Biology subjects

Niu, G.

Publications and source records attributed to Niu, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Targeting the AgMOBP1-PfSyn5 mosquito-parasite interface completely blocks malaria transmission

Malaria control remains constrained by an incomplete understanding of the molecular interactions that enable Plasmodium falciparum transmission within mosquito vectors. Although blood-stage parasite biology has been extensively studied, the mosquito-stage processes required for transmission are less well defined. Here, we characterize a previously unannotated Anopheles gambiae midgut factor, Midgut Ookinete Binding Protein 1 (AgMOBP1; AGAP008138), and define its role in parasite infection. AgMOBP1 is a membrane-associated protein localized predominantly to the apical surface of midgut epithelial cells, is induced by blood feeding, and appears restricted to anopheline mosquitoes. Functional infection assays showed that exogenous recombinant AgMOBP1 enhanced Plasmodium infectivity by increasing midgut oocyst burden, whereas anti-AgMOBP1 antibodies significantly reduced infection, establishing AgMOBP1 as a host factor that promotes transmission. Using biochemical interaction assays, we identified the parasite binding partner of AgMOBP1 as the P. falciparum syntaxin-5-like protein PfSyn5. Disruption of this interaction with anti-PfSyn5 polyclonal antibodies produced exceptionally potent transmission-blocking activity, with complete inhibition at 1 {micro}g/mL and an estimated IC50 of [~]3 ng/mL ([~]20 pM). This potency is approximately one million-fold lower than the total IgG concentration in normal human plasma. Together, these findings identify a critical mosquito-parasite molecular interface required for malaria transmission and establish the AgMOBP1-PfSyn5 axis as a promising target for transmission-blocking vaccines, monoclonal antibodies, and other intervention strategies. Significance StatementInterrupting malaria transmission requires a deeper mechanistic understanding of how Plasmodium parasites interact with their mosquito vectors. Here, we define a previously uncharacterized mosquito midgut factor, AgMOBP1, and identify its parasite binding partner, the Plasmodium falciparum membrane protein PfSyn5. We show that this molecular interaction is required for efficient parasite transmission to Anopheles mosquitoes. Remarkably, antibodies against PfSyn5 completely blocked transmission at low concentrations, revealing exceptional functional potency. These findings uncover a previously unknown mosquito-parasite invasion pathway and establish the AgMOBP1-PfSyn5 interface as a high-value target for transmission-blocking vaccines, monoclonal antibodies, and next-generation malaria control strategies.

microbiology↗

bioRxiv2026

HMA proteins produce 2',3'-cNMP signaling molecules and activate CNL-mediated immunity in rice

Plants deploy a sensor repertoire, usually NLRs, to perceive pathogen effectors and activate executor NLR-triggered immunity. Here we reveal that rice HMA proteins function as sensors detecting the Magnaporthe oryzae MAX effector AvrPigm to trigger broad-spectrum blast resistance mediated by the CNL PigmR. AvrPigm is conserved with multiple copies in blast genomes and targets HMA proteins, facilitating HMA translocation into the cytoplasm. Cryo-EM structure of the HPP04HMA reveals a filament-like oligomer with ssDNA/RNA bound inside the filament, which display cyclic nucleotide synthase activity to generate 2',3'-cNMP in a CNL-dependent manner. We further discovered that the LRR domains of the executor CNLs perceive 2',3'-cNMP to mount immunity. Our study thus establishes an unrecognized immunity mode with a distinct repertoire of sensor receptors that produce signaling molecules that are perceived by the LRR domains of executor NLRs to mediate immunity, shedding new light on the sensor-executor conception and immune activation in plants. HighlightsO_LIHMA proteins and CNL receptors form a new sensor-executor mode in plant immunity C_LIO_LICryo-EM reveals the filament-like structure of HMA-ssRNA/ssDNA C_LIO_LIHMA proteins are cyclic nucleotide synthetases to generate 2',3'-cNMP C_LIO_LILRR domains of CNLs perceive 2',3'-cNMP to mediate immunity C_LI

plant biology↗

bioRxiv2026

Population-Scale Analysis of Frequency-Dependent Calcium Dynamics in Retinal Ganglion Cells Under Electric Field Stimulation

