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Li, W.

Publications and source records attributed to Li, W..

At least 217 records · Page 12Linked to original sources

DNACSE: Enhancing Genomic LLMs with Contrastive Learning for DNA Barcode Identification

DNA barcoding is a powerful tool for exploring biodiversity, and DNA language models have significantly facilitated its construction and identification. However, since DNA barcodes come from a specific region of mitochondrial DNA and there are structural differences between DNA barcodes and reference genomes used to train existing DNA language models, it is difficult to directly apply the existing DNA language models to the DNA barcoding task. To address this, this paper introduce DNACSE (DNA Contrastive Learning for Sequence Embeddings), an unsupervised noise contrastive learning framework designed to fine-tune the DNA language foundation model while enhancing the distribution of the embedding space. The results demonstrate that DNACSE outperforms direct usage of DNA language models in DNA barcoding-related tasks. Specifically, in fine-tuning and linear probe tasks, it achieves accuracy rates of 99.17% and 98.31%, respectively, surpassing the current state-of-the-art BarcodeBERT by 6.44% and 6.44%. In zero-shot clustering tasks, it raises the Adjusted Mutual Information (AMI) score to 92.25%, an improvement of 8.36%. In addition, zero-shot benchmarking and genomic benchmarking tests are evaluated, indicating that DNACSE enhances the performance of DNA language models in generalized genomic tasks. In summary, DNACSE has demonstrated excellent performance in DNA barcode species classification by making full use of multi-species information and DNA barcode information, providing a feasible way to further explore and protect biodiversity. The code repository is available at https://github.com/Kavicy/DNACSE.

bioinformatics↗

The disordered JM motif in RTKs promotes classical DFGout conformation formation via dynamic effect

Receptor tyrosine kinases (RTKs) are validated anti-cancer targets, and targeting their DFGout conformations represents a mainstream strategy for developing highly selective type II inhibitors. RTKs can adopt various DFGout conformations, but only the classical ones with a fully formed back pocket are structurally validated to accommodate type II inhibitors. However, such classical DFGout conformations are scarce, presenting a significant obstacle for selective RTK inhibitor design. Recently, a conserved disordered motif N-terminal to the kinase domain of RTKs, called the juxtamembrane (JM) motif, has been reported to regulate inhibitor binding to the DFGout conformation of VEGFR2, an RTK involved in angiogenesis. In this study, we performed extensive MD simulations to explore the impact of the disordered JM motif on the conformational space of the DFG motif in RTKs and its relationship to inhibitor binding at the active site of VEGFR2. We revealed that in VEGFR2, the disordered JM is highly dynamic and forms transient contacts with the kinase domain, and consequently fine-tunes the DFGout sub-conformational space to shift populations from non-classical to classical DFGout conformations. This dynamic model provides the structural basis underpinning the reported regulatory effects of JM on inhibitor binding toward VEGFR2. Addtionally, we demonstrated that in other RTKs beyond VEGFR2, the disordered JM similarly promotes classical DFGout conformations. Such role of JM is particularly favorable for creating druggable DFGout conformations that can be exploited for designing high-selectivity type II inhibitors.

biophysics↗

Screening of Oyster Peptides for Anti-Muscle Atrophy Based on Machine Learning and Computer Simulation: Guided by Antioxidant Pathways

Muscle atrophy poses a serious threat to human health, with its primary pathogenic mechanisms closely linked to oxidative stress. This study focuses on the potential of oyster peptides in alleviating dexamethasone (DEX)-induced skeletal muscle atrophy and their underlying antioxidant mechanisms. Utilizing efficient integrated machine learning and computer simulation methods, a systematic screening of active peptides and mechanistic research was conducted. The results revealed that oyster peptides at concentrations of 25-50 g/mL significantly improved the decline in cell viability and myotube atrophy induced by DEX, while downregulating the expression of muscle atrophy markers Atrogin-1 and MuRF1. Through LC-MS/MS, 220 high-activity peptide sequences were identified. Following the replication and extension of the iAnOxPep integrated learning model, 15 potential antioxidant peptides were selected. Among them, the short peptide AWPGPQ demonstrated the strongest binding affinity with Keap1 and PPAR{gamma} targets. Molecular dynamics simulations confirmed its stability, suggesting that AWPGPQ may exert its dual effects--antioxidant and anti-muscle atrophy--by modulating the Keap1-Nrf2 and PPAR{gamma} signaling pathways. This study established a systematic and efficient strategy for screening natural active peptides, providing theoretical support and technical pathways for the discovery of multifunctional short peptide candidates, with significant theoretical value and application prospects.

