Biology subjects

Zhang, H.

Publications and source records attributed to Zhang, H..

At least 649 records · Page 36Linked to original sources

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

Rating Pome Fruit Quality Traits Using Deep Learning and Image Processing

Quality assessment of pome fruits (i.e. apples and pears) is used not only crucial for determining the optimal harvest time, but also the progression of fruit-quality attributes during storage. Therefore, it is typical to repeatedly evaluate fruits during the course of a postharvest experiment. This evaluation often includes careful visual assessments of fruit for apparent defects and physiological symptoms. A general best practice for quality assessment is to rate fruit using the same individual rater or group of individuals raters to reduce bias. However, such consistency across labs, facilities, and experiments is often not feasible or attainable. Moreover, while these visual assessments are critical empirical data, they are often coarse-grained and lack consistent objective criteria. Granny, is a tool designed for rating fruit using machine-learning and image-processing to address rater bias and improve resolution. Additionally, Granny supports backwards compatibility by providing ratings compatible with long-established standards and references, promoting research program continuity. Current Granny ratings include starch content assessment, rating levels of peel defects, and peel color analyses. Integrative analyses enhanced by Grannys improved resolution and reduced bias, such as linking fruit outcomes to global scale-omics data, environmental changes, and other quantitative fruit quality metrics like soluble solids content and flesh firmness, will further enrich our understanding of fruit quality dynamics. Lastly, Granny is open-source and freely available.

plant biology↗

bioRxiv2024

Caspase-8-mediated CYLD cleavage boots LPS-induced endotoxic shock.

Caspase-8, a pivotal protease intricately involved in various cellular signaling pathways related to cell death and inflammation, has been identified as a contributor to cytokine production during septic shock. However, the mechanisms governing this regulatory role remain enigmatic. In this study, we uncovered that mice harboring a specific mutation in CYLD at its D215 position (CyldD215A/D215A mutant mice), rendering CYLD resistant to caspase8 cleavage, exhibited marked protection against lethal endotoxic shock. Moreover, the removal of Cyld in Caspase8-/-Mlkl-/- mice restored their sensitivity to endotoxic shock, indicating Caspase8 promotes LPS-induced endotoxic shock by cleaving its substrate CYLD and maintaining CYLD stability confers resistance to endotoxic shock. Mechanistically, CYLD was found to catalyze the removal of LUBAC-mediated M1-linked ubiquitination of NF-kB p65 at K301/K303, thereby suppressing the nuclear translocation and activation of p65 for subsequent cytokines production. Notably, the cleaved N-terminal fragment of CYLD (named CP25) is secreted in a TRIF/Caspase8-dependent manner. Moreover, CP25 can be detected in the serum of septic mice, and its levels show a strong correlation with corresponding serum IL-1{beta}, suggesting its potential utility as an inflammatory biomarker. Overall, these findings highlight the significance of CYLD cleavage as a promising therapeutic target and diagnostic marker for endotoxic shock.

immunology↗

bioRxiv2024

The subcommissural organ regulates brain development via secreted peptides

The subcommissural organ (SCO) is a gland located at the entrance of the aqueduct of Sylvius in the brain. It exists in species as distantly related as amphioxus and humans, but its function is largely unknown. To explore its function, we compared transcriptomes of SCO and non-SCO brain regions and found three genes, Sspo, Car3, and Spdef, that are highly expressed in the SCO. Mouse strains expressing Cre recombinase from endogenous promoter/enhancer elements of these genes were used to genetically ablate SCO cells during embryonic development, resulting in severe hydrocephalus and defects in neuronal migration and development of neuronal axons and dendrites. Unbiased peptidomic analysis revealed enrichment of three SCO-derived peptides, namely thymosin beta 4, thymosin beta 10, and NP24, and their reintroduction into SCO-ablated brain ventricles substantially rescued developmental defects. Together, these data identify a critical role for the SCO in brain development.

neuroscience↗

bioRxiv2024

Bacterial-tyramine-induced renal-gut countercurrent flow regulates gut immune response by promoting ROS accumulation and gut peristalsis in the fly Bactrocera dorsalis

