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Lan, W.

Publications and source records attributed to Lan, W..

13 recordsLinked to original sources

Transferable spatial omics deconvolution with SpaRank

By resolving cell-type compositions from multi-cellular spatial measurements, deconvolution is central to resolving the cellular landscape of complex tissues. Existing deconvolution methods fit continuous expression values and are therefore sensitive to batch effects between single-cell references and spatial data, requiring retraining for each new context. Here we present SpaRank, a context-aware framework that performs spatial deconvolution by representing spots as ranked feature sequences. Adapting the rank-based encodings of single-cell foundation models, this formulation is inherently robust to technical variation, enabling a pretrain-transfer paradigm. On simulated benchmarks, SpaRank achieves strong deconvolution accuracy, robustness to expression perturbations, and substantial computational efficiency. On experimental datasets, pretrained models generalize across diverse biological contexts: a model pretrained on a multi-organ lymphoid atlas accurately resolved cell-type distributions across distinct tissues and sequencing platforms; likewise, a model pretrained on an integrated breast atlas delineated cell-type compositions across normal and malignant disease states. Furthermore, the framework naturally extends to multimodal spatial deconvolution by employing gated fusion to adaptively integrate diverse omics signals, improving accuracy over single-modality approaches. Overall, SpaRank establishes a transferable deconvolution paradigm, enabling unified cellular atlases to support direct, context-aware inference across diverse biological states and profiling modalities.

bioinformatics↗

ERFMTDA: Predicting tsRNA-disease associations using an enhanced rotative factorization machine

MotivationtRNA-derived small RNAs (tsRNAs) have emerged as a novel class of regulatory molecules implicated in the pathogenesis of many human diseases, making them as promising biomarkers and therapeutic targets. However, existing computational methods for tsRNA-disease association prediction often overlook explicit biological attributes and complex feature interactions, limiting their predictive performance. ResultsWe propose ERFMTDA, an enhanced rotative factorization machine framework for predicting potential tsRNA-disease associations. ERFMTDA explicitly models complex interactions among heterogeneous biological features while integrating latent structural representations derived from the global association matrix. In addition, a biologically informed negative sampling strategy based on motif-level sequence similarity is introduced to improve the reliability of negative samples. Extensive experiments demonstrate that ERFMTDA consistently outperforms eleven state-of-the-art methods. Case studies on diabetic retinopathy and hepatocellular carcinoma further confirm its ability to prioritize biologically meaningful tsRNA-disease associations. Availability and implementationThe source codes and datasets of ERFMTDA are available at https://github.com/lanbiolab/ERFMTDA.

bioinformatics↗

Looking backward for the future: long-term population recovery, habitat associations, and future climatic vulnerability of the critically endangered Sino-Mongolian beaver (Castor fiber birulai) in China

Despite the successful population recovery of the Eurasian beaver (Castor fiber) across much of Eurasia, its subspecies, the Sino-Mongolian beaver (C. f. birulai), remains critically endangered, with an estimated population of approximately 1,500 individuals confined to a small number of isolated and fragmented refugia along the China-Mongolia border. Effective conservation of this highly threatened subspecies requires a holistic perspective that integrates constraints on population dynamics, habitat associations, and future climatic vulnerability. Here, we combined systematic annual field surveys conducted between 2003 and 2023 with historical survey records from 1975 to 1989 in northern Xinjiang, China, to synthesize long-term spatiotemporal population dynamics, evaluate habitat preferences based on nine local environmental variables, and assess future climatic vulnerability using ensemble species distribution models (SDMs) under projected climate change scenarios. We detected a significant and phased population recovery, with beaver colony numbers increasing from 27 (approximately 100 individuals) in 1975 to 227 (681-908 individuals) in 2023. This recovery closely corresponded with major conservation milestones, including the establishment and upgrading of nature reserves, strengthened legislative protection, and enhanced multi-stakeholder collaboration. Habitat analyses further indicated that the Sino-Mongolian beaver preferentially occupied areas characterized by minimal anthropogenic disturbance and stable hydro-geomorphic conditions. Critically, SDM projections revealed that only 14% of the current study area presently exhibits high climatic suitability, and these highly suitable habitats are expected to disappear entirely by the 2050s. Together, our findings provide a comprehensive overview of the historical population recovery and conservation trajectory of the Sino-Mongolian beaver in China, and offer robust scientific support for developing adaptive management strategies in the face of ongoing climate change and increasing human pressures.

ecology↗

Chromosomal-level genome of the Pinus massoniana 'Minlin WY36'