molecular biology↗

Genetic diversity in horseshoe bat ACE2 and sarbecovirus spike proteins mutually shape one another

Angiotensin-converting enzyme 2 (ACE2) serves as the entry receptor for a wide diversity of sarbecoviruses naturally harboured by horseshoe bats (genus Rhinolophus). Despite the extensive circulation of these viruses in many horseshoe bat species, the potential interactions between virus and receptor evolution remain poorly understood. We sampled individuals of the intermediate horseshoe bat (Rhinolophus affinis) across Vietnam and identified 15 genotypes of ACE2 proteins, 10 of which are previously unreported. Phylogenetic analysis and infectivity assays with a panel of 36 sarbecovirus spike proteins indicated that the R. affinis ACE2 phylogeny has geographic structuring and genotypes originating from different geographic regions exhibit distinct infectivity phenotypes. We detected site-specific positive selection on ACE2 site 24 with the associated substitutions largely affecting the receptors sarbecovirus infectivity profile. Together, our findings suggest that the R. affinis within-species ACE2 diversity has likely been shaped through selection by past sarbecovirus infection. Similarly on the virus end, we use mutagenesis assays and structural analysis through cryo-EM, to delineate the proximal evolution of the Ra22QT77 spike defined by specialization to the ACE2 genotypes of horseshoe bats found in and near southern Vietnam, where the virus was sampled. Our findings contribute to a better understanding of host-sarbecovirus co-evolution dynamics and provide valuable insights into the receptor usage determinants of these viruses. HighlightsO_LIWe identify a total of 15 ACE2 genotypes in R. affinis bats from Vietnam. C_LIO_LIACE2 intraspecific polymorphism is geographically separated and associated with distinct sarbecovirus infectivity. C_LIO_LISite 24 of R. affinis ACE2 experiences positive selection and controls susceptibility to sarbecoviruses. C_LIO_LIBat ACE2s and sarbecovirus spikes are bidirectionally shaped by each others evolution. C_LI

microbiology↗

Identification and functional characterization of an AMD associated c-ABL binding SNP streak within the ARMS2 gene promoter region

BackgroundLarge-scale genome-wide association studies (GWAS) have identified the human 10q26 locus as a major genetic risk factor for age-related macular degeneration (AMD). The AMD-associated interval has been refined to a 5,196 bp segment flanking the ARMS2-HTRA1 region, excluding HTRA1 and the ARMS2 3' indel (443del54ins) variant by risk haplotype analysis. Although the missense SNP rs10490924 has been proposed as a functional variant, its role in AMD remains controversial, and the causative variants and underlying mechanisms within this region remain unresolved. MethodsAn unbiased bioinformatic screen identified a 5-SNP block within the 5,196 bp interval that potentially alters c-ABL protein binding. Protein-DNA interactions were validated using electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays. Genetic association with AMD (dry and wet subtypes) was assessed in patient cohorts using blood genomic DNA. The regulatory effect of the 5-SNP block was further examined using luciferase reporter assays. FindingsWe identified a 5-SNP block located [~]556 bp upstream of the ARMS2 start codon, representing a cluster of predicted c-ABL tyrosine kinase binding sites. This block, in complete linkage disequilibrium with rs10490924 (A69S), showed a strong association with both wet and dry AMD (136 controls, 179 dry AMD, 251 wet AMD). EMSA and ChIP confirmed direct c-ABL binding, while luciferase reporter assays demonstrated reduced transcriptional activity mediated by the 5-SNP block in the presence of c-ABL. InterpretationOur results suggest that the c-ABL-responsive 5-SNP regulatory streak in the ARMS2 promoter region act as functional non-coding elements that may contribute to AMD pathogenesis through altered transcriptional regulation.

molecular biology↗

Graph-based tracing of dynamically functioning gene circuits in cell fate decisions with isoform resolution