Insects increase gut peristalsis to purge ingested pathogens. They also rely on the Duox-ROS system to mount an efficient gut response. However, how these two host defense mechanisms are coordinated to clear pathogens remained unclear. We found that gut peristalsis is the major force for bacteria elimination, while Duox is necessary as a signaling molecule to activate gut peristalsis in a Tephritidae fruit fly Bactrocera dorsalis. We found an insect-conserved renal-gut countercurrent flow formed upon recognizing bacteria-derived tyramine counteracts the gut peristalsis forced defecation and drives the accumulation of ROS. Furthermore, we demonstrated that the renal-gut countercurrent flow maintains proper microbiota composition. Our work provided a novel renal-gut interaction that ensures an efficient gut-immune response.

immunology↗

bioRxiv2024

Exploring Pathogenic Mutation in Allosteric Proteins: the Prediction and Beyond

Allosteric regulation that triggers the functional activity of a protein through conformational changes is an inherent function of the protein in numerous physiological and pathological scenarios. In the post-genomic era, a central challenge for disease genomes is the identification of the biological effects of specific somatic variants on allosteric proteins and the phenotypes they influence during the initiation and progression of diseases. Here, we analyzed more than 38539 mutations observed in 90 human genes with 740 allosteric protein chains. We found that existing allosteric protein mutations are associated with many diseases, but the clinical significance of the majority of mutations in allosteric proteins remains unclear. Next, we developed a machine-learning-based model for pathogenic mutation prediction of allosteric proteins based on the intrinsic characteristics of proteins and the prediction results from existed methods. When tested on the benchmark allosteric protein dataset, the proposed method achieves AUCs of 0.868 and AUPR of 0.894 on allosteric proteins. Furthermore, we explored the performance of existing methods in predicting the pathogenicity of mutations at allosteric sites and identified potential significant pathogenic mutations at allosteric sites using the proposed method. In summary, these findings illuminate the significance of allosteric mutation in disease processes, and contribute a valuable tool for the identification of pathogenic mutations as well as previously unknown disease-causing allosteric-protein-encoded genes.

bioinformatics↗

bioRxiv2024

Virological characteristics of SARS-CoV-2 Omicron BA.5.2.48

With the prevalence of sequentially-emerged sublineages including BA.1, BA.2 and BA.5, SARS-CoV-2 Omicron infection has transformed into a regional epidemic disease. As a sublineage of BA.5, the BA.5.2.48 outbreak and evolved into multi-subvariants in China without clearly established virological characteristics, especially the pathogenicity. Though reduced airborne transmission and pathogenicity of former Omicron sublineages have been revealed in animal models, the virological characteristics of BA.5.2.48 was unidentified. Here, we evaluated the in vitro and in vivo virological characteristics of two isolates of the prevalent BA.5.2.48 subvariant, DY.2 and DY.1.1 (a subvariant of DY.1). DY.2 replicates more efficiently than DY.1.1 in HelahACE2+ cells and Calu-3 cells. The A570S mutation (of DY.1) in a normal BA.5 spike protein (DY.2) leads to a 20% improvement in the hACE2 binding affinity, which is slightly reduced by a further K147E mutation (of DY.1.1). Compared to the normal BA.5 spike, the double-mutated protein demonstrates efficient cleavage and reduced fusogenicity. BA.5.2.48 demonstrated enhanced airborne transmission capacity in hamsters than BA.2. The pathogenicity of BA.5.2.48 is greater than BA.2, as revealed in K18-hACE2 rodents. Under immune selection pressure, DY.1.1 shows stronger fitness than DY.2 in hamster turbinates. Thus the outbreaking prevalent BA.5.2.48 multisubvariants exhibites divergent virological features. ImportanceOmicron continues to circulate and evolves novel sublineages with indistinguishable pathogenicity and transmission. Therefore humanized Omicron-sensitive animal models must be applied to evaluate the virological characteritics and antiviral therapeutics. By using multiple models including the Omicron-lethal H11-K18-hACE2 rodents, BA.5.2.48 revealed higher pathogenicity in the novel H11-K18-hACE2 rodent models than the previously epidemic BA.2, and thus the models are more adapted to Omicron studies. Moreover, the regional outbreaking of BA.5.2.48 promotes the multidirectional evolution of its subvariants, gaining either enhanced pathogenicity or a fitness in upper airways which is associated with higher transmission, highlighting the importance of surveillance and virological studies on regionally endemic sublineages which represents the short-run evolutionary direction of Omicron.