Electric field (EF) stimulation is an emerging neuromodulatory strategy for promoting the repair and functional recovery of degenerated neural networks in neurodegenerative conditions such as glaucoma. EF stimulation therapeutic potential is thought to arise, in part, from modulation of calcium-dependent signaling pathways that regulate neuronal survival and plasticity. However, despite extensive use of EF stimulation in retinal research and clinical studies, it remains unclear how EF waveform frequency and shape govern population-level intracellular calcium dynamics in retinal ganglion cells (RGCs), limiting the rational design of stimulation protocols. Here we address this gap by combining large-scale ex-vivo calcium imaging of Thy1-GCaMP6f mouse retinas with controlled EF stimulation spanning a wide frequency range and a uniform, non-contact stimulation geometry. This approach enables direct measurement of intracellular calcium responses across thousands of individual RGCs under stimulation conditions relevant to non-invasive and translational paradigms. We further develop a morphologically detailed RGC model in NEURON incorporating reaction-diffusion calcium dynamics and admittance-based extracellular stimulation to mechanistically interpret the frequency-dependent responses observed under sinusoidal EF stimulation. Using this integrated experimental-computational framework, we reveal how electric field stimulation modulates population-level calcium signaling in retinal ganglion cells, enabling simultaneous characterization of spatial response patterns and ensemble-averaged activity across thousands of cells. At this scale, RGC calcium responses are constrained to a distinct frequency regime: low frequencies (below 5 Hz) evoke oscillatory transients, intermediate frequencies (10-100 Hz) produce sustained calcium elevation across the population, and high-frequency stimulation (>3 kHz) leads to a sharp attenuation of calcium responses. Among all tested waveforms, a 1:4 asymmetric charge-balanced stimulus at 50 Hz most effectively and consistently elevated intracellular calcium across the RGC population. The computational model reproduces the experimentally observed frequency dependence for sinusoidal stimulation and reveals that the behavior of these different frequency regimes emerges from the interplay between calcium influx, calcium-activated potassium feedback, calcium extrusion kinetics, and soma geometry. Beyond these findings, this work delivers, to our knowledge, the first large-scale dataset of single-cell calcium responses from RGC populations exposed to diverse EF waveforms and frequencies. This dataset enables future data-driven and hybrid modeling approaches that require rich mappings between extracellular stimulation parameters and intracellular calcium dynamics, and establishes a foundation for systematic, physiology-informed optimization of EF stimulation strategies targeting retinal neurodegenerative disease.

bioengineering↗

bioRxiv2025

Mitochondrial CircRNA CircMT-RNR2 Safeguards Antioxidant Defense to Support Fibroblast Functions in Wound Repair

Diabetic foot ulcers (DFUs) are a debilitating diabetes complication in which mitochondrial dysfunction and oxidative stress are prominent but mechanistically unresolved features. Here, we identify the mitochondria-encoded circular RNA circMT-RNR2 as a novel modulator of mitochondrial redox homeostasis in human skin wound healing. CircMT-RNR2 is reduced in DFU patient tissue and diabetic mouse wounds, enriched in dermal fibroblasts, and localized to mitochondria. Its loss impairs fibroblast proliferation, migration, extracellular matrix production, and contraction by destabilizing the mitochondrial antioxidant protein PRDX3, leading to elevated oxidative stress, mitochondrial damage, and mitophagy. In murine and human ex vivo wound models, circMT-RNR2 knockdown delays healing, whereas overexpression accelerates repair and boosts antioxidant defenses. These findings position circMT-RNR2 as a mitochondrial guardian of skin healing and a promising therapeutic target for DFUs. One Sentence SummaryCircMT-RNR2, a mitochondria-encoded circular RNA suppressed in diabetic foot ulcers, promotes fibroblast function and maintains mitochondrial redox balance via stabilization of the antioxidant protein PRDX3, offering a promising therapeutic target for chronic wound repair.

molecular biology↗

bioRxiv2024

Graph Network-Based Analysis of Disease-Gene-Drug Associations: Zero-Shot Disease-Drug Prediction and Analysis Strategies