Transcription factor (TF) regulatory networks govern complex cellular processes, yet their inference from single-cell transcriptomes is hindered by TFs low abundance, tissue-specific functions, and isoform diversity. We evaluated the utility of transcription factor activity (TFA) to infer TF-TF interactions, demonstrating its superiority over expression-based methods in capturing tissue-specific, high-fidelity regulatory relationships. Using simulated and real-world transcriptomes across human hematopoiesis and early embryonic development, we validated TFAs ability to render regulatory relationships. Through utilizing the concept of propagated regulome, we uncovered TFAs utility in retrospectively resolving dynamic regulatory circuits. To address regulome limitations, we developed an embryonic stem cell-specific Consensus REgulome Database (CRED) with isoform resolution, revealing functional heterogeneity among TF isoforms. Applied to human preimplantation single-cell datasets, CRED outperformed existing regulomes, identifying isoform-specific regulators and tracing regulatory modules despite severe dropouts. Our work unleashes TFA as a robust tool for reconstructing TF networks and highlights the importance of transited, isoform-level, cell-type-specific analysis in unraveling transcriptional regulatory circuits. HighlightsO_LITFA (Transcription Factor Activity) renders regulatory relationships with high fidelity compared to expression. C_LIO_LIUsing transited regulons enables TFA to retrospectively resolve dynamic regulatory interactions in cell fate decisions. C_LIO_LIAn integrated ESC-specific transited regulome database reveals isoform-level heterogeneity. C_LIO_LITFA successfully identifies key TF regulatory modules during human preimplantation from datasets with severe dropout. C_LI

systems biology↗

Benchmarking remote sensing methods to capture plant functional diversity from space

The development of remote sensing methods to estimate plant functional diversity is limited by mismatches between ecology and remote sensing sampling schemes, and the limited representativeness of local field campaigns. The Biodiversity Observing System Simulation Experiment (BOSSE) provides a modeling framework for benchmarking new methodologies. We used BOSSE to simulate 180 different synthetic "Scenes" encompassing a two-year-long time series of plant trait maps and imagery of hyperspectral reflectance factors, spectral indices, sun-induced chlorophyll fluorescence, land surface temperature, and estimates of plant traits (optical traits). We used these simulations to answer five fundamental, yet unsolved, questions: Q1. How should remote sensing characterize functional diversity in large surfaces (sites)? Diversity metric values saturate with the number of pixels involved, hampering comparisons between plant traits and remote sensing estimates in large areas. The average value of metrics computed over small samples should be used instead. Q2. Which sources of spectral information (or combinations thereof) can best capture plant functional diversity at the site scale? Accounting for background effects is the key. Optical traits (remote sensing estimates of plant traits) are the best estimators for plant functional diversity. Other variables succeed when filtered out of the soil pixels; their combination did not yield additional advantages. Q3. How should remote sensing estimates be validated/compared with plant functional diversity measurements? Leaf area index (LAI) is a better proxy of abundance than the pixel for QRao, but not for variance-based partitioning. It is more sensitive to sample size, but also more resistant to suboptimal spatial resolution. Q4. When (in the phenological year) can remote sensing best capture site-scale plant functional diversity? The estimation error decreased with LAI and stabilized at values above 1 m{superscript 2}/m{superscript 2}. Q5. Which approaches and remote sensing variables are more resistant to the effects of suboptimal spatial resolution? Optical traits, fluorescence, and reflectance factors were the most robust variables. Still, field data resolution needs to be degraded to match the sensors resolution. We found a relative spatial resolution threshold of [~]30 % (where the pixel is around three times larger than the plants). Simulation frameworks like BOSSE enable testing methodologies beyond local contexts and address the current shortage of suitable global datasets, supporting the application and development of methods for assessing plant functional diversity with remote sensing. In the future, BOSSE could contribute to understanding observational results, refining and pre-testing new methodologies, and supporting the development of comparable experimental datasets.

ecology↗

Transplantation of active mitochondria condensed in liquid-liquid phase-separated hydrogels ameliorates myocardial ischemia-reperfusion injury

