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Zeng, Z.

Publications and source records attributed to Zeng, Z..

At least 55 records · Page 3Linked to original sources

Sky islands of Southwest China. II: Unraveling hidden species diversity of talpid moles using phylogenomics and skull-based deep learning

The sky islands of Southwest China, characterized by dramatic topographical and climatic variations, are prominent hotspots of biodiversity and endemism. Organisms inhabiting middle-to-high elevation habitats in this region are geographically isolated within distinct mountain chains, which over geological time have been subjected to isolation-by-distance and isolation-by-environment. These processes have led to profound allopatric diversification and strong phylogeographic structuring, resulting in a plethora of genetically distinct cryptic species, as is becoming increasingly evident for many small mammal families. However, morphological conservatism can pose significant challenges in delineating these clades within species complexes. In this study, we leverage artificial intelligence technologies to unravel the hidden species diversity of moles (family Talpidae) in Southwest Chinas sky islands. We first employed ultraconserved elements (UCEs) to investigate the evolutionary history of talpid moles, conducted molecular species delimitation using mitochondrial and multi-locus genes, and utilized both traditional and geometric morphometrics to examine their morphological disparity. To address the challenges of morphology based cryptic species identification, we developed a deep learning Hierarchical Identification of Species NETwork (HIS-NET) to create an image-based model that analyzes four different views of the skull/mandible to distinguish genera and species hierarchically. HIS-NET not only achieved expert-level accuracy in species identification but also effectively distinguished between cryptic and known species, aiding in the identification of key morphological variation intervals. Our results support the recognition of allopatrically distributed taxa in Euroscaptor and Parascaptor as full species, thereby confirming that species diversity in this region remains underestimated. Beyond advancing our understanding of speciation in this unique and fragile ecosystem, our study serves as a proof-of-concept, demonstrating the power of deep learning in unraveling hidden biodiversity within this and other species complexes.

zoology↗

FT-Kernel: An innovative kernel for decoding cellular secrets related time

The cell fate participants characterization based on single-cell RNA sequencing (scRNA-seq) data greatly facilitates the mechanism understandings of cellular differentiation. However, inferring these fate factors dynamics along the pseudotime is challenging. Based on cell-state density and pseudotime regression weights, we present an algorithm TimeFactorKernel (FT-Kernel), to predict the key cell fate factors, not only the minimum lineage transition genes, but also the related genesets/pathways, and cellular interaction dynamics along the pseudotime. By extrapolating the pseudotime-related key genes from spectral data as a pseudotime-kernel, FT-Kernel outperformed previous methods. Beyond time-related genes, FT-Kernel offered a comprehensive analysis of the inferred cellular interactions dynamics and lineage pathways dynamics along the pseudotime, which were limited in other methods. Additionally, it facilitated time-related fate factors prediction across various data modalities. Our work developed an important pseudotime-kernel in predicting the fate factors, and provided insights into the cellular hierarchies during development. SignificanceUnderstanding cellular changes over time is key to deciphering lifes processes from development to disease. Current single-cell methods miss crucial information by overlooking cell-state density dynamics and thus neglecting rare, low-density transitional states vital for cell fate decisions. TimeFactorKernel, a novel computational tool, overcomes this limitation. By prioritizing genes active in these low-density transitional states and employing machine learning for precise gene identification, TimeFactorKernel provides a powerful new approach to decode cell fate. Validated and widely adopted, TimeFactorKernel also uniquely models cell-cell interactions, opening new avenues for understanding complex biological systems in health and disease. KeypointsO_LIFT-Kernel is a novel kernel algorithm designed to predict time-related fate factors dynamics from the cell state density and pseudotime regression weights. C_LIO_LIFT-Kernel can be applied to identify lineage transition key genes, cellular interactions, and the multimodal fate kernel inference of genesets/pathways. C_LIO_LICompared to other temporal-related kernels, FT-Kernel minimizes the skewness of gene distribution and more accurately captures the state of fate transitions. C_LIO_LIFT-Kernel is an extensible multimodal framework facilitating to understand the mechanisms of cell differentiation and is available on GitHub. C_LI

bioinformatics↗

Single cell resolved spatial immune repertoire unveils spatial heterogeneity of lymphoid aggregates in human immune disorders

