulates and activates the signaling. MAOHUZI3 LIKE1 (MHL1) and MHL2 stabilize EIN2, and the mhl1 mhl2 double mutation confers ethylene insensitivity. Here, we reported that the regulation of EIN2-activated ethylene signaling can be independent of CTR1-mediated phosphorylation, ETP1/ETP2-directed degradation, and MHL1/MHL2-dependent stabilization. Both the etp1 etp2 double mutant and wild type showed identical ethylene dose-response curves, and the nontreated mhl1 mhl2 double mutant displayed substantial growth inhibition. The reported ethylene-insensitive root phenotype of mhl1 mhl2 seedlings requires sucrose and is associated with unknown loci. The ethylene receptor ETHYLENE RESPONSE1 (ETR1) and EIN2 interact at the rough endoplasmic reticulum. We propose that the docking of CTR1 to ETR1 promotes receptor signaling, which inhibits EIN2-activated ethylene signaling. The discrepancy between our findings and the current model is discussed. Our findings may disrupt the knowledge boundary of the present molecular model, developing a niche for findings outside the framework to advance our understanding of ethylene signaling.

plant biology↗

bioRxiv2024

Horizontally acquired CSP genes contribute to wheat adaptation and improvement

Although horizontal gene transfer (HGT) often facilitates environmental adaptation of recipient organisms, whether and how they might affect crop evolution and domestication is unclear. Here we show that three genes encoding cold shock proteins (CSPs) were transferred from bacteria to the last common ancestor of Triticeae, a tribe of the grass family that includes several major staple crops such as wheat, barley, and rye. The acquired CSP genes in wheat (TaCSPs) are functionally conserved with their bacterial homologs by encoding a nucleic acid binding protein. Experimental evidence indicates that TaCSP genes positively regulate drought response and improve photosynthetic efficiency under water deficit conditions, by directly targeting a type 1 metallothionein gene to increase ROS scavenging, which in turn contributed to the geographic expansion of wheat. We identified an elite CSP haplotype in Aegilops-tauschii, introduction of which to wheat significantly increased drought tolerance, photosynthetic efficiency and grain yields. These findings not only provide major insights into the role of HGT in crop adaptation and domestication, but also demonstrate that novel microbial genes introduced through HGT offer a stable and naturally optimized resource for transgenic crop breeding and improvement.

plant biology↗

bioRxiv2024

Conserved mycobacterial sRNA B11 regulates lipooligosaccharide synthesis at post-transcriptional level

Extractable glycolipids of mycobacteria, such as lipooligosaccharides (LOS), play key roles in responding to environmental stress and altering the host immune response. However, although the biosynthesis of LOS is likely controlled at multiple levels to ensure proper composition of the cell wall, the key regulators are currently unknown. Here, we studied B11, a conserved mycobacterial sRNA, and found that it post-transcriptionally regulates LOS synthesis in Mycobacteria marinum. Deletion of B11 alters the colony morphology and RNA sequencing combined with mass spectrometry identified several genes in the LOS synthesis locus that are regulated by B11. We found that B11 uses the cytosine-rich loops of its rho-independent transcriptional terminator to interact with guanine-tracks adjacent to the ribosome binding sites of its target genes, thereby impeding translation and promoting mRNA degradation by RNase E. These comprehensive functional studies of mycobacterial sRNA B11 demonstrate sRNA-based regulation of cell wall synthesis in mycobacteria. ImportanceDespite being identified for more than a decade, the functional characterization and regulatory mechanisms of mycobacterial sRNAs remain largely unexplored. We present here the most comprehensive functional study of mycobacterial sRNAs to date, employing convincible target screening using multifaceted experimental approaches and phenotype analysis. Our work reveals how synthesis of mycobacterial lipooligosaccharides (LOS), one of the crucial extractable glycolipids involved in environmental stress response and host immune modulation, is regulated at the post-transcriptional level by the conserved sRNA B11. Furthermore, our discovery of a highly conserved sRNA exhibiting distinct functions across mycobacterial species exemplifies divergent functional evolution among sRNAs.

microbiology↗

bioRxiv2024

Time-division multiplexing (TDM) sequence removes bias in T2 estimation and relaxation-diffusion measurements