Mitochondrial dysfunction is a key driver of myocardial ischemia-reperfusion injury (MIRI), which exacerbates cardiac damage following the restoration of blood flow. Although single-phase hydrogel-based mitochondria transplantation therapy (MTT) holds promise for restoring cellular energy metabolism, its effectiveness is limited by extracellular calcium-induced mitochondrial degradation. In this study, we design a thermo-sensitive hydrogel utilizing liquid-liquid phase separation (LLPS), composed of gelatin and polyethylene glycol (PEG), to condense freshly isolated mitochondria. Compared to conventional single-phase hydrogels, the LLPS hydrogel significantly increases the sol-gel transition temperature above physiological levels, allowing it to remain injectable at body temperature while enabling rapid mitochondrial release following transplantation. More importantly, the LLPS structure enhances mitochondrial packing density and protects the activity of condensed mitochondria against calcium toxicity through spatial confinement and gelatin-mediated calcium chelation. In vitro, LLPS hydrogel-condensed mitochondria exhibit improved mitochondrial membrane potential and ATP production ability compared to those delivered via single-phase gelatin hydrogel. In vivo, mitochondria released from the LLPS hydrogel are effectively internalized by cardiomyocytes, resulting in improved cardiac function and reduced tissue damage after MIRI. These findings suggest that LLPS-based hydrogels offer a promising strategy to enhance MTT efficacy for MIRI and other mitochondria-related disorders.

bioengineering↗

POI-associated LMD-3 mutation impairs B12-regulated lysosomal function and reproductive capacity in C. elegans

Reproductive longevity decline is a key feature of aging and premature ovarian insufficiency (POI). While proteostasis collapse is implicated in reproductive aging, the molecular link remains elusive. Here, we engineered the clinically relevant W690C mutation into C. elegans lmd-3 gene, the human NCOA7 ortholog, to establish a valuable in vivo POI model. The mutation severely compromises LMD-3 protein stability and expression, leading to a profound collapse in reproductive capacity driven by germline apoptosis. We demonstrate that this defect drives catastrophic autophagic-lysosomal dysfunction, blocking degradation and causing proteotoxic accumulation of misfolded proteins. Crucially, we define this pathology as a functional B12 deficiency and show that mecobalamin (meCbl) supplementation successfully restores proteostasis. Together, these findings delineate a conserved genetic pathway from LMD-3 destabilization to reproductive failure and propose vitamin B12 as a readily translatable therapeutic intervention for age-related reproductive decline.

cell biology↗

Automatic Change Detection of Human Attractiveness: Comparing Visual and Auditory Perception

Change detection of social cues across individuals plays an important role in human interaction. Here we investigated the automatic change detection of facial and vocal attractiveness in 19 female participants by recording ERPs. We adopted a deviant-standard-reverse oddball paradigm where high- or low-attractive items were embedded as deviants in a sequence of opposite attractive standard stimuli. Both high- and low-attractive faces and voices elicited mismatch negativities (MMNs). Furthermore, low-attractive versus high-attractive items induced larger mismatch negativities in the voice condition but larger P3 amplitudes in the face condition. These data indicate that attractiveness can be automatically detected but that differences exist between facial and vocal attractiveness processing. Generally, change detection seems to work better for unattractive than attractive information possibly in line with a negativity bias.

neuroscience↗

Psoralen Enhances Direct Cardiac Reprogramming via PPARα Activation and Promotion of Mitochondrial Fission