Adaptive immunity, mediated by T and B cell responses, is essential for defending against infections and cancers while also being implicated in autoimmune diseases. Tracking T and B cell repertoires in situ at single-cell resolution is essential for understanding adaptive immune responses. To address the lack of tools for in situ single-cell T/BCR (XCR) sequencing, we developed Stereo-XCR-seq, an efficient strategy for retrieving and sequencing TCR and BCR from Stereo-seq cDNA libraries at subcellular resolution. Stereo-XCR-seq provides unbiased full-length XCR reads alongside spatial transcriptomics, enabling the identification of heterogeneous lymphoid aggregates with distinct clonal activities in cancers and inflammatory bowel disease (IBD). We identified plasma cell aggregates that differ from tertiary lymphoid structures (TLSs) in both transcriptomic profiles and clonal activities, with spatial positioning potentially mediating unique immune responses. Collectively, Stereo-XCR-seq enables in situ single-cell profiling of T and B cell clonal activities within tissue microenvironments, providing insights into lymphocyte adaption to environmental stimuli. This technology provides potential for advancing our understanding of tissue immunity and the development of therapeutic strategies for immune disorders.

immunology↗

Unveiling the Evolution of Antimicrobial Peptides in Gut Microbes via Foundation Model-Powered Framework

Antimicrobial resistance poses a growing threat to public health, emphasizing the urgent need for novel therapeutic strategies. Antimicrobial peptides (AMPs), short peptide sequences with diverse mechanisms of action, offer a promising alternative due to their broad-spectrum activity against pathogens. Recent advances in protein language models (PLMs) have revolutionized protein structure prediction and functional annotation, highlighting their potential for AMP discovery and therapeutic development. In this context, we present AMP-SEMiner (Antimicrobial Peptide Structural Evolution Miner), an AI-driven framework designed to identify AMPs from metagenome-assembled genomes (MAGs). By integrating PLMs, structural clustering and evolutionary analysis into the framework, AMP-SEMiner can identify AMPs encoded by small open reading frames (smORFs) and encrypted peptides (EPs), significantly expanding the discovery space. Using this approach, we identified 1,670,600 AMP candidates from diverse habitats. Experimental validation of 29 candidates revealed antimicrobial activity in 18, with 13 surpassing antibiotics in effectiveness. Further analysis of AMPs from human gut microbiomes demonstrated both conserved and adaptive evolutionary strategies, ensuring their functional efficacy in the dynamic gut environment. These findings position AMP-SEMiner as a powerful tool for the discovery and characterization of novel AMPs, with significant potential to drive the development of new antimicrobial therapies.

microbiology↗

Rapid clonal selection within early hematopoietic cell compartments presages outcome to ivosidenib combination therapy

Acquired resistance to targeted non-intensive therapies is common in myeloid malignancies. Yet, key questions remain as to how rapidly resistant clones are selected by treatment and in which hematopoietic cell compartments clonal selection occurs. To address this gap, we studied clonal responses to ivosidenib + venetoclax {+/-} azacitidine combination therapy in 8 patients with IDH1-mutant myeloid malignancy. Whilst all 8 patients initially responded to treatment, 6 relapsed and 2 remained in sustained remission for > 4 years. To study longitudinal clonal dynamics through hematopoietic differentiation, we performed high-sensitivity single-cell genotyping in index-sorted sequential patient samples. In all patients who relapsed, therapy-resistant clones were selected rapidly, within 1-3 treatment cycles, at times when hematopoiesis was still largely sustained by either normal or pre-leukemic cells. Selection of therapy-resistant clones preceded overt treatment failure by months or even years. Relapse was associated either with clones harboring newly-detected myeloid driver mutations or expansion of minor pre-existing clones that had reduced fitness prior to treatment. In both cases, resistant clones were selected within immature cell populations previously shown to contain leukemic stem cell (LSC) potential, preceding malignant expansion of these compartments by immunophenotyping. In contrast, in both patients remaining in remission, leukemic clones were eradicated and rapidly replaced by clonal and wild-type hematopoiesis. These observations suggest that, in patients treated with non-intensive ivosidenib combination therapy, rapid clonal selection occurs in populations with LSC potential, where failure to eliminate either genetically evolved or persistent leukemic clones ultimately leads to relapse. Key points- Rapid selection of leukemic clones occurs within small populations with LSC potential, months or years prior to relapse. - Rapid eradication of leukemic clones leads to sustained remission in the context of ivosidenib combination therapy.

cancer biology↗

Systematic Benchmarking of High-Throughput Subcellular Spatial Transcriptomics Platforms

Recent advancements in spatial transcriptomics technologies have significantly enhanced resolution and throughput, underscoring an urgent need for systematic benchmarking. To address this, we collected clinical samples from three cancer types - colon adenocarcinoma, hepatocellular carcinoma, and ovarian cancer - and generated serial tissue sections for systematic evaluation. Using these uniformly processed samples, we generated spatial transcriptomics data across five high-throughput platforms with subcellular resolution: Stereo-seq v1.3, Visium HD FFPE, Visium HD FF, CosMx 6K, and Xenium 5K. To establish ground truth datasets, we profiled proteins from adjacent tissue sections corresponding to all five platforms using CODEX and performed single-cell RNA sequencing on the same samples. Leveraging manual cell segmentation and detailed annotations, we systematically assessed each platforms performance across key metrics, including capture sensitivity, specificity, diffusion control, cell segmentation, cell annotation, spatial clustering, and transcript-protein alignment with adjacent CODEX. The uniformly generated, processed, and annotated multi-omics dataset is valuable for advancing computational method development and biological discoveries. The dataset is accessible via SPATCH, a user-friendly web server for visualization and download (http://spatch.pku-genomics.org/).

genomics↗

Base-modified nucleotides mediate immune signaling in bacteria

Signaling from pathogen sensing to effector activation is a fundamental principle of cellular immunity. While cyclic (oligo)nucleotides have emerged as key signaling molecules, the existence of other messengers remains largely unexplored. Here, we reveal a bacterial anti-phage system that mediates immune signaling through nucleobase modification. Immunity is triggered by phage nucleotide kinases, which, combined with the system-encoded adenosine deaminase, produce deoxyinosine 5-triphosphate (dITP) as immune messengers. The dITP signal activates downstream effector to mediate cellular NAD+ depletion, resulting in population-level defense through the death of infected cells. To counteract immune signaling, phages deploy specialized enzymes that deplete cellular dAMP, the precursor of dITP messengers. Our findings uncover a nucleobase modification-based anti-phage signaling pathway, establishing noncanonical nucleotides as a new type of immune messengers in bacteria.

microbiology↗

Divergent effects of 3-nitrooxypropanol on enteric methane emissions in Holstein and Brown Swiss cows, and its lack of synergy with Acacia mearnsii tannin extract

The objectives of this study were to investigate the combined effects of 3-nitrooxypropanol (3-NOP) and Acacia mearnsii tannin extract (TAN), and their interactions with dairy cattle breed [Brown Swiss (BS) vs. Holstein Friesian (HF)], on lactational performance, and enteric methane (CH4) emissions. Sixteen multiparous mid-lactation cows, including 8 BS and 8 HF cows were used in a split-plot design, with breed as the main plot. Cows within each subplot were arranged in a replicated 4 x 4 Latin Square design with a 2 x 2 factorial arrangement of treatments across four 24-d periods. The experimental diets were: 1) CON (basal total mixed ration), 2) 3-NOP (60 mg/kg DM), 3) TAN (3% of DM), and 4) 3-NOP + TAN. Spot samples of urine, feces, and gas emissions (via GreenFeed) were collected at the end of each period 8 times over 3 days. No 3-NOP x TAN x Breed interactions were observed for DM intake (DMI), milk production, or enteric gas emissions, except for CH4 yield (g/kg DMI) and CO2 production. Breed influenced DMI, milk production, and component yields, with HF cows consuming 3.7 kg/d more DMI, producing 9.3 kg/d more milk, and achieving greater feed efficiency and higher milk component yields than BS cows. Milk yield and energy-corrected milk (ECM) tended to increase in HF but tended to decrease in BS cows by 3-NOP. Cows fed TAN had 1 kg/d lower DMI with the tendency for 3-NOP x TAN showed greater reduction when TAN was fed alone, but milk yield, ECM, and feed efficiency remained unchanged. Cows fed TAN exhibited 18% lower milk urea nitrogen (N) concentration and 23.0% lower urinary N but 36.7% greater fecal N excretions as a percentage of daily N intake. A 3-NOP x Breed interaction was observed in CH4 production (g/d), with a 21.7% reduction in HF, and a 13.0% reduction in BS. Similarly, there were 3-NOP x Breed tendencies in CH4 yield and intensity (g/kg ECM), with reductions in HF cows of 21.8% and 23.4%, respectively, compared to 11.0% and 10.8% in BS cows. In conclusion, there were no synergistic or additive effects between 3-NOP and TAN on enteric CH4 mitigation. The enteric CH4 emission mitigating effect of 3-NOP was more pronounced in HF cows than in BS cows. Further research is needed to understand breed-specific responses and to optimize CH4 mitigation strategies for inclusion in national greenhouse gas inventories. ImplicationsThis study demonstrated that the feed additive 3-nitrooxypropanol reduces enteric methane emissions in dairy cows, with a greater reduction observed in Holsteins (22%) compared to Brown Swiss (13%) cows. While combining 3-NOP with Acacia mearnsii tannin extract did not further reduce methane. Feeding Acacia mearnsii extract decreased nitrogen excretion, potentially reducing environmental nitrogen pollution from manure. Neither additive substantially impacted milk production; however, 3-nitrooxypropanol tended to increase milk yield in Holsteins while reducing it in Brown Swiss. Overall, this study suggests that enteric methane mitigation efficacy of dietary strategies for different cattle breeds should be further investigated.

animal behavior and cognition↗

Laser Speckle Particle Sizer (SPARSE) Informs the Size Distribution of Tissue Granularities

Particle sizing of biomaterials and tissues holds profound implications across diverse industrial and clinical disciplines. Conventional approaches such as dynamic light scattering (DLS) are restricted to dilute liquids, and unable to assess particle size distribution in intact, untampered biomaterials and tissues in their native state. Here, we introduce the laser Speckle PARticle SizEr (SPARSE), which leverages the size-dependent attributes of polarized back-scattered laser speckle to characterize the average radius of a continuum of endogenous scattering particles, in the 10nm-10m range, in biological fluids and soft tissues in their native state. The SPARSE approach exploits cross- and co-polarized attributes of spatial and temporal laser speckle intensity fluctuations to quantify the average particle size in various specimens, including polystyrene microspheres, milk, whole blood specimens, and intact soft tissues, without prior knowledge or explicit account of refractive index and scattering concentrations. Through scanning the laser beam across the tissue surface, we establish the capability of SPARSE to evaluate a spatial map of heterogenous scattering particle sizes with a resolution of a few 10s of m that closely mirrors histopathological microstructures in benign and carcinoma breast tissue specimens. By enabling the size characterization of intact tissues and biomaterials across a continuum of granularities, non-destructively in native specimens, SPARSE opens substantial opportunities for quality control in industrial applications, drug development, and advanced clinical diagnostics.

biophysics↗

Twisted Sister1: an agravitropic mutant of bread wheat (Triticum aestivum) with altered root and shoot architectures.

We identified a mutant of hexaploid wheat (Triticum aestivum) with impaired responses to gravity. The mutant named Twisted Sister1 (TS1) had agravitropic roots that were often twisted along with altered shoot phenotypes. Roots of TS1 were insensitive of externally applied auxin with the genetics and physiology suggestive of a mutated AUX/IAA transcription factor gene. Hexaploid wheat possesses over eighty AUX/IAA genes and sequence information did not identify an obvious candidate. Bulked segregant analysis of an F2 population mapped the mutation to chromosome 5A and subsequent mapping located the mutation to a 41 Mbp region. RNA-seq identified the TraesCS5A03G0149800 gene encoding a TaAUX/IAA protein to be mutated in the highly conserved domain II motif. We confirmed TraesCS5A03G0149800 as underlying the mutant phenotype by generating transgenic Arabidopsis thaliana. Analysis of RNA-seq data suggested broad similarities between Arabidopsis and wheat for the role of AUX/IAA genes in gravity responses. Here we show that the sequenced wheat genome along with previous knowledge largely from the model species Arabidopsis, gene mapping, RNA-seq and expression in Arabidopsis have enabled cloning of a key wheat gene defining plant architecture.

plant biology↗

YTHDF2 upregulation and relocation dictate CD8 T cell polyfunctionality in tumor immunity

Epigenetic traits impact the antitumor function of CD8 T cells, yet whether and how RNA methylation programs engage in T cell immunity is poorly understood. Here we show that the N6-methyladenosine (m6A) RNA reader YTHDF2 is highly expressed in early effector or effector-like CD8 T cells and is partially distributed in the nucleus. YTHDF2 loss in T cells exacerbates tumor progression and confers unresponsiveness to PD-1 blockade in mice and humans. In addition to initiating RNA decay for mitochondrial fitness, YTHDF2 can orchestrate chromatin regulation to promote T cell polyfunctionality. YTHDF2-mediatd preservation of gene transcription arises from the interaction of YTHDF2 with IKZF1/3. Accordingly, immunotherapy-induced efficacy could be largely restored in YTHDF2-deficient T cells through combinational use of lenalidomide. Moreover, m6A recognition is fundamental for YTHDF2 translocation to the nucleus and autoregulation at the RNA level. Thus, YTHDF2 coordinates epitranscriptional and transcriptional networks to potentiate T cell immunity. HighlightsO_LIYTHDF2 expression and distribution underpin the threshold for bona fide CD8 T cell effector response C_LIO_LICanonical YTHDF2-mRNA decay pathway alleviates mitochondrial stress and CD8 T cell exhaustion C_LIO_LINuclear YTHDF2 sequesters IKZF1/3-mediated transcriptional repression to safeguard CD8 T cell polyfunctionality C_LIO_LIThe tumoricidal activity of YTHDF2-deficient CD8 T cells could be repaired through the synergy of anti-PD-1 and lenalidomide C_LI

immunology↗

Production and functional verification of 8-gene (GGTA1, CMAH, β4GalNT2, hCD46, hCD55, hCD59, hTBM, hCD39)-edited donor pigs for xenotransplantation

Gene-edited pig-to-human xenotransplantation continues to make breakthroughs and is expected to enter clinic to solve the global shortage of donor organs. However, which gene combination is suitable for which organ transplantation remains unclear. In this study, we utilized CRISPR/Cas9 gene editing technology, PiggyBac transposon system and somatic cell cloning to construct GTKO/CMAHKO/{beta}4GalNT2KO/hCD46/hCD55/hCD59/hCD39/hTBM 8 gene-edited cloned (GEC) donor pigs, and performed pig to non-human primate (NHP) transplantation to evaluate the effectiveness of these GEC pigs. The multiple vectors were co-transfected into fetal fibroblasts of Diannan miniature pig with O blood type, and 25 colonies were screened out, and one of them carried GGTA1, CMAH and {beta}4GalNT2 biallelic knockout and integration of hCD46, hCD55, hCD59, hTBM and hCD39 genes, which was used as a donor cell for cloning, and a 33-day-old viable fetus was obtained. The fetus was identified and confirmed for normal karyotype and the absence of three xenogeneic antigens -Gal, Neu5Gc and Sda, and expression of hCD46, hCD55, hCD59, hTBM and hCD39 genes, then the recloning was carried out and 28 cloned piglets were obtained by natural delivery. Molecular identification at DNA, mRNA and protein levels showed that 8 gene editing (GE) was successful in these GEC piglets. Moreover, antigen-antibody binding assay and complement-dependent cytotoxicity assay demonstrated that 8GE effectively reduced the immune incompatibility and kidney xenograft survived up to 15 and 17 days into two NHPs, respectively. During this period, the recipient serum antibodies IgA and IgM, complements C3 and C4, coagulation indicators PT, APTT, TT and FIB, as well as most electrolytes and liver function indicators remained relatively stable. The 24-hour urine output and serum creatinine remained normal at a period of post-transplantation. These results indicated that the 8GEC pigs effectively alleviated immune rejection and exerted life-supporting kidney function in the recipient.

genetics↗

LucaOne: Generalized Biological Foundation Model with Unified Nucleic Acid and Protein Language

AbstractThe language of biology, encoded in DNA, RNA, and proteins, forms the foundation of life but remains challenging to decode due to its complexity. Traditional computational methods often struggle to integrate information across these molecules, limiting a comprehensive understanding of biological systems. Advances in Natural Language Processing (NLP) with pre-trained models offer new possibilities for interpreting biological language. Here, we introduce LucaOne, a pre-trained foundation model trained on nucleic acid and protein sequences from 169,861 species. Through large-scale data integration and semisupervised learning, LucaOne demonstrates an understanding of key biological principles, such as DNA-Protein translation. Using few-shot learning, it effectively comprehends the central dogma of molecular biology and performs competitively on tasks involving DNA, RNA, or protein inputs. Our results highlight the potential of unified foundation models to address complex biological questions, providing an adaptable framework for bioinformatics research and enhancing the interpretation of lifes complexity.

bioinformatics↗

CDHu40: a novel marker gene set of neuroendocrine prostate cancer (NEPC)

Prostate cancer (PCa) is the most prevalent cancer affecting American men. Castration-resistant prostate cancer (CRPC) can emerge during hormone therapy for PCa, manifesting with elevated serum prostate-specific antigen (PSA) levels, continued disease progression, and/or metastasis to the new sites, resulting in a poor prognosis. A subset of CRPC patients shows a neuroendocrine (NE) phenotype, signifying reduced or no reliance on androgen receptor (AR) signaling and a particularly unfavorable prognosis. In this study, we incorporated computational approaches based on both gene expression profiles and protein-protein interaction (PPI) networks. We identified 500 potential marker genes, which are significantly enriched in cell cycle and neuronal processes. The top 40 candidates, collectively named as CDHu40, demonstrated superior performance in distinguishing NE prostate cancer (NEPC) and non-NEPC samples based on gene expression profiles compared to other published marker sets. Notably, some novel marker genes in CDHu40, absent in the other marker sets, have been reported to be associated with NEPC in the literature, such as DDC, FOLH1, BEX1, MAST1, and CACNA1A. Importantly, elevated CDHu40 scores derived from our predictive model showed a robust correlation with unfavorable survival outcomes in patients, indicating the potential of the CDHu40 score as a promising indicator for predicting the survival prognosis of those patients with the NE phenotype. Motif enrichment analysis on the top candidates suggests that REST and E2F6 may serve as key regulators in the NEPC progression. Significanceour study integrates gene expression variances in multiple NEPC studies and protein-protein interaction network to pinpoint a specific set of NEPC maker genes namely CDHu40. These genes and scores based on their gene expression levels effectively distinguish NEPC samples and underscore the clinical prognostic significance and potential mechanism.

bioinformatics↗

Genetic dissection of the tissue-specific roles of type III effectors and phytotoxins in the pathogenicity of Pseudomonas syringae pv. syringae to cherry

When compared with other phylogroups (PGs) of the Pseudomonas syringae (Ps) species complex, Ps pv. syringae strains within PG2 have a reduced repertoire of type III effectors (T3Es) but produce several phytotoxins. Effectors within the cherry pathogen Pss9644 were grouped based on their frequency in strains from Prunus as: the conserved effector locus (CEL) common to most Ps pathogens; a CORE of effectors common to PG2; a set of PRUNUS effectors common to cherry pathogens; and a FLEXIBLE set of T3Es. Pss9644 also contains gene clusters for biosynthesis of toxins syringomycin/syringopeptin and syringolin A. After confirmation of virulence gene expression, mutants with a sequential series of T3E and toxin deletions were pathogenicity tested on wood, leaves and fruits of sweet cherry (Prunus avium) and leaves of ornamental cherry (Prunus incisa). The toxins had a key role in disease development in fruits but were less important in leaves and wood. An effectorless mutant retained some pathogenicity to fruit but not wood or leaves. Striking redundancy was observed amongst effector groups. The CEL effectors have important roles during the early-stages of leaf infection and acted synergistically with toxins in all tissues. Deletion of separate groups of T3Es had much more effect in Prunus incisa than in sweet cherry. Mixed inocula were used to complement the toxin mutations in trans and indicated that strain mixtures may be important in the field. Our results highlight the niche-specific role of toxins in cherry tissues and the complexity of effector redundancy in the pathogen Pss9644.

microbiology↗

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

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

microbiology↗

LightRoseTTA: High-efficient and Accurate Protein Structure Prediction Using an Ultra-Lightweight Deep Graph Model

Accurately predicting protein structure, from amino acid sequences to three-dimensional structures, is of great significance in biological research. To tackle this issue, a representative deep big model, RoseTTAFold, has been proposed with promising success. Here, we report an ultra-lightweight deep graph network, named LightRoseTTA, to achieve accurate and high-efficient prediction for proteins. Notably, three highlights are possessed by our LightRoseTTA: (i) high-accurate structure prediction for proteins, being competitive with RoseTTAFold on multiple popular datasets including CASP14 and CAMEO; (ii) high-efficient training and inference with an ultra-lightweight model, costing only one week on one single general NVIDIA 3090 GPU for model-training (vs 30 days on 8 high-speed NVIDIA V100 GPUs for RoseTTAFold) and containing only 1.4M parameters (vs 130M in RoseTTAFold); (iii) low dependency on multi-sequence alignments (MSA, widely-used homologous information), achieving the best performance on three MSA-insufficient datasets: Orphan, De novo, and Orphan25. Besides, our LightRoseTTA is transferable from general proteins to antibody data, as verified in our experiments. We visualize some case studies to demonstrate the high-quality prediction, and provide some insights on how the structure predictions facilitate the understanding of biological functions. We further make a discussion on the time and resource costs of LightRoseTTA and RoseTTAFold, and demonstrate the feasibility of lightweight models for protein structure prediction, which may be crucial in the resource-limited research for universities and academy institutions. We release our code and model to speed biological research.

bioinformatics↗

Binary Discriminator Facilitates GPT-based Protein Design

Generative pre-trained transformers (GPT) models provide powerful tools for de novo protein design (DNPD). GPT-based DNPD involves three procedures: a) finetuning the model with proteins of interest; b) generating sequence candidates with the finetuned model; and c) prioritizing the sequence candidates. Existing prioritization strategies heavily rely on sequence identity, undermining the diversity. Here, we coupled a protein GPT model with a custom discriminator, which enables selecting candidates of low identity to natural sequences while highly likely with desired functions. We applied this framework to creating novel antimicrobial peptides (AMPs) and malate dehydrogenases (MDHs). Experimental verification pinpointed four broad-spectrum AMPs from 24 candidates. Comprehensive computational analyses on the prioritized MDHs candidates provide compelling evidence for the anticipated function. During experimental validation, 4/10 and 3/10 natural MDHs and generated-prioritized novel candidates, respectively, were expressed and soluble. All the soluble candidates (3/3) are functional in vitro. This framework is time- and data-efficient and may therefore considerably expedite the DNPD process.

bioinformatics↗