Owing to conifers complex and large genomes, it is challenging to construct a comprehensive reference genome and conduct evolutionary and genomic research. Here, we present the chromosome-level assembly of Pinus massoniana Minlin WY36, a pioneering conifer species used for afforestation, timber production, and oleoresin extraction. The genome size was determined to be 23.41 Gb, with a contig N50 value of 1.15 Mb and a scaffold N50 value of 2.02 Gb. A total of 23.16 Gb of reads (98.93% of the assembled genome) were anchored and oriented onto 12 pseudochromosomes, with chromosome lengths from 1.47 to 2.29 Gb. A total of 32,144 protein-coding genes were predicted, of which 27,173 (84.54%) were functionally annotated. The P. massoniana Minlin WY36 genome consists of 79.41% (18.57 Gb) repetitive sequences, among which long terminal repeat sequences (LTR) were the most abundant. Through comparative genomic analysis, we found that the unique and significantly expanded genes in P. massoniana Minlin WY36 were enriched in the metabolism related to resin synthesis. This study offers valuable insights into conifer evolution and contributes resources for further investigations of conifer adaptation and developmental processes.

genomics↗

Senolytics enhance longevity in Caenorhabditis elegans by altering betaine metabolism

Aging triggers physiological changes in organisms, which are tightly interlinked to metabolic changes. Senolytics are being developed. However, metabolic responses to natural senescence and the molecular intricacies of how senolytics confer antiaging benefits remain enigmatic. We performed a metabolomics study on natural senescence based on the C.elegans model. The results suggest that age-dependent metabolic changes of natural aging occur in C. elegans. Betaine was identified as a crucial metabolite in the natural aging process. To explore the common pathway coregulated by different senolytics prolonging nematodes lifespan, we fed nematodes three antiaging drugs metformin, quercetin, and minocycline. Our data show that the coregulated metabolic pathways associated with aging include the forkhead box transcription factor (FoxO), p38-mitogen-activated protein kinase (MAPK) and the target of rapamycin (mTOR) signaling pathway, etc. Three antiaging drugs raised betaine levels, consistent with high betaine levels in the younger nematode. Supplement of betaine prolonged the lifespan of nematodes via stimulating autophagy and improving antioxidant capacity. Altogether, our data support proof-of-concept evidence that betaine at appropriate concentrations can extend the lifespan of nematodes.

biochemistry↗

Inherited retinal degeneration: T-type voltage-gated channels, Na+/Ca2+-exchanger, and calpain-2 promote photoreceptor cell death.

Inherited retinal degeneration (IRD) refers to a group of untreatable blinding diseases characterized by a progressive loss of photoreceptors. IRD pathology is often linked to an excessive activation of cyclic nucleotide-gated channels (CNGC) leading to Na+- and Ca2+-influx, subsequent activation of voltage-gated Ca2+-channels (VGCC), and further Ca2+ influx. However, whether and how exactly intracellular Ca2+ overload contributes to photoreceptor degeneration is still controversial. Here, we used whole-retina and single-cell RNA-sequencing to compare gene expression between the rd1 mouse model for IRD and wild-type (wt) mice. Differentially expressed genes were linked to several Ca2+-signalling related pathways. To explore this further, organotypic retinal explant cultures derived from rd1 and wt mice were treated with the intracellular Ca2+-chelator BAPTA-AM and with inhibitors for different Ca2+-permeable channels, including CNGC, L-type VGCC, T-type VGCC, Ca2+-release-activated channel (CRAC), and Na+/Ca2+ exchanger (NCX). Moreover, we employed the compound NA-184 to selectively inhibit the Ca2+-dependent protease calpain-2. The overall activity of poly(ADP-ribose) polymerases (PARPs), sirtuin-type histone-deacetylases, calpains, as well as the activation of calpain-1, and -2 were analysed in situ on retinal tissue sections. Cell viability was assessed via the TUNEL assay. While rd1 photoreceptor cell death was reduced by BAPTA-AM, the effects of Ca2+-channel blockers were ambiguous, with T-type VGCC and NCX inhibition showing protection, while blocking CNGC and CRAC was detrimental. Activity of calpains and PARPs generally followed similar trends as cell death. Remarkably, sirtuin activity and calpain-1 activation was associated with photoreceptor protection, while calpain-2 activity was linked to degeneration. Accordingly, the calpain-2 inhibitor NA-184 protected rd1 photoreceptors. Together, these results indicate that Ca2+ overload in rd1 photoreceptors may be triggered by T-type VGCC in conjunction with NCX. High Ca2+-levels likely suppress the protective activity of calpain-1 and promote neurodegeneration via activation of calpain-2. Our study details the complexity of Ca2+-signalling in photoreceptors and emphasizes the importance of identifying and targeting degenerative processes to achieve a therapeutic benefit for IRD.