BACKGROUNDCell-based therapy is a promising strategy for heart repair and regeneration. However, its clinical application has been hampered by the low efficiency of cell direct reprogramming and the immature state of the inducing cells. Developing novel strategies to enhance direct reprogramming efficiency and yield mature functional cardiomyocytes remains a critical challenge. METHODSWe evaluated the effect of Psr on cardiac reprogramming using RepSox and Forskolin (RF) as the baseline cocktail. Reprogramming efficiency, cardiomyocyte marker expression, and calcium handling were assessed by RT-qPCR, immunofluorescence. Ultrastructural features were examined by transmission electron microscopy. Metabolic profiles were analyzed using Seahorse assays. Transcriptomic changes were explored by RNA sequencing, followed by pathway and protein-protein interaction analyses. A myocardial infarction (MI) mouse model was used for in vivo validation. RESULTSSupplementation with Psr (10 M) markedly enhanced the induction of induced cardiomyocytes (iCMs), leading to earlier appearance of beating clusters (day 1 vs. day 6-8), improved sarcomere organization, robust calcium transients, and higher energy metabolism. Transcriptomic profiling identified activation of the PPAR signaling pathway, with PPAR, RXRG, and UCP1 as central regulators. Mechanistically, Psr promoted mitochondrial fission, thereby facilitating metabolic remodeling essential for cardiomyocyte maturation. In vivo, RF+Psr treatment significantly improved cardiac function and reduced fibrosis after MI compared to RF alone. CONCLUSIONPsr enhances direct cardiac reprogramming by activating PPAR signaling and promoting mitochondrial fission. These findings provide a novel mechanistic framework and suggest psoralen as a promising natural enhancer for cardiac regeneration strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/681288v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@13a5d27org.highwire.dtl.DTLVardef@b9cce5org.highwire.dtl.DTLVardef@3afef8org.highwire.dtl.DTLVardef@1398972_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

Chronic kidney disease exacerbates hyperlipidemia and atherosclerosis via miR-148a-3p targeting SIK1/AMPKα1 in liver

BackgroundCardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). As a major risk factor for atherosclerotic cardiovascular disease (ASCVD), hyperlipidemia is a common sequela of CKD, which is linked to increased lipid synthesis, impaired lipoprotein clearance, and maladapted reverse cholesterol transport. Because exosomes can transport miRNAs to modulate intercellular and tissue communication, we hypothesized that exosomal miRNAs can act as endocrine-like molecules to modulate the CKD-associated hyperlipidemia and ASCVD. MethodsSmall RNA-seq and qPCR were used to determine the differential plasma level of exosomal miR-148a-3p in ASCVD patients with and without CKD. RNA-seq and in silico analysis were used to establish the regulation of lipid metabolism via miR-148a-3p/salt-inducible kinase 1 (SIK1)/AMP-activated protein kinase alpha 1 subunit (AMPK1) in the liver. Inhibition of miR-148a-3p or overexpression of SIK1/AMPK1 in ApoE-/- mice with 5/6 nephrectomy was used to elucidate the role of the miR-148a-3p/SIK1/AMPK1 axis in CKD-related hyperlipidemia and atherosclerosis. ResultsThe plasma level of exosomal miR-148a-3p was significantly elevated in patients with ASCVD and CKD (ASCVD/CKD) and ApoE-/- mice with 5/6 nephrectomy. Via circulating exosomes, kidney-generated miR-148a-3p was delivered to the liver, where it targeted SIK1/AMPK1 transcripts, thereby upregulating SREBP2/PCSK9 and reciprocally downregulating LDLR. Levels of SIK1 and AMPK1 were decreased in hepatocytes transfected with miR-148a-3p or treated with plasma exosomes from ASCVD/CKD patients, with attendant SREBP2 activation and attenuated LDL-C binding. The decreased LDL-C binding was rectified by SIK1/AMPK1 or LNA-miR-148a-3p overexpression. LNA-miR-148a-3p or AAV8-SIK1/AMPK administration in 5/6 nephrectomy/ApoE-/- mice significantly ameliorated hyperlipidemia and atherosclerosis. ConclusionIn ASCVD/CKD patients and nephrectomy/ApoE-/- mice, kidney-originating miR-148a-3p targeted hepatic SIK1/AMPK1 mRNA. This exosome-mediated endocrine effect upregulated SREBP2/PCSK9 and reciprocally reduced LDLR level, which elevated plasma LDL-C level and exacerbated ASCVD. These findings underscore a kidney-liver-artery axis involved in cardiovascular-kidney-metabolic syndrome.

pathology↗

Belief updating in uncertain environments are differentially sensitive to reward and punishment learning: Evidence from ERP

