Over the past two decades there have been remarkable advances in stem cell biology, bioengineering, and lung regenerative research, transforming our understanding of pulmonary biology from development to repair, and disease. Strategies using endogenous lung progenitor cells, pluripotent stem cell technologies, and engineered tissue platforms have become central tools for interrogating lung biology. Major breakthroughs have included the identification of diverse cell populations that coordinate lung homeostasis and repair, facilitated by the extensive adoption of single cell, multiomic and spatialomics approaches. Simultaneous progress in biomaterials, organoid systems, decellularized lung scaffolds, and lung-on-chip platforms has uncovered how extracellular matrix composition, mechanical forces, and tissue architecture contribute to the regulation of cell fate and function. These advances have enabled increasingly physiologically relevant in vitro, and ex vivo models while informing tissue engineering strategies aimed ultimately at functional lung replacement. Translation toward the clinic has advanced through both cell-based and cell-free therapeutic strategies. Early efforts focused largely on mesenchymal stromal cell-based approaches and extracellular vesicles, which have demonstrated safety and context-dependent efficacy in inflammatory lung diseases, alongside emerging preclinical evidence of functional engraftment of induced pluripotent stem cell-derived lung lineages. The past twenty years of progress, captured at the 20th Anniversary Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases Conference, highlights the power of interdisciplinary collaboration in advancing lung regeneration from foundational discovery toward therapeutic reality.
The recent records of Prostephanus truncatus Horn (Coleoptera: Bostrichidae) in certain regions of Burkina Faso make it a potential pest for maize, its preferred host, and for other cereals grown in the country. To estimate the extent of its possible large-scale invasion, we determined its survival and reproductive parameters on grains of maize, red sorghum, millet, and paddy rice. Bioassays consisted of infesting healthy grains from each of the four cereals, contained in Petri dishes, with a pair of P. truncatus aged up to 24 h old. Observations were made daily to replace the grains and collect data until the pair died and the F1 generation of insects emerged. Then the main biological parameters of P. truncatus were determined on each cereal. The results showed that female P. truncatus generally lived longer than males, regardless of the cereal used as food substrate. However, longevity was higher on maize than on red sorghum, millet, and paddy rice, respectively. There was no oviposition activity on paddy rice unlike other cereals. Female P. truncatus laid more eggs on maize than on other cereals. Red sorghum and millet did not allow for the complete development of the larvae. The pest developed successfully on maize, and a sex ratio biased in favor of females was observed. Given these results, significant damage by P. truncatus could occur on maize grains. Further studies should focus on climatic adaptation of P. truncatus and its other possible alternative hosts including woody and tuberous plants growing in Burkina Faso.
Endothelial cells (ECs) are crucial in cancer development and progression, partly by regulating tumor angiogenesis and immune modulation. As a key component of the RNA-induced silencing complex, Argonaute 1 (AGO1) regulates tumor biology, yet the specific function of AGO1 within ECs in the tumor microenvironment remains undefined. Here, we investigated the effects of endothelial-specific AGO1 knockout (EC-AGO1-KO) on tumor vascularization and immune regulation in a mouse syngeneic breast cancer model induced by E0771 cells. EC-AGO1-KO mice exhibited significantly reduced tumor burden compared to their wild-type (WT) littermates, accompanied by reduced vascularization and enhanced immune cell infiltration. Histological and single-cell RNA sequencing analyses revealed increased infiltration of CD8⁺ T cells and macrophages in EC-AGO1-KO tumors, indicative of an immunostimulatory microenvironment. In vitro, AGO1 knockdown in mouse ECs co-cultured with E0771 tumor cells led to higher levels of Cxcl10 and Vcam1 expression, suggesting a pro-inflammatory and leukocyte-recruiting effect. Together, these findings identify endothelial AGO1 as a key regulator of tumor vasculature and immune homeostasis in breast cancer, suggesting that targeting endothelial AGO1 may represent a novel therapeutic strategy to modulate tumor vasculature while enhancing anti-tumor immunity.
The sequence-specific recognition of double-stranded DNA by biocompatible molecules is fundamental to molecular medicine and synthetic biology. Triplex-forming oligonucleotides (TFOs) enable programmable major groove recognition via Hoogsteen base pairing; however, the limited repertoire of natural nucleobases imposes strict constraints on target sequences and parallel motif triplexes require acidic conditions for stability. Here, we have expanded the triplex recognition space using nucleobases from an artificially expanded genetic information system (AEGIS). Through a systematic evaluation of 120 base triad combinations, we identify at least 12 modular triads that can be combined interchangeably to target duplex DNA containing standard, damaged, or synthetic base pairs with nanomolar affinity at neutral pH. We further demonstrate the versatility of this expanded recognition code by detecting oxidative lesions or AEGIS base pairs in enzymatically assembled duplex constructs using both chemically and enzymatically synthesized TFOs. This generalized framework provides a robust platform for precision gene-targeting, molecular sensing, and nucleic acid nanotechnology.