neuroscience↗

DBP2Vec: Predicting DNA-binding proteins directly using pre-trained protein language model

DNA-binding proteins (DBPs) play a crucial role in numbers of biological processes and have received wide attention in recent years. Meanwhile, the rapid development of sequencing technologies lead to the explosive growth of new protein sequences, it is highly desired to develop a fast and accurate method for DNA-binding proteins prediction. Experimental methods such as chromatin immunoprecipitation on microarray (ChIP-chip) and X-ray crystallography are highly accurate but expensive and time-consuming. To address this issue, many computational methods have been proposed, they usually exploit multiple information about protein sequence, e.g., sequence composition information, physicochemical properties, evolutionary information, structural information, etc. Despite the effectiveness of these approaches, they heavily depend on prior biological knowledge and undergo a very complex process of feature extraction. In view of these shortcomings, here, we present a novel method, named DBP2Vec, to predict DNA-binding proteins directly from pre-trained protein language model (e.g., ESM-1b) which effectively encode biological properties without any prior knowledge by virtue of deep representation learning (e.g., BERT) on large protein sequences databases (e.g., UniParc). Tests on two DBPs benchmark datasets (e.g., PDB296, UniSwiss-Tst) demonstrate that our proposed method significantly outperforms existing state-of-the-art methods. The source code and the datasets used in the paper are publicly available at: https://github.com/hgcwei/DBP2Vec.

bioinformatics↗

Identifying disease-associated circRNAs based on edge-weighted graph attention and heterogeneous graph neural network

MotivationCircular RNAs (circRNAs) with varied biological activities are implicated in pathogenic processes, according to new findings. They are regarded as promising biomarkers for the diagnosis and prognosis due to their structural features. Computational approaches, as opposed to traditional experiments, can identify the circRNA-disease connections at a lower cost. Multi-source pathogenesis data can help to reduce data sparsity and infer probable connections at the system level. The majority of available approaches create a homologous network using multi-source data, but they lose the datas heterogeneity. Effective solutions that make use of the peculiarities of multi-source data are urgently needed. ResultsIn this paper, we propose a model (CDHGNN) based on edge-weighted graph attention and heterogeneous graph neural networks for discovering probable circRNA-disease correlations prediction. The circRNA network, miRNA network, disease network and heterogeneous network are constructed based on the introduced multi-source data on circRNAs, miRNAs, and diseases. The features for each type of node in the network are then extracted using a designed edge-weighted graph attention network model. Using the revised node features, we learn meta-path contextual information and use heterogeneous neural networks to assign attention weights to different types of edges. CDHGNN outperforms state-of-the-art algorithms with comparable accuracy, according to the findings of the trial. Edge-weighted graph attention networks and heterogeneous graph networks have both improved performance significantly. Furthermore, case studies suggest that CDHGNN is capable of identifying particular molecular connections and can be used to investigate pathogenic pathways. Contactjxwang@mail.csu.edu.cn

bioinformatics↗

Tracking SARS-CoV-2 Omicron diverse spike gene mutations identifies multiple inter-variant recombination events

The current pandemic of COVID-19 is fueled by more infectious emergent Omicron variants. Ongoing concerns of emergent variants include possible recombinants, as genome recombination is an important evolutionary mechanism for the emergence and re-emergence of human viral pathogens. Although recombination events among SARS-CoV-1 and MERS-CoV were well-documented, it has been difficult to detect the recombination signatures in SARS-CoV-2 variants due to their high degree of sequence similarity. In this study, we identified diverse recombination events between two Omicron major subvariants (BA.1 and BA.2) and other variants of concern (VOCs) and variants of interest (VOIs), suggesting that co-infection and subsequent genome recombination play important roles in the ongoing evolution of SARS-CoV-2. Through scanning high-quality completed Omicron spike gene sequences, eighteen core mutations of BA.1 variants (frequency >99%) were identified (eight in NTD, five near the S1/S2 cleavage site, and five in S2). BA.2 variants share three additional amino acid deletions with the Alpha variants. BA.1 subvariants share nine common amino acid mutations (three more than BA.2) in the spike protein with most VOCs, suggesting a possible recombination origin of Omicron from these VOCs. There are three more Alpha-related mutations (del69-70, del144) in BA.1 than BA.2, and therefore BA.1 may be phylogenetically closer to the Alpha variant. Revertant mutations are found in some dominant mutations (frequency >95%) in the BA.1 subvariant. Most notably, multiple additional amino acid mutations in the Delta spike protein were also identified in the recently emerged Omicron isolates, which implied possible recombination events occurred between the Omicron and Delta variants during the on-going pandemic. Monitoring the evolving SARS-CoV-2 genomes especially for recombination is critically important for recognition of abrupt changes to viral attributes including its epitopes which may call for vaccine modifications.