Existing drug repurposing methods have key limitations, primarily stemming from their reliance on known direct associations between diseases and drugs for supervised learning, as well as the need for large amounts of prior disease or drug information or feature data. In practice, many disease-drug connections remain unknown, and prior information is often complex and difficult to acquire and organize, limiting the applicability of these models. Furthermore, these models generally lack interpretability, making it difficult for experts to assess the reliability of predictions based solely on standard metrics, which raises doubts about the trustworthiness of their results. To address these challenges, we propose ZS-GNT, an innovative new workflow for zero-shot drug repurposing that leverages a novel and ingenious graph data meta-path linking scheme, which does not require any known disease-drug associations or their prior features. This approach is implemented using the Graph Neural Transformer (GNT) algorithm. The method infers disease-drug relationships indirectly through gene action, utilizing disease-gene associations and gene-drug interactions. It also generates a top drug-top gene linkage map, providing clinicians with a visual tool to assess the plausibility of suggested drugs before advancing to clinical trials. Experimental results show that, under the same linking scheme, the GNT algorithm achieved interaction link prediction accuracies of 95.86%, 99.28%, and 99.54% for three diseases, surpassing four other baseline methods. In a test involving a random selection of 100 diseases for drug discovery, among the top 5 recommended drugs from the candidates identified by ZS-GNT from a pool of 33,251 total drugs, the validation rate reached 47.05%, demonstrating the models effectiveness in drug discovery.

bioinformatics↗

bioRxiv2024

Telomere-to-Telomere Genome Assembly Uncovers Wolbachia-Driven Sex-Specific Demography and Challenges Fisher's Principle in a Sawfly

Wolbachia, a widespread endosymbiotic bacterium, can reshape the evolutionary fates of its insect hosts by distorting reproduction and altering population dynamics. Despite extensive laboratory research, its long-term effects on host evolution in nature remain poorly understood, particularly regarding genetic mechanisms underlying changes in sex determination and reproduction. Here, we report the first telomere-to-telomere (T2T) genome assembly of the sawfly Analcellicampa danfengensis and the complete genome of it symbiotic Wolbachia. Comparative population genomics of six closely related Analcellicampa species revealed that Wolbachia-infected populations experience marked changes in sex-specific demography. While uninfected species maintain balanced genetic features between males and females, infected species show a persistent reduction in male effective population size alongside a stable or even growing female population, ultimately driving males toward extinction. Genomic scans identified positively selected genes associated with reproductive functions, sensory perception, neural development, and longevity, suggesting that Wolbachia manipulates critical host biological pathways to promote its transmission. These findings provide direct genomic evidence that Wolbachia acts as a powerful evolutionary force, reshaping host genomes in a way that disrupts Fishers principle, ultimately driving female-biased demography and the extinction of males at evolutionary timescales. This work provides deeper insights into host- endosymbiont coevolution and has important implications for evolutionary theory and pest management strategies.

evolutionary biology↗

bioRxiv2024

A negative feedback loop between small GTPase Rap1 and mammalian tumor suppressor homolog KrsB regulates cell-substrate adhesion in Dictyostelium

Cell adhesion to the substrate influences a variety of cell behaviors and its proper regulation is essential for migration, although details of the molecular pathways regulating cell adhesion during migration are lacking. Rap1 is a small GTPase that regulates adhesion in mammalian cells, as well as in Dictyostelium discoideum social amoeba, which is an established model for studying directed cell migration. In Dictyostelium, Rap1 controls adhesion via its effects on adhesion mediator talin and Ser/Thr kinase Phg2, which inhibits myosin II function. Kinase responsive to stress B (KrsB), a homolog of mammalian tumor suppressor MST1/2 and Drosophila Hippo, also regulates cell adhesion and migration, although the molecular mechanism of KrsB action is not understood. Since KrsB has been shown to interact with active Rap1 by mass spectroscopy, we investigated the genetic interaction between Rap1 and KrsB. Cells lacking KrsB have increased adhesion to the substrate, which leads to reduced movement. Expression of constitutively active Rap1 G12V increased cell spreading and adhesion even in the absence of KrsB, suggesting that Rap1 does not require KrsB to mediate cell adhesion. In contrast, dominant negative Rap1 S17N completely reversed the over-adhesive phenotype of KrsB-null cells and impaired KrsB phosphorylation, suggesting that KrsB activation and function in adhesion requires Rap1. Even though Rap1 did not require KrsB for its function in adhesion, KrsB negatively regulates Rap1 function as seen by increased cortical localization of Rap1 in KrsB-null cells. Consistent with this, chemoattractant-induced activation of downstream effectors of Rap1, TalB and Phg2, was increased in the absence of KrsB. Taken together, these findings suggest that Rap1 leads to activation of KrsB, which inhibits Rap1 and its downstream targets, shutting off adhesion. The existence of a negative feedback loop between Rap1 and KrsB may contribute to the dynamic regulation of cell adhesion that is necessary for rapid amoeboid-type migration.