Lynch syndrome is an inherited cancer predisposition syndrome caused by germline pathogenic variants in mismatch repair (MMR) genes and is primarily associated with colorectal and endometrial cancers. Classically, Lynch syndrome-associated tumors exhibit microsatellite instability (MSI) and loss of MMR protein expression on immunohistochemistry (IHC); therefore, MSI and IHC are routinely used in screening algorithms to support diagnostic evaluation. ; Methods: In this study, we present the molecular and pathological characteristics of four cases from three unrelated families carrying the same MSH2 variant [c.70C > T (p.Gln24Ter)], interpreted as pathogenic, who were diagnosed with breast and colorectal cancer. MSI analysis and MMR protein expression were evaluated in available tumor tissues. ; Results: Preserved MMR protein expression was observed in three cases, and two cases were microsatellite stable (MSS), whereas only one case demonstrated loss of MMR protein expression and an MSI-high phenotype consistent with the classical Lynch syndrome profile. These findings suggest that individuals carrying the same MSH2 variant may exhibit heterogeneous tumor-level MMR/MSI phenotypes. Early truncating variants in MSH2 may allow partially functional protein production via alternative translation initiation, potentially limiting complete loss of MMR function. Variability in somatic second-hit mechanisms and tumor-specific molecular pathways may also contribute to this heterogeneity. ; Conclusion: In conclusion, Lynch syndrome tumor biology may be more heterogeneous than expected, and MSI and IHC should not be interpreted in isolation as exclusionary tests for an underlying germline MMR variant, but rather as markers of tumor-level biological consequences. Therefore, germline findings, tumor characteristics, and family history should be evaluated together in Lynch syndrome diagnosis and risk assessment.
Perihilar cholangiocarcinoma (pCCA) frequently presents as an indeterminate perihilar biliary stricture. The diagnosis is often delayed or uncertain because of the limited sensitivity of conventional endobiliary sampling and blood-based markers, especially in patients with additional confounding conditions such as primary sclerosing cholangitis (PSC). This diagnostic ambiguity can significantly impact clinical outcomes as timely detection and accurate classification are critical for referral and curative-intent treatment. As such, research focused on advancing diagnostic methodologies is a priority. pCCA has a distinct proteomic signature, pattern of activated signaling cascades, epigenetic modifications, and metabolic interactions within its anatomic niche. Recent advances in omics-based diagnostics have leveraged these biological features to identify biomarkers for accurate pCCA diagnosis. In this review, we summarize emerging evidence for omics-based diagnostics in pCCA using clinically accessible samples, including biliary brushings, bile and serum/plasma samples. We discuss the key aspects of pCCA biology that form the foundation for development of novel techniques including glyco-/phospho-/proteomic, genomic, methylomic, metabolomic, and lipidomic analyses as well as multiomic approaches. We conclude by outlining how artificial intelligence may help integrate the data into diagnostic algorithms and identifying areas requiring further investigation to advance these diagnostics into routine clinical practice.
Understanding the biology of B1 metallo-β-lactamases (MβLs) in their native hosts and the molecular bases of the adaptive mechanisms during the transfer process to human pathogens, may provide novel therapeutic insights against these important resistance factors. Through large scale phylogenomic analyses, we identify Bacteroidota and Myxococcota as the primary hosts of the enzymes in environmental habitats. The monophyletic lineage of MβL homologues from the predatory members of the latter phylum shares common ancestry with clinically relevant families found in γ-Proteobacteria, highlighting their evolutionary significance. Resistance phenotypes and biochemical properties of native MβLs from three myxobacterial genera expressed in the model γ-proteobacterium, Escherichia coli, and comparisons with the New Delhi Metallo-β-lactamase reveal that evolution of the enzymes concerned mainly adaptations enhancing their production in the new hosts rather than functional differentiation. Periplasmic localization is the main evolved trait, with E. coli not recognizing optimally the signal peptides of the environmental MβLs which are secreted as soluble proteins in the cell envelope despite predicted to be lipoproteins. The unique features of N-terminal secretory signals of myxobacterial MβLs likely reflect the enzymes integration into the physiology of their hosts and point to naturally occurring molecules potentially controlling their expression.
We like to imagine that our students are cheerfully unaware of the ocean of educational bureaucracy that surrounds their peaceful island of learning. Despite the hassles of registering and paying for classes, students are supposed to run head-on into the dreaded bureaucracy only when they join the so-called real world. What is all that bureaucracy doing anyway? Is it a superstructure created by self-serving and parasitic bureaucrats? Strangely, perhaps the most elaborate bureaucracy we know of lies within each of us, whether student, professor or paper-pushing Vice President. This bureaucracy is the cell. The vast majority of genes and proteins within cells are effectively bureaucrats, regulating each other rather than building things. Regulation requires communication through a complex network of intracellular signaling, which in turn extends beyond the cells as the chatter among cells that regulates tissues. Why is the most remarkable self-organized system in the known universe so bureaucratic? This paper, based on a presentation at the 2025 Annual Meeting of the Society for Mathematical Biology in Edmonton, presents models of how bureaucracy grows, how it can provide robustness, its points of vulnerability, and how these complex systems can be corrupted.
The niche concept is central to ecology, evolution, and conservation biology. To assess resource dynamics in biological communities, the most widely used niche metrics are niche breadth and niche overlap. Colwell and Futuyma (1971) were the first to propose niche metrics that incorporated resource distinctness. In their framework, niche breadth and overlap are calculated using either a relative weighting factor d j or an absolute weighting factor δ j . Hanski (1978) later introduced an alternative weighting factor δ j ∗ , which accounts for both the quality and quantity of resource states in niche calculations. However, metrics based on d j , δ j and δ j ∗ have inherent mathematical and conceptual limitations. To overcome these issues, the present study introduces modified forms of these factors ( e d j , e δ j and e δ j ∗ ) and evaluates their performance using eight hypothetical and one empirical (ecological) resource matrix. The findings indicate that niche metrics incorporating the e d j factor represent the most coherent and biologically meaningful option.
The spittlebug Mahanarva spectabilis (Distant, 1909) (Hemiptera: Cercopidae) is an important pest of forage grasses in South America, where its nymphs cause pasture damage by feeding on xylem sap and producing a characteristic foam that protects them against environmental stressors. To investigate the molecular basis of this adaptation, we integrated RNA-seq analysis of nymphs with LC-MS/MS proteomics of the Batelli gland, the primary source of foam secretion. De novo assembly of 100,666 unigenes revealed broad functional diversity, with strong representation of detoxification enzymes (CYP450s, GSTs, UGTs, carboxylesterases), transporters and ion pumps, cuticle proteins, and stress- and immunity-related genes. Nearly 16% of loci exhibited alternative splicing, particularly within detoxification, chemosensory and osmoregulatory gene families, highlighting evidence of transcriptomic variability. Signal peptide and secreted protein predictions identified 168 high-confidence candidate secreted proteins, including detoxification enzymes, proteases, structural proteins and immune-related factors, several of which are consistent with antimicrobial and surfactant-related functions. Proteomic profiling of the Batelli gland confirmed 500 proteins, enriched in chaperones, metabolic enzymes, detoxification pathways and osmoregulatory components, with the most abundant proteins corresponding to Hsp70 chaperones, ATP synthases, cuticle proteins and carbonic anhydrases. Together, these results provide an integrative transcriptomic and proteomic overview for M. spectabilis nymphs, highlighting genes and proteins associated with xylem feeding, foam production and responses potentially related to environmental stress tolerance. This comprehensive dataset not only advances the understanding of spittlebug biology but also identifies candidate molecular targets that may inform innovative strategies for controlling nymphal stages and mitigating spittlebug damage in forage systems.
Amplifying asymmetry via supramolecular self-assembly is essential for understanding homochirality in biology and developing functional chiroptical materials. While the "majority rules" dictates the handedness of heterochiral assemblies, their chiroptical signals are typically weaker than those of homochiral ones. Here, we demonstrate that controlled enantiomeric imbalance can enhance chiroptical activity beyond that of homochiral assemblies. Using dansyl-glutamic acid diamide enantiomers, we show that fine-tuning enantiomeric excess (ee) triggers structural reorganization, yielding maximum circular dichroism (CD) and circularly polarized luminescence (CPL) intensities exceeding those of pure enantiomer assemblies at specific ee values. Simulations reveal that the incorporation of the minority enantiomer constructively forms "chiral oligomers", which are composed of different ratios of enantiomers and optimize local chromophore alignment via effective pitch angle to amplify the chiroptical activity. This strategy overcomes the conventional signal attenuation from racemic or near-racemic mixing, enabling chiral imbalance-driven asymmetric amplification and offering a rational design principle for high-performance chiroptical materials.
Population admixture is a pivotal evolutionary process that has profoundly shaped genetic diversity and population structure in modern human populations. However, most existing methods for inferring admixture history rely on simplified assumptions, such as