Learning from rewards and punishments is crucial for adaptive decision-making, but it is still unclear how individuals integrate prediction errors to update beliefs in uncertain environments, particularly the distinctions between reward and punishment learning. We employed a probabilistic classification task and situated electroencephalography (EEG) signals within a hierarchical Bayesian framework, investigating distinctions between reward and punishment learning. Our findings indicate that participants exhibited superior learning performance in reward context compared to punishment context. Fitting the hierarchical Bayesian model revealed that punishment drives faster Bayesian belief updates, although these did not translate into improved behavioral outcomes. At the neural level, higher-level precision-weighted prediction error (pwPE2) was significantly positively correlated with FRN amplitude in the punishment context but not in the reward context, and the positive effect of pwPE2 on P300 amplitude was stronger in the punishment than the reward condition. These results provide electrophysiological signatures of punish context driving faster belief updates in uncertain environments. Our results provide novel evidence for a dual-process framework in reinforcement learning, underscoring distinct neural mechanisms underlying reward and punishment learning.

neuroscience↗

A Unifying Mechanism for Shared Splicing Aberrations in Splicing Factor Mutant Cancers

Cancer-associated splicing factor (SF) mutations in SF3B1, U2AF1, and SRSF2 induce distinct changes in alternative splicing (AS). Yet these mutations are strikingly mutually exclusive, pointing to a convergent downstream mechanism. We hypothesized this would be reflected in the AS transcriptome. By analyzing transcriptomes of 395 patients with clonal myeloid disorders and 64 healthy donors, we found most AS alterations to be mutation-specific. However, a robust subset, enriched in the retained intron (RI) program, was shared across mutants. These RI events were bidirectional but highly concordant, and mirrored the effects of SRSF1 loss. SF-mutant states induced hypophosphorylation of RS domains in SRSF1, reducing its function. This arose from an altered AMPK-AKT balance impairing the AKT-SRPK1-SRSF1 axis. A common upstream trigger was activation of DNA damage response (DDR) by transcriptional R-loops, which increased AMPK signaling and reduced AKT activity. Pharmacologic DDR activation recapitulated reduced AKT/SRPK1 activity and SRSF1 hypophosphorylation, while relieving DDR restored SRSF1 phosphorylation and corrected RI defects. Thus, beyond cis-acting, mutation-specific changes, SF-mutant cancers share a trans-acting, stress-driven AS signature wherein DDR signaling rewires SRSF1 activity impacting AS. Our results link replication stress, kinase signaling, and RNA processing across genetically diverse clonal states, highlighting potential therapeutic approaches at these nodes. HighlightsO_LIWhile most splicing changes differ by splicing factor (SF) mutation, certain retained introns are common across subtypes. C_LIO_LIChanges in RI are bidirectional, concordant across mutant groups, and mirrors SRSF1 loss. C_LIO_LISF mutations activate DDR, triggering an AMPK/AKT imbalance that culminates in SRSF1 hypophosphorylation. C_LIO_LIRelieving R-loop induced DDR restores SRSF1 phosphorylation and reverses RI. C_LI

cancer biology↗

Chryseobacterium indologenes mediates resistance to osimertinib by activating the IGF1R pathway in EGFR-mutant lung adenocarcinoma

IntroductionLung cancers harboring sensitizing epidermal growth factor receptor (EGFR) mutations typically exhibit an initial response to osimertinib; however, the development of resistance is inevitable, and there are currently no approved targeted therapies available once resistance emerges. Accumulating evidence indicates that intra-tumoral bacteria can influence tumor biology and contribute to therapy resistance in several cancer types, including pancreatic and colorectal cancer. Despite these findings, whether intra-tumoral bacteria play a role in modulating response and resistance to osimertinib in EGFR-mutant lung adenocarcinoma remains largely unexplored. This study aims to investigate the contribution of intra-tumoral bacteria to osimertinib resistance, thereby providing new insights into resistance mechanisms and identifying potential therapeutic strategies. MethodsBacteria previously identified in lung cancer tissue samples were cultured in liquid growth medium, and their preconditioned medium (PCM) was collected. PC9 cells were treated with PCM in the presence or absence of osimertinib to screen for bacteria capable of mediating resistance. Cell viability was assessed using Cell Counting Kit-8 assays. To investigate potential mechanisms, Western blotting and receptor tyrosine kinase (RTK) phosphorylation arrays were performed. Control groups included cells treated with osimertinib alone, PCM alone, or vehicle. Statistical analyses were conducted using Students t-test as appropriate, with p < 0.05 considered statistically significant. Data represent mean {+/-} SD from at least three independent experiments. ResultsThe addition of PCM from Chryseobacterium indologenes restored cell viability in EGFR-mutant lung adenocarcinoma cells treated with osimertinib. PCM exposure markedly increased insulin-like growth factor-1 receptor (IGF1R) phosphorylation levels. PCM did not enhance cell viability when IGF1R was silenced or inhibited with linsitinib, demonstrating the pathways essential role. Proteinase K treatment abolished the ability of PCM to protect cells from osimertinib, and removal of proteins potentially interacting with IGF1R further diminished its efficacy. Finally, PCM also conferred resistance to osimertinib in patient-derived EGFR-mutant lung adenocarcinoma cell lines. ConclusionOur study demonstrates that the intra-tumoral bacteria C. indologenes may significantly influence sensitivity to osimertinib or impart resistance in EGFR-mutant lung adenocarcinoma by activating the IGF1R signaling pathway.