cell biology↗

bioRxiv2024

Circular RNA circASH1L(4,5) protects microRNA-129-5p from target-directed microRNA degradation in human skin wound healing

Both circular RNAs (circRNA) and microRNAs (miRNA) have emerged to play important roles in health and disease. To understand their function in tissue repair, we profiled circRNA, linear RNA, and miRNA expression dynamics in human wound-edge keratinocytes across the wound healing process. Our investigation spotlighted circASH1L(4,5) and its engagement with miR-129-5p, both of which levels were increased with wound repair. Unlike conventional miRNA sponging, circASH1L enhanced miR-129 stability and silencing activity by protecting this miRNA from target-directed miRNA degradation (TDMD) triggered by NR6A1 mRNA. TGF-{beta} signaling, pivotal in wound healing, fostered circASH1L expression while suppressing NR6A1, thus enhancing the miR-129 abundance at the post-transcriptional level. Functionally, circASH1L and miR-129 enhanced keratinocyte migration and proliferation, crucial for re-epithelialization of human wounds. Collectively, our study uncovers circRNAs novel role as shields for miRNAs and sheds light on the physiological importance of regulated miRNA degradation in human skin wound healing.

molecular biology↗

bioRxiv2023

Optics-aware super-resolution light-field microscopy for long-term volumetric imaging of dynamic intracellular processes at millisecond timescales

Long-term and high-spatiotemporal-resolution 3D imaging of living cells remains an unmet challenge for super-resolution microscopy, owing to the noticeable phototoxicity and limited scanning speed. While emerging light-field microscopy can mitigate this issue through three-dimensionally capturing biological dynamics with merely single snapshot, it suffers from suboptimal resolution insufficient for resolving subcellular structures. Here we propose an Adaptive Learning PHysics-Aware Light-Field Microscopy (Alpha-LFM) with a physics-aware deep learning framework and adaptive-tuning strategies capable for highly-generalizable light-field reconstruction of diverse subcellular dynamics. Alpha-LFM delivers sub-diffraction-limit spatial resolution ([~]120 nm) while maintaining high temporal resolution and low phototoxicity. It enables rapid (at hundreds of volumes per second), long-term (up to 60 hours) 3D super-resolution imaging of diverse intracellular dynamics with exceptional details. Using Alpha-LFM approach, we finely resolve the lysosome-mitochondrial interactions, capture rapid motion of peroxisome and the endoplasmic reticulum, and reveal the variations in mitochondrial fission activity throughout two complete cell cycles.

microbiology↗

bioRxiv2023

Mitochondrial genome evolution in the Diprionidae: Major gene rearrangement in the basal Hymenoptera

In comparison to other non-parasitic basal lineages, Apocrita have consistently demonstrated a greatly accelerated rate of gene rearrangement. A number of mechanisms or correlates have been proposed for this observation, such as oxidative stress tolerated by exposure to the host immune system might lead to a high proportion of rearranged mt-genomes. Our studies reveal that gene rearrangements involving the protein-coding gene are present in the basal Hymenoptera lineage based on enriched sampling. We speculate the processes of diversification of rearrangements in the vicinity of nad2 involved tRNAs and NCRs by producing the chronogram of Diprionids. Furthermore, we investigated the relationship between rearranged genes and their nucleotide sequences. In conclusion, we demonstrate the great potential of gene order and associated sequence features as phylogenetic markers in the study of Hymenoptera evolution, offering a new perspective on studying organisms that undergo frequent gene rearrangements.