microbiology↗

bioRxiv2024

Bacteria adapt nutrient deprivation by reducing vacant 70S ribosomes via the silencing factor RsfS

Bacteria rapidly remodel protein synthesis to survive nutrient limitation, yet how inactive ribosomes are selectively regulated remains incompletely understood. Ribosome silencing factor S (RsfS) is the only known bacterial factor that selectively dissociates vacant 70S ribosomes, but its physiological function in bacterial adaptation has remained elusive. Here, we demonstrate that RsfS promotes bacterial survival during nutrient starvation by selectively dismantling non-translating vacant 70S ribosomes while sparing translating ribosomes. Biochemical analyses show that RsfS efficiently dissociates vacant 70S ribosomes but has little effect on programmed ribosomes in the pre-translocation or post-translocation states, thereby preserving ongoing protein synthesis. Ribosome profiling further reveals that loss of RsfS results in a global reduction in translational efficiency and widespread translational reprogramming during starvation. Mechanistically, dissociation of vacant ribosomes by RsfS suppresses futile EF-G-dependent GTP hydrolysis and prevents unnecessary energy expenditure associated with inactive ribosome cycling. Consistent with this mechanism, RsfS enhances bacterial adaptation to nutrient deprivation without compromising active translation. Together, our findings identify RsfS as a unique regulator of bacterial ribosome homeostasis that conserves cellular energy through selective dissociation of vacant 70S ribosomes, revealing a previously unrecognized strategy by which bacteria optimize translation under nutrient-limited conditions.

microbiology↗

bioRxiv2024

Bioorthogonal labeling and enrichment of histone monoaminylation reveal its accumulation and regulatory function in cancer cell chromatin

Histone monoaminylation (i.e., serotonylation and dopaminylation) is an emerging category of epigenetic mark occurring on the fifth glutamine (Q5) residue of H3 N-terminal tail, which plays significant roles in gene transcription. Current analysis of histone monoaminylation is mainly based on site-specific antibodies and mass spectrometry, which either lacks high resolution or is time-consuming. In this study, we report the development of chemical probes for bioorthogonal labeling and enrichment of histone serotonylation and dopaminylation. These probes were successfully applied for the monoaminylation analysis of in vitro biochemical assays, cells, and tissue samples. The enrichment of monoaminylated histones by the probes further confirmed the crosstalk between H3Q5 monoaminylation and H3K4 methylation. Finally, combining the ex vivo and in vitro analyses based on the developed probes, we have shown that both histone serotonylation and dopaminylation are highly enriched in tumor tissues that overexpress transglutaminase 2 (TGM2) and regulate the three-dimensional architecture of cellular chromatin. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/586010v3_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1bee3f7org.highwire.dtl.DTLVardef@1687013org.highwire.dtl.DTLVardef@1960bd0org.highwire.dtl.DTLVardef@1e19a04_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep, intense circuit activity, or dietary restrictions, posing significant metabolic stress. Here, we demonstrate that the mammalian brain utilizes pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability within a neuron and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation which in turn modulates mitochondrial pyruvate uptake. Importantly, our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in synaptic transmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval, functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of synaptic transmission in hippocampal terminals. HIGHLIGHTSO_LISerum pyruvate is taken up by the brain and efficiently oxidized in the TCA cycle. C_LIO_LIThe mitochondrial pyruvate carrier (MPC) is essential for presynaptic energy metabolism. C_LIO_LIAcetylation of the MPC complex modulates mitochondrial pyruvate uptake. C_LIO_LIMPC activity regulates the release and retrieval of synaptic vesicles in nerve terminals. C_LI

neuroscience↗

bioRxiv2024

Normative growth modeling of brain morphology reveals neuroanatomical heterogeneity and biological subtypes in children with ADHD