PurposeTo compare the performance of multi-echo (ME) and time-division multiplexing (TDM) sequences for accelerated relaxation-diffusion MRI (rdMRI) acquisition and to examine their reliability in estimating accurate rdMRI microstructure measures. MethodThe ME, TDM, and the reference single-echo (SE) sequences with six echo times (TE) were implemented using Pulseq with single-band (SB-) and multi-band 2 (MB2-) acceleration factors. On a diffusion phantom, the image intensities of the three sequences were compared, and the differences were quantified using the normalized root mean squared error (NRMSE). For the in-vivo brain scan, besides the image intensity comparison and T2-estimates, different methods were used to assess sequence-related effects on microstructure estimation, including the relaxation diffusion imaging moment (REDIM) and the maximum-entropy relaxation diffusion distribution (MaxEnt-RDD). ResultsTDM performance was similar to the gold standard SE acquisition, whereas ME showed greater biases (3-4x larger NRMSEs for phantom, 2x for in-vivo). T2 values obtained from TDM closely matched SE, whereas ME sequences underestimated the T2 relaxation time. TDM provided similar diffusion and relaxation parameters as SE using REDIM, whereas SB-ME exhibited a 60% larger bias in the map and on average 3.5x larger bias in the covariance between relaxation-diffusion coefficients. ConclusionOur analysis demonstrates that TDM provides a more accurate estimation of relaxation-diffusion measurements while accelerating the acquisitions by a factor of 2 to 3.

neuroscience↗

bioRxiv2024

FOXP3+ Regulatory T Cells Require TBET to Regulate Activated CD8+ T Cells During Recovery from Influenza Infection

FOXP3+ regulatory T (Treg) cells are necessary to coordinate resolution of lung inflammation and a return to homeostasis after respiratory viral infections, but the specific molecular requirements for these functions and the cell types governed by Treg cells remain unclear. This question holds significance as clinical trials of Treg cell transfer therapy for respiratory viral infection are being planned and executed. Here, we report causal experiments in mice determining that Treg cells are necessary to control the numbers of activated CD8+ T cells during recovery from influenza infection. Using a genetic strategy paired with adoptive transfer techniques, we determined that Treg cells require the transcription factor TBET to regulate these potentially pro-inflammatory CD8+ T cells. Surprisingly, we found that Treg cells are dispensable for the generation of CD8+ lung tissue resident-memory T (Trm) cells yet similarly influence the transcriptional programming of CD8+ Trm and activated T cells. Our study highlights the role of Treg cells in regulating the CD8+ T cell response during recovery from influenza infection.

immunology↗

bioRxiv2024

Novel enzyme-based reduced representation method for DNA methylation profiling with low inputs

DNA methylation at cytosine-phospho-guanine (CpG) residues is a vital biological process that regulates cell identity and function. Although widely used, bisulfite-based cytosine conversion procedures for DNA methylation sequencing require high temperature and extreme pH, which lead to DNA degradation, especially among unmethylated cytosines. Enzymatic methylation sequencing (EM-seq), an enzyme-based cytosine conversion method, has been proposed as a less biased alternative for methylation profiling. Compared to bisulfite-based methods, EM-seq boasts greater genome coverage with less GC bias and has the potential to cover more CpGs with the same number of reads (i.e., higher signal-to-noise ratio). Reduced representation approaches enrich samples for CpG-rich genomic regions, thereby enhancing throughput and cost effectiveness. We hypothesized that enzyme-based technology could be adapted for reduced representation methylation sequencing to enable high-resolution DNA methylation profiling on low-input samples, including those obtained from clinical specimens. We leveraged the well-established differences in methylation profile between mouse CD4+ T cell populations to compare the performance of a novel reduced representation EM-seq (RREM-seq) procedure against an established reduced representation bisulfite sequencing (RRBS) protocol. While the RRBS method failed to generate reliable DNA libraries when using <2 ng of DNA (equivalent to DNA from around 350 cells), the RREM-seq method successfully generated reliable DNA libraries from 1-25 ng of mouse and human DNA. Ultra-low-input (<2-ng) RREM-seq libraries final concentration, regulatory genomic element coverage, and methylation status within lineage-defining Treg cell-specific super-enhancers were comparable to RRBS libraries with more than 10-fold higher DNA input. RREM-seq also successfully detected lineage-defining methylation differences between alveolar Tconv and Treg cells obtained from mechanically ventilated patients with severe SARS-CoV-2 pneumonia. Our RREM-seq method enables single-nucleotide resolution methylation profiling using low-input samples, including from clinical sources.