evolutionary biology↗

bioRxiv2022

Chi-miR-3880 mediates the regulatory role of interferon gamma in goat mammary gland

A healthy mammary gland is a necessity for milk production of dairy goats. The role of chi-miR-3880 in goat lactation is illustrated in our previous study. Among the differentially expressed genes regulated by chi-miR-3880, one seventh are interferon stimulated genes, including MX1, MX2, IFIT3, IFI44L, and DDX58. As the inflammatory cytokine interferon gamma (IFN{gamma}) has been identified as a potential marker of caseous lymphadenitis in lactating sheep, the interaction between IFN{gamma} and immune-related microRNAs is explored. In this study, it was found that chi-miR-3880 could be one of the microRNAs downregulated by IFN{gamma} in goat mammary epithelial cells (GMECs). The regulation among IFN{gamma}, chi-miR-3880, and DDX58, as well as their roles in mammary gland were investigated. The study illustrated that IFN{gamma}/chi-miR-3880/DDX58 axis modulates GMEC proliferation and lipid formation through PI3K/AKT/mTOR pathway, and regulates apoptosis through Caspase-3 and Bcl-2/Bax. The role of the axis in involution was reflected by the expression of p53 and NF-{kappa}B. In conclusion, IFN{gamma}/chi-miR-3880/DDX58 axis plays an important part in lactation.

cell biology↗

bioRxiv2022

The injury-induced circular RNA circGLIS3 activates dermal fibroblasts to promote wound healing

Delayed skin wound healing and excessive scarring are consequences of an impaired healing process and represent a major health and economic burden worldwide. Current intervention strategies lack efficacy and suffer from high recurrence rates necessitating the investigation into alternative treatment modalities like circular RNAs (circRNAs). By RNA sequencing, we profiled circRNA expression changes during human skin wound healing as well as in keratinocytes and fibroblasts isolated from donor-matched skin and acute wounds. CircGLIS3 was found to be transiently upregulated in the dermal fibroblasts upon skin injury, which was at least partially due to the activated IL-1 signaling. Similarly, overabundant circGLIS3 expression was detected in human keloid lesions compared to the surrounding healthy skin. We found that circGLIS3 resided mainly in the cytoplasm, where it interacted with and stabilized Procollagen C-endopeptidase enhancer 1 (PCPE-1) protein to enhance TGF-{beta} signaling, fibroblast activation, and production of extracellular matrix - important biological processes required for wound repair. Accordingly, knockdown of circGLIS3 in human ex vivo wounds potently reduced wound contraction and delayed re-epithelialization. Collectively, we have identified a previously uncharacterized circRNA regulator of human skin wound healing that may open an avenue for circRNA-based therapeutics for abnormal scarring or nonhealing wounds. One Sentence SummaryTransient increase of the circular RNA circGLIS3 promotes the wound fibroblast activation and extracellular matrix production to facilitate wound closure.

molecular biology↗

bioRxiv2022

Identification and calibration of ultrabright localizations to eliminate quantification error in SMLM

Single molecule localization microscopy (SMLM) is irreplaceable among super-resolution microscopies in revealing biological ultra-structures, given its unmatched high resolution. However, its sub-optimal quantitative capability, which is critical for characterizing true biomolecular organization of ultra-structures in cells, has hindered its widest application in biomedical research. Here, in SMLM imaging of cellular structures such as lipid rafts and microtubules with saturation labelling, we identified ultra-bright localizations, each of which is contributed by simultaneous emission of multiple molecules within a diffraction-limit region and has been regarded before as a regular localization from single molecule. Consistently, ultra-bright localizations are also observed in simulated SMLM imaging of endoplasmic reticulum or microtubules from public resource. Furthermore, after calibrating each ultrabright localization into multiple single-molecule localizations using the photon-number-based models, the density of total localizations shows linear correlation with the true molecule density, presenting SMLM with new reconstruction method as a quantitative analysis approach. Therefore, identification and dissection of ultra-bright localizations in SMLM enable the close and quantitative estimate of the true biomolecular organization.