BackgroundNeuroimaging studies suggest substantial individual heterogeneity in brain phenotypes in attention-deficit/hyperactivity disorder (ADHD). However, how these individual-level brain phenotypes contribute to the identification of ADHD biotypes and whether these biotypes have different treatment outcomes and neurobiological underpinnings remain largely unknown. MethodsWe collected multisite, high-quality structural magnetic resonance imaging data from 1,006 children aged 6-14 years, including 351 children with ADHD and 655 typically developing children. Normative growth models of cortical thickness were established for 219 regions in the typically developing children. Individual-level deviations from these normal references were quantified and clustered to identify ADHD biotypes. We validated the replicability and generalizability of the ADHD biotypes using two independent datasets and evaluated the associations of the biotypes with symptomatic, cognitive, and gene expression profiles, as well as follow-up treatment outcomes. FindingsNo more than 10% of children with ADHD had extreme deviations in cortical thickness in a single region, suggesting high heterogeneity among individuals with ADHD. On the basis of the brain deviation maps, we discovered two robust ADHD biotypes, an infra-normal subtype with cortical thinning associated with ADHD symptoms and a supranormal subtype with cortical thickening associated with cognition. Patients with the infra-normal subtype responded better to methylphenidate than to atomoxetine, although both subtypes showed treatment efficacy. Brain deviations in the infra-normal subtype were explained by the expression levels of genes enriched in presynaptic and axonal development and polygenic risk of ADHD. InterpretationWe identified anatomically distinct, clinically valuable, and biologically informed ADHD subtypes, providing insight into the neurobiological basis of clinical heterogeneity and facilitating a personalized medication strategy for ADHD patients. Panel: Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSubstantial individual heterogeneity in brain phenotypes in attention-deficit/hyperactivity disorder (ADHD) motivates the need to discover homogeneous biotypes. We searched PubMed for research articles on ADHD biotypes using brain MRI published before December 1, 2023, using the search terms ((attention deficit hyperactivity disorder [Title/Abstract]) OR (ADHD [Title/Abstract])) AND ((subtypes [Title/Abstract]) OR (subgroups [Title/Abstract]) OR (subtyping [Title/Abstract])) AND ((MRI [Title/Abstract]) OR (neuroimaging [Title/Abstract]) OR (brain [Title/Abstract])) without language restrictions. Of the eight included studies, two identified ADHD biotypes using structural morphology, four used functional activity, and two used multimodal features. However, none of these studies considered the developmental effect of the brain phenotypes, examined treatment response, or investigated the genetic correlates of the biotypes. Added value of this studyThis study is the first to use individualized brain measures extracted from normative models to investigate ADHD biotypes in a large sample of more than 1,000 children. We identified two reproducible ADHD biotypes, characterized by distinct symptomatic, cognitive, and gene expression profiles, as well as differential treatment responses. This study advances our understanding of the neurobiological basis underlying the clinical heterogeneity of ADHD and highlights the critical need to discover ADHD biotypes using an unbiased and individualized approach. Implications of all the available evidenceThis study revealed remarkable neuroanatomical heterogeneity in ADHD patients and identified anatomically distinct, clinically valuable, and biologically informed ADHD biotypes. Our findings have potential value for the investigation of data-driven biotypes to evaluate treatment efficacy and facilitate personalized treatment. We also highlight the need for future studies to move beyond the understanding of ADHD solely based on the "average patient" perspective.

neuroscience↗

bioRxiv2024

Scaled and Efficient Derivation of Loss of Function Alleles in Risk Genes for Neurodevelopmental and Psychiatric Disorders in Human iPSC

Translating genetic findings for neurodevelopmental and psychiatric disorders (NPD) into actionable disease biology would benefit from large-scale and unbiased functional studies of NPD genes. Leveraging the cytosine base editing (CBE) system, here we developed a pipeline for clonal loss-of-function (LoF) allele mutagenesis in human induced pluripotent stem cells (hiPSCs) by introducing premature stop-codons (iSTOP) that lead to mRNA nonsense-mediated-decay (NMD) or protein truncation. We tested the pipeline for 23 NPD genes on 3 hiPSC lines and achieved highly reproducible, efficient iSTOP editing in 22 NPD genes. Using RNAseq, we confirmed their pluripotency, absence of chromosomal abnormalities, and NMD. Interestingly, for three schizophrenia risk genes (SETD1A, TRIO, CUL1), despite the high efficiency of base editing, we only obtained heterozygous LoF alleles, suggesting their essential roles for cell growth. We replicated the reported neural phenotypes of SHANK3-haploinsufficiency and found CUL1-LoF reduced neurite branches and synaptic puncta density. This iSTOP pipeline enables a scaled and efficient LoF mutagenesis of NPD genes, yielding an invaluable shareable resource.