cancer biology↗

Comparative population genomics reveals adaptive convergence in two Drosophila species across global environments

The extent to which evolution is predictable across lineages remains unclear. To address this question, we investigated convergent adaptation in a pair of globally distributed sibling species, Drosophila melanogaster and D. simulans. We integrated whole-genome data from approximately 2,000 strains sampled across major continents, and revealed a more recent global colonization of D. simulans relative to D. melanogaster. Using a suite of complementary selection scans, we quantified signatures of positive selection across evolutionary timescales and genomic contexts. Despite substantial divergence, approximately 9-13% of adaptively evolving genes were shared between species across methods, revealing widespread convergence at the gene and pathway levels. Convergence was particularly pronounced for insecticide resistance genes, and was also evident in oxidative stress experiment. This study provides a quantitative, multiscale framework for dissecting molecular convergence, offering insights into the predictability of evolution, the constraints imposed by genomic architecture, and the dynamics of adaptation under global environmental change.

evolutionary biology↗

Generation of Region-specific Airway Basal Stem Cells from Human Pluripotent Stem Cells via Regulation of BMP-NOGGIN Axis

Basal cells (BCs) are the primary stem cell population of adult human airways and a key target for hPSC-based models of airway development, disease and regenerative medicine. Recent studies have revealed substantial regional differences between human proximal and distal airway cell types, including BCs. Here, we show that the NOGGIN-BMP signaling axis governs proximal-distal patterning of hPSC-derived lung progenitors leading to the generation of region-specific induced BCs (iBCs). Continuous BMP inhibition through NOGGIN, coupled with tapered WNT activation, generates proximal iBCs that molecularly and functionally resemble human proximal airway BCs and differentiate in vitro and in vivo into the full repertoire of specialized proximal airway cell types, including ionocytes and pulmonary neuroendocrine cells. In sharp contrast, BMP activation with tapered WNT generates distal airway-like cells and distal BCs with limited ionocyte differentiation potential. Progeny of proximal iBCs derived from G551D CFTR mutant hiPSCs also recapitulate a cystic fibrosis-associated ionocyte phenotype.

cell biology↗

A comprehensive functional landscape of α-tubulin TUBA1A variants illuminates microtubule biology and refines clinical classification

Missense variant interpretation in highly conserved, paralog-rich gene families remains a critical bottleneck for precision medicine. Here, we developed an integrated experimental-computational platform to systematically assess the functional impact of all possible missense mutations in the -tubulin TUBA1A. Combining high-throughput comprehensive mutagenesis, high-content imaging, convolutional neural network- driven phenotyping, and machine learning-guided prediction, we quantified microtubule assembly phenotypes for every coding variant. This approach outperforms conservation-based predictors and enables functional reinterpretation of disease-associated variants. Structural mapping of the TUBA1A mutational landscape reveals distinct domains critical for GTP binding, chaperone-assisted folding or protofilament interaction, illuminating diverse mechanisms of tubulin-related diseases. Integration with ACMG-AMP guidelines demonstrates this mutational landscape improves clinical variant classification in redundant gene families. This framework is broadly applicable to other structurally conserved proteins, linking variant effect prediction to mechanistic insight and clinical translation.

genetics↗