biophysics↗

bioRxiv2021

Loss of TBK1 activity leads to TDP-43 proteinopathy through lysosomal dysfunction in human motor neurons

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss accompanied by cytoplasmic localization of TDP-43 proteins and their insoluble accumulations. Haploinsufficiency of TBK1 has been found to associate with or cause ALS. However, the cell-autonomous mechanisms by which reduced TBK1 activity contributes to human motor neuron pathology remain elusive. Here, we generated a human cellular model harboring loss-of-function mutations of TBK1 by gene editing and found that TBK1 deficiency was sufficient to cause TDP-43 pathology in human motor neurons. In addition to its functions in autophagy, we found that TBK1 interacted with endosomes and was required for normal endosomal maturation and subsequent lysosomal acidification. Surprisingly, TDP-43 pathology resulted more from the dysfunctional endo-lysosomal pathway than the previously recognized autophagy inhibition mechanism. Restoring TBK1 levels ameliorated lysosomal dysfunction and TDP-43 pathology and maintained normal motor neuron homeostasis. Notably, using patient-derived motor neurons, we found that haploinsufficiency of TBK1 sensitized neurons to lysosomal stress, and chemical regulators of endosomal maturation rescued the neurodegenerative process. Together, our results revealed the mechanism of TBK1 in maintaining TDP-43 and motor neuron homeostasis and suggested that modulating endosomal maturation was able to rescue neurodegenerative disease phenotypes caused by TBK1 deficiency.

neuroscience↗

bioRxiv2021

Enhancing the localization precision of single molecule localization microscopy by analyzing Brownian motion of individual fluorescent probe

Single-molecule localization microscopy (SMLM) boosts its applications when combined with the studies of cells, in which nanometer-sized biomolecules are irresolvable due to diffraction limit unless being subjected to SMLM. Although being well immobilized, given the nanometer sizes of biological molecules, they are still capable of movement stochastically around their immobilized sites. The influence of such motion on image quality and possible improvements have not yet been systematically investigated. Here, we accessed the biomolecule stochastic motion in SMLM by calculating the displacements between different localizations from the same molecule in single-molecule samples of Alexa Fluor-647-conjugated oligonucleotides. We found that, for most molecules, localization displacements at random frame intervals are remarkably larger than those between temporally neighbouring frames despite of drift correction, showing that biomolecule stochastic motion is involved in SMLM. Furthermore, the localization displacements were observed to increase with frame intervals and then saturate, suggesting biomolecule stochastic motion is confined within a finite area. Moreover, we showed that the localization precision is deteriorated by enlarging molecule sizes and improved by sample post-fixation. This study reveals confined stochastic motion of biomolecules increase localization uncertainty in SMLM, and improved localization precision can be achieved via restricting biomolecule stochastic motion.

biophysics↗

bioRxiv2020

Porcine model elucidates function of p53 isoform in carcinogenesis

BackgroundThe pig has long been an important animal species for biomedical research. Recent years has also seen an increasing number of genetically engineered pig models of human diseases including cancer. We previously generated pigs with a modified TP53 allele which carries a Cre-removable transcriptional stop signal in intron 1, and an oncogenic mutation TP53R167H (orthologous to human TP53R175H and mouse Trp53R172H) in exon 5. Pigs with the unrecombined mutant allele (flTP53R167H) develop osteosarcoma (OS) in aged heterozygous and young homozygous animals. In addition, some homozygous animals also developed nephroblastomas and lymphomas. This observation suggested that TP53 gene dysfunction is itself the key initiator of tumorigenesis, but raises the question which aspects of the TP53 regulation leads to the development of such a narrow tumour spectrum, mainly OS. MethodsWe performed a series of molecular and cellular analyses to study the regulation of TP53 and its family members in both healthy tissue and tumours (n= 48) from flTP53R167H pigs. Human OS cell lines were used to prove relevance to human patients. ResultsMolecular analyses of p53 revealed the presence of two internal TP53 promoters (Pint and P2) equivalent to those found in human. Consequently, both pigs and human express TP53 isoforms. Data presented here strongly suggest that P2-driven expression of the mutant R167H-{Delta}152p53 isoform (equivalent to the human R175H-{Delta}160p53 isoform) and its circular counterpart circTP53 determine the tumour spectrum and play a critical role in the malignant transformation of bones, kidney or spleen in flTP53R167H pigs. The detection of {Delta}152p53 isoform mRNA in serum is indicative of tumorigenesis. Furthermore, we showed a tissue-specific p53-dependent deregulation of the p63 and p73 isoforms in these tumours. ConclusionsThis study highlights important species-specific differences in the transcriptional regulation of TP53. For the first time a circTP53 RNA was identified. Results indicate that the {Delta}152p53 isoform, its circular circTP53 and p53 family members, TAp63{delta} and TAp73{delta}, likely play a role in the malignant transformation of bone and other tumours. Considering the similarities of TP53 regulation between pig and human, these observations provide useful pointers for further investigation into isoform function including the novel circTP53 in both the pig model and human patients.

cancer biology↗

bioRxiv2020

Compositional Variability and Mutation Spectra of Monophyletic SARS-CoV-2 Clades

COVID-19 and its causative pathogen SARS-CoV-2 have rushed the world into a staggering pandemic in a few months and a global fight against both is still going on. Here, we describe an analysis procedure where genome composition and its variables are related, through the genetic code, to molecular mechanisms based on understanding of RNA replication and its feedback loop from mutation to viral proteome sequence fraternity including effective sites on replicase-transcriptase complex. Our analysis starts with primary sequence information and identity-based phylogeny based on 22,051 SARS-CoV-2 genome sequences and evaluation of sequence variation patterns as mutation spectrum and its 12 permutations among organized clades tailored to two key mechanisms: strand-biased and function-associated mutations. Our findings include: (1) The most dominant mutation is C-to-U permutation whose abundant second-codon-position counts alter amino acid composition toward higher molecular weight and lower hydrophobicity albeit assumed most slightly deleterious. (2) The second abundance group includes: three negative-strand mutations U-to-C, A-to-G, G-to-A and a positive-strand mutation G-to-U generated through an identical mechanism as C-to-U. (3) A clade-associated and biased mutation trend is found attributable to elevated level of the negative-sense strand synthesis. (4) Within-clade permutation variation is very informative for associating non-synonymous mutations and viral proteome changes. These findings demand a bioinformatics platform where emerging mutations are mapped on to mostly subtle but fast-adjusting viral proteomes and transcriptomes to provide biological and clinical information after logical convergence for effective pharmaceutical and diagnostic applications. Such thoughts and actions are in desperate need, especially in the middle of the War against COVID-19.

microbiology↗

bioRxiv2020

TWIRLS, an automated topic-wise inference method based on massive literature, suggests a possible mechanism via ACE2 for the pathological changes in the human host after coronavirus infection

Faced with the current large-scale public health emergency, collecting, sorting, and analyzing biomedical information related to the "coronavirus" should be done as quickly as possible to gain a global perspective, which is a basic requirement for strengthening epidemic control capacity. However, for human researchers studying the viruses and the hosts, the vast amount of information available cannot be processed effectively and in a timely manner, particularly when the scientific understanding may be limited, which can further lower the information processing efficiency. We present TWIRLS, a method that can automatically acquire, organize, and classify information. Additionally, independent functional data sources can be added to build an inference system using a machine-based approach, which can provide relevant knowledge to help human researchers quickly establish subject cognition and to make more effective decisions. TWIRLS can automatically analyze more than three million words in more than 14,000 literature articles in only 4 hours. Combining with generalized gene interaction databases creates a data interface that can help researchers to further analyze the information. Using the TWIRLS system, we found that an important regulatory factor angiotensin-converting enzyme 2 (ACE2) may be involved in the host pathological changes on binding to the coronavirus after infection. After triggering functional changes in ACE2/AT2R, an imbalance in the steady-state cytokine regulatory axis involving the Renin-Angiotensin System and IP-10 leads to a cytokine storm.

bioinformatics↗