genomics↗

bioRxiv2024

Multi-omics reveals AKR1B1-regulated galactose metabolic as a driver of gastrointestinal stromal tumor progression

The underlying mechanism of malignant progression in gastrointestinal stromal tumors (GISTs) is not fully understood. Despite recent advancements, a comprehensive profile of metabolome, transcriptome, and proteome of GISTs is lacking. This study conducted an integrated multi-omics analysis of GISTs across different risk classifications. By integrating metabolomics, transcriptomics, and proteomics, we identify distinct metabolic patterns and associated biological pathways implicated in the malignant progression of GISTs. Moreover, we identified galactose metabolism and the pivotal rate-limiting enzyme AKR1B1 is dysregulated in GISTs progression. AKR1B1 was upregulated and predicted poor prognosis in GISTs. In addition, AKR1B1 knockdown resulted in trehalose accumulation in GIST cells, thereby inhibiting cell proliferation and mitosis. These findings not only enhance our comprehension of the underlying mechanisms governing GIST progression from a metabolic reprogramming standpoint but also furnish prognostic biomarkers and potential therapeutic targets for GISTs.

cancer biology↗

bioRxiv2024

Signatures of social pain empathy: general and process-specific brain-wide representations of social exclusion and separation

Empathy can be elicited by physiological pain, as well as in social contexts. Although physiological and different social contexts induce a strong subjective experience of empathy, the general and context-specific neural representations remain elusive. Here, we combine fMRI with multivariate pattern analysis to establish neurofunctional models for pain empathy triggered by social exclusion and separation. Our findings revealed both overlapping and distinct neural representations for social exclusion and separation empathy across cortical and subcortical regions. This study established an evolutionary model that traces the progression from social pain to physiological pain empathy. In conclusion, this study establishes neural decoding models for pain empathy evoked by social exclusion and social separation, revealing their neural foundations and interconnectedness of empathy induced by social and physiological stimuli. These findings deepen our understanding of the neurobiological mechanisms underlying social pain empathy and provide robust neuromarkers to precisely evaluate empathy across physiological and social domains.

neuroscience↗

bioRxiv2024

StarFunc: fusing template-based and deep learning approaches for accurate protein function prediction

Deep learning has significantly advanced the development of high-performance methods for protein function prediction. Nonetheless, even for state-of-the-art deep learning approaches, template information remains an indispensable component in most cases. While many function prediction methods use templates identified through sequence homology or protein-protein interactions, very few methods detect templates through structural similarity, even though protein structures are the basis of their functions. Here, we describe our development of StarFunc, a composite approach that integrates state-of-the-art deep learning models seamlessly with template information from sequence homology, protein-protein interaction partners, proteins with similar structures, and protein domain families. Large-scale benchmarking and blind testing in the 5th Critical Assessment of Function Annotation (CAFA5) consistently demonstrate StarFuncs advantage when compared to both state-of-the-art deep learning methods and conventional template-based predictors.

bioinformatics↗

bioRxiv2024

Hijacking a dedicated entorhinal-hippocampal extinction circuit to remove traumatic memory

Effective psychotherapy of post-traumatic stress disorder (PTSD) remains challenging due to the fragile nature of fear extinction, for which ventral hippocampal CA1 (vCA1) region is considered as a central hub. However, neither the core pathway nor the cellular mechanisms involved in implementing extinction are known. Here, we unveil a direct pathway, where layer 2a fan cells in the lateral entorhinal cortex (LEC) target parvalbumin-expressing interneurons (PV-INs) in the vCA1 region to propel low gamma-band synchronization of the LEC-vCA1 activity during extinction learning. Bidirectional manipulations of either hippocampal PV-INs or LEC fan cells suffice fear extinction. Gamma entrainment of vCA1 by deep brain stimulation (DBS) or noninvasive transcranial alternating current stimulation (tACS) of LEC persistently enhances the PV-IN activity in vCA1, thereby promoting fear extinction. These results demonstrate that the LEC-vCA1 pathway forms a top-down motif to empower low gamma-band oscillations that facilitate fear extinction. Finally, application of low gamma DBS and tACS to a mouse model with persistent PTSD shows potent efficacy, suggesting that the dedicated LEC-vCA1 pathway can be hijacked for therapy to remove traumatic memory trace. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/593830v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@ca6768org.highwire.dtl.DTLVardef@4ae574org.highwire.dtl.DTLVardef@11e4ff5org.highwire.dtl.DTLVardef@1136cc2_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Coxsackievirus group B3 regulates ASS1-mediated metabolic reprogramming and promotes macrophage inflammatory polarization in viral myocarditis

Coxsackievirus group B3 (CVB3) belongs to the genus Enteroviruses of the family Picornaviridae and is the main pathogen underlying viral myocarditis (VMC). No specific therapeutic is available for this condition. Argininosuccinate synthase 1 (ASS1) is a key enzyme in the urea cycle that converts citrulline and aspartic acid to argininosuccinate. Here, we found that CVB3 and its capsid protein VP2 inhibit the autophagic degradation of ASS1 and that CVB3 consumes citrulline to upregulate ASS1, triggers urea cycle metabolic reprogramming, then activates macrophages to develop pro-inflammatory polarization, thereby promoting the occurrence and development of VMC. Conversely, citrulline supplementation to prevent depletion can downregulate ASS1, rescue macrophage polarization, and alleviate the pathogenicity of VMC. These findings provide a new perspective on the occurrence and development of VMC, revealing ASS1 as a potential new target for the treatment of this disease. IMPORTANCEViral myocarditis (VMC) is a common and potentially life-threatening myocardial inflammatory disease, most commonly caused by CVB3 infection. So far, the pathogenesis of VMC caused by CVB3 is mainly focused on two aspects: one is the direct myocardial injury caused by a large number of viral replication in the early stage of infection, and the other is the local immune cell infiltration and inflammatory damage of the myocardium in the adaptive immune response stage. There are few studies on the early innate immunity of CVB3 infection in myocardial tissue, but the appearance of macrophages in the early stage of CVB3 infection suggests that they can play a regulatory role as early innate immune response cells in myocardial tissue. Here, we discovered a possible new mechanism of VMC caused by CVB3, revealed new drug targets for anti-CVB3 and discovered the therapeutic potential of citrulline for VMC.

microbiology↗

bioRxiv2024

Diversity and ecological potentials of viral assemblages from the seamount sediments of the Northwest Pacific Ocean

Viruses are the most abundant life forms in the sea, influencing the community structure and metabolism of host cells as well as biogeochemical cycles. However, the diversity and ecological roles of viruses within seamount ecosystems, natural microbiota havens characterized by high biodiversity, remain unknown. Here, the first seamount viral genome (SMVG) dataset, based on a metagenomic analysis of twelve seamount sediment samples collected from the seamount regions of the Northwest Pacific Ocean, is established. A total of 78,069 viral operational taxonomic units (vOTUs) were found, spanning 18 viral classes and 63 viral families. The detection of sixteen viral auxiliary metabolic genes (vAMGs) suggests that viruses may participate in both the complex metabolic dynamics associated with sediment microbial communities and also biogeochemical cycles, including carbon, sulfur, metal, heme, and cobalamin cycling. vAMGs involved in the metabolism of heme, cobalamin and metals, in particular, are more often detected in seamount sediments than in trenches, cool seeps, and hydrothermal vents. This investigation of the viral communities in these seamount sediments provides new insights into the high diversity and ecological potential of the viruses and establishes a foundation for the future study of benthic viruses from deep-sea seamounts.

ecology↗

bioRxiv2024

5-HT Neurons Integrate GABA and Dopamine Inputs to Regulate Meal Initiation

Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRN{lozenge}arcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRN neurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.

neuroscience↗