genetics↗

bioRxiv2024

Structural diversity and clustering of bacterial flagellar outer domains

Supercoiled flagellar filaments function as mechanical propellers within the bacterial flagellum complex, playing a crucial role in motility. Flagellin, the building block of the filament, features a conserved inner D0/D1 core domain across different bacterial species. In contrast, approximately half of the flagellins possess additional, highly divergent outer domain(s), suggesting varied functional potential. In this study, we elucidate atomic structures of flagellar filaments from three distinct bacterial species: Cupriavidus gilardii, Stenotrophomonas maltophilia, and Geovibrio thiophilus. Our findings reveal that the flagella from the facultative anaerobic G. thiophilus possesses a significantly more negatively charged surface, potentially enabling adhesion to positively charged minerals. Furthermore, we analyzed all AlphaFold predicted structures for annotated bacterial flagellins, categorizing the flagellin outer domains into 682 structural clusters. This classification provides insights into the prevalence and experimental verification of these outer domains. Remarkably, two of the flagellar structures reported herein belong to a previously unexplored cluster, indicating new opportunities on the study of the functional diversity of flagellar outer domains. Our findings underscore the complexity of bacterial flagellins and open up possibilities for future studies into their varied roles beyond motility.

microbiology↗

bioRxiv2024

Widespread innervation of motoneurons by spinal V3 neurons globally amplifies locomotor output in mice.

While considerable progress has been made in understanding the neuronal circuits that underlie the patterning of locomotor behaviours such as walking, less is known about the circuits that amplify motoneuron output to enable adaptable increases in muscle force across different locomotor intensities. Here, we demonstrate that an excitatory propriospinal neuron population (V3 neurons, Sim1+) forms a large part of the total excitatory interneuron input to motoneurons ([~]20%) across all hindlimb muscles. Additionally, V3 neurons make extensive connections among themselves and with other excitatory premotor neurons (such as V2a neurons). These circuits allow local activation of V3 neurons at just one segment (via optogenetics) to rapidly depolarize and amplify locomotor-related motoneuron output at all lumbar segments in both the in vitro spinal cord and the awake adult mouse. Interestingly, despite similar innervation from V3 neurons to flexor and extensor motoneuron pools, functionally, V3 neurons exhibit a pronounced bias towards activating extensor muscles. Furthermore, the V3 neurons appear essential to extensor activity during locomotion because genetically silencing them leads to slower and weaker mice with a poor ability to increase force with locomotor intensity, without much change in the timing of locomotion. Overall, V3 neurons increase the excitability of motoneurons and premotor neurons, thereby serving as global command neurons that amplify the locomotion intensity.

neuroscience↗

bioRxiv2024

A Trisomy 21-linked Hematopoietic Gene Variant in Microglia Confers Resilience in Human iPSC Models of Alzheimers Disease

SUMMARYWhile challenging, identifying individuals displaying resilience to Alzheimers disease (AD) and understanding the underlying mechanism holds great promise for the development of new therapeutic interventions to effectively treat AD. Down syndrome (DS), or trisomy 21, is the most common genetic cause of AD. Interestingly, some people with DS, despite developing AD neuropathology, show resilience to cognitive decline. Furthermore, DS individuals are at an increased risk of myeloid leukemia due to somatic mutations in hematopoietic cells. Recent studies indicate that somatic mutations in hematopoietic cells may lead to resilience to neurodegeneration. Microglia, derived from hematopoietic lineages, play a central role in AD etiology. We therefore hypothesize that microglia carrying the somatic mutations associated with DS myeloid leukemia may impart resilience to AD. Using CRISPR-Cas9 gene editing, we introduce a trisomy 21-linked hotspot CSF2RB A455D mutation into human pluripotent stem cell (hPSC) lines derived from both DS and healthy individuals. Employing hPSC-based in vitro microglia culture and in vivo human microglia chimeric mouse brain models, we show that in response to pathological tau, the CSF2RB A455D mutation suppresses microglial type-1 interferon signaling, independent of trisomy 21 genetic background. This mutation reduces neuroinflammation and enhances phagocytic and autophagic functions, thereby ameliorating senescent and dystrophic phenotypes in human microglia. Moreover, the CSF2RB A455D mutation promotes the development of a unique microglia subcluster with tissue repair properties. Importantly, human microglia carrying CSF2RB A455D provide protection to neuronal function, such as neurogenesis and synaptic plasticity in chimeric mouse brains where human microglia largely repopulate the hippocampus. When co-transplanted into the same mouse brains, human microglia with CSF2RB A455D mutation phagocytize and replace human microglia carrying the wildtype CSF2RB gene following pathological tau treatment. Our findings suggest that hPSC-derived CSF2RB A455D microglia could be employed to develop effective microglial replacement therapy for AD and other age-related neurodegenerative diseases, even without the need to deplete endogenous diseased microglia prior to cell transplantation.