microbiology↗

MicroRNA840 accelerates leaf senescence by targeting the overlapping 3'UTRs of PPR and WHIRLY3 in Arabidopsis

MicroRNAs (miRNAs) negatively regulate gene expression by cleaving the target mRNA and/or impairing its translation, thereby playing a crucial role in plant development and environmental stress responses. In Arabidopsis, MIR840 is located within the overlapping 3UTR of PPR and WHIRLY3 (WHY3), both being predicted targets of miR840. Gain- and loss-of-function of miR840 in Arabidopsis resulted in opposite senescent phenotypes. Highest expression of pri-miR840 is observed at senescence initiation, and is negatively correlated with a significant reduction of PPR transcripts but not of WHY3. Although WHY3 transcript levels were not significantly affected by miR840 overexpression, its protein synthesis was strongly reduced. Mutating the cleavage sites or replacing the target sequences abolishes the miR840-mediated degradation of PPR transcripts and inhibition of WHY3 translation. In support for this, concurrent knock-down of both PPR and WHY3 in the WT resulted in the senescent phenotype resembling that of the miR840-overexpressing mutant. This indicates that both PRR and WHY3 are targets in the miR840-regulated senescent pathway. Moreover, single knockout mutant of PPR or WHY3 shows a convergent up-regulated subset of senescence-associated genes, which are also found among those induced by miR840 overexpression. Our data provide evidences for a regulatory role of miR840 in plant senescence. HighlightMicroRNA840 (miR840) has a unique miRNA-target configuration regulating PPR and WHIRLY3 genes in Arabidopsis. MiR840 is highly expressed at the onset of plant senescent stage. Both PPR and WHIRLY3 transcripts are specifically targeted in vivo within their 3UTR region by mature miR840 or its star strand in vivo. Interestingly, PPR expression is mainly repressed on mRNA transcript level by cleavage, while WHIRLY3 is predominantly translationally inhibited. We conclude that miR840 enhances plant senescence via post transcriptional gene silencing of PPR and WHIRLY3, which appear to be novel negative joint regulators of plant senescence. Footnote: The author(s) responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the intructions for Authors is: Ying Miao (ymiao@fafu.edu.cn)

molecular biology↗

Molecular Typing of Human Respiratory Adenoviruses with Universal PCR and Sequencing Primers for Three Major Capsid Genes: Penton base, Hexon, and Fiber

Human adenoviruses (HAdVs) within species B, C, and E include the predominant types responsible for highly contagious and potentially severe respiratory infections. The traditional method to type these pathogens was based on virus neutralization and hemagglutination assays using antisera, which is both time-consuming and difficult, particularly due to the non-availability of reagents. Molecular typing based on partial characterization of HAdV hexon, as well as the restriction enzyme analysis (REA) of the genomics DNA, is difficult to identify recombinants. Here, a rapid, simple, and cost-effective molecular typing of respiratory HAdVs is presented. This incorporates three pairs of universal PCR primers that target the variable regions of the three major capsid genes, i.e. hexon, penton base and fiber genes. The protocol developed enables detection and typing of respiratory HAdVs within species B, C, and E, as well as of some strains within species D and F. Using this method, we surveyed a total of 100 children with acute respiratory infection caused by HAdVs in Hong Kong, Summer 2014 (July to October). 100 Throat swab specimens were collected. The samples were analyzed by PCR and the sequences were characterized by BLAST. HAdVs were detected in 98 out of 100 (98%) samples. The predominant HAdV type was species B type 3. Among the patients, 74 were of HAdV-B3 (74%), 10 were of HAdV-E4 (10%), 6 were of HAdV-C2 (21.7%), 2 were of HAdV-C6 (2%), 1 were of HAdV-B7 (2%), 1 were of HAdV-C1 (74%), and 2 were of recombinant types. The developed method allows the rapid identification of HAdVs with recombinant genomes, and bypasses the need for whole genome data, for the real-time surveillance of circulating adenovirus strains in immediate outbreaks and populations by clinical microbiologists, public health officers, and epidemiologists.