neuroscience↗

bioRxiv2024

CircRNA-Pro: A Novel Toolkit for High-Precision Detection of Differentially Expressed Circular RNAs and Translatable Circular RNAs

With the increasing discovery of circular RNAs (circRNAs) and their critical roles in gene regulation and disease progression, there is a growing need for more accurate and efficient tools for circRNAs research. In response, we have developed an integrated software suite specifically for circRNAs. This all-in-one tool specializes in detecting differentially expressed circRNAs, including those with the potential to be translated into proteins, and allows for comparing against relevant databases, thereby enabling comprehensive circRNA profiling and annotation. To enhance the accuracy in detecting differentially expressed circRNAs, we incorporated three different software algorithms and cross-validated their results through mutual verification. Additionally, this toolkit improves the effectiveness in identifying translatable circRNAs by optimizing Ribo-seq alignment and verifying against public circRNA databases. The performance of circRNA-pro has been evaluated through its application to public RNA-seq and Ribo-seq datasets on breast cancer and SARS-CoV-2 infected cells, and the results obtained have been validated against previous literature and databases. Overall, our integrated toolkit provides a reliable workflow for circRNA research, facilitating insights into their diverse roles across life sciences.

bioinformatics↗

bioRxiv2024

Residual Partial Least Squares Learning: Brain Cortical Thickness Simultaneously Predicts Eight Non-pairwise-correlated Behavioural and Disease Outcomes in Alzheimer's Disease

Alzheimers Disease (AD) is the leading cause of dementia, affecting brain structure, function, cognition, and behaviour. While previous studies have linked brain regions to univariate outcomes (e.g., disease status), the relationship between brain-wide changes and multiple disease and behavioural outcomes of AD is still not well understood. Here, we propose Residual Partial Least Squares (re-PLS) Learning, an explainable and generalisable framework that models high-dimensional brain features and multivariate outcomes, accounting for confounders. Using re-PLS, we map the many-to-many pathways between cortical thickness and multivariate AD outcomes; identify neural biomarkers that simultaneously predict multiple outcomes; control for confounding variables; conduct longitudinal AD prediction; and perform cross-cohort AD prediction. To evaluate its efficacy, we first carry out within-cohort cross-subject validation using ADNI data, and further examine its reproducibility via between-cohort cross-validation using ADNI and OASIS data. Together, our results unveil brain regions jointly but differentially predictive of distinctive cognitive-behavioural scores in AD.

neuroscience↗

bioRxiv2024

RevGraphVAMP: A protein molecular simulation analysis model combining graph convolutional neural networks and physical constraints

Molecular simulation (MD) is an important research area in the field of life sciences, focusing on understanding the mechanisms of biomolecular interactions at atomic scales. Protein simulation, as a critical subfield of life science, has frequently adopted MD for implementation, where the trajectory data play an important role in drug discovery. With the advancement of high-performance computing and deep learning technology, machine-prediction of protein properties from enormous trajectory data becomes popular and critical, which puts challenges on how to extract useful data features from the complicated simulation data and reasonably reduce the dimensionality. At the same time, in order to better study the Protein system, it is necessary to provide a meaningful explanation of biological mechanism for dimensionality reduction. In order to address this issue, a new unsupervised model RevGraphVAMP is proposed to intelligently analyze the simulation trajectory. RevGraphVAMP is based on the Markov variation method (VAMP) and innovatively integrates graph convolutional neural networks and physical constraint optimization to improve the learning performance of the model. Besides, the attention mechanism is introduced to calculate the importance of protein molecules, leading to interpretation of molecular mechanism. Compared with other VAMPNets models, the new model presented in this paper has achieved the highest VAMP scores and better state transition prediction accuracy in two public datasets. Additionally, it has higher dimensionality reduction discrimination ability for different substates and provides interpretable results for protein structural characterization.

bioinformatics↗