microbiology↗

RBD mutations from circulating SARS-CoV-2 strains enhance the structure stability and infectivity of the spike protein

The current global pandemic of COVID-19 is caused by a novel coronavirus SARS-CoV-2. The SARS-CoV-2 spike protein receptor-binding domain (RBD) is the critical determinant of viral tropism and infectivity. To investigate whether naturally occurring mutations in the RBD during the early transmission phase have altered the receptor binding affinity and infectivity, firstly we analyzed in silico the binding dynamics between mutated SARS-CoV-2 RBDs and the human ACE2 receptor. Among 32,123 genomes of SARS-CoV-2 isolates (January through March, 2020), 302 non-synonymous RBD mutants were identified and clustered into 96 mutant types. The six dominant mutations were analyzed applying molecular dynamics simulations. The mutant type V367F continuously circulating worldwide displayed higher binding affinity to human ACE2 due to the enhanced structural stabilization of the RBD beta-sheet scaffold. The increased infectivity of V367 mutants was further validated by performing receptor-ligand binding ELISA, surface plasmon resonance, and pseudotyped virus assays. Genome phylogenetic analysis of V367F mutants showed that during the early transmission phase, most V367F mutants clustered more closely with the SARS-CoV-2 prototype strain than the dual-mutation variants (V367F + D614G) which emerged later and formed a distinct sub-cluster. The analysis of critical RBD mutations provides further insights into the evolutionary trajectory of SARS-CoV-2 under negative selection pressure and supports the continuing surveillance of spike mutations to aid in the development of new COVID-19 drugs and vaccines. ImportanceA novel coronavirus SARS-CoV-2 has caused the pandemic of COVID-19. The origin of SARS-CoV-2 was associated with zoonotic infections. The spike protein receptor-binding domain (RBD) is identified as the critical determinant of viral tropism and infectivity. Thus, whether the mutations in the RBD of the circulating SARS-CoV-2 isolates have altered the receptor binding affinity and caused them more infectious, should be paid more attentions to. Given that SARS-CoV-2 is a novel coronavirus, the significance of our research is in identifying and validating the RBD mutant types emerging during the early transmission phase that have increased human ACE2 receptor binding affinity and infectivity. The RBD mutation analysis provides insights into SARS-CoV-2 evolution. The continuous surveillance of RBD mutations with increased human ACE2 affinity in human or other animals is important and necessary, particularly when the direct correlation between the virus variations and vaccine effectiveness is underdetermined during the sustained COVID-19 pandemic.

microbiology↗

Inactivation of NUPR1 promotes cell death by coupling ER-stress responses with necrosis

Genetic inhibition of NUPR1 induces tumor growth arrest. Inactivation of NUPR1 expression in pancreatic cancer cells results in lower ATP production, higher consumption of glucose with a significant switch from OXPHOS to glycolysis followed by necrotic cell death. Importantly, induction of necrosis is independent of the caspase activity. We demonstrated that NUPR1 inactivation triggers a massive release of Ca2+ from the endoplasmic reticulum (ER) to the cytosol and a strong increase in ROS production by mitochondria with a concomitant relocalization of mitochondria to the vicinity of the ER. In addition, transcriptomic analysis of NUPR1-deficient cells shows the induction of an ER stress which is associated to a decrease in the expression of some ER stress response-associated genes. Indeed, during ER stress induced by the treatment with thapsigargin, brefeldin A or tunicamycin, an increase in the mitochondrial malfunction with higher induction of necrosis was observed in NUPR1-defficent cells. Finally, activation of NUPR1 during acute pancreatitis protects acinar cells of necrosis in mice. Altogether, these data enable us to describe a model in which inactivation of NUPR1 in pancreatic cancer cells results in an ER stress that induces a mitochondrial malfunction, a deficient ATP production and, as consequence, the cell death by necrosis.\n\nHighlightsNUPR1 expression promotes pancreatic cancer development and progression\n\nNUPR1-depletion is a promising therapeutic strategy to be used for treating cancers\n\nNUPR1-depletion induces ER stress, mitochondrial malfunction and a significant switch from OXPHOS to glycolysis followed by necrotic cell death\n\nInactivation of NUPR1 antagonizes cell growth by coupling a defective ER-stress response and a caspase-independent necrosis.

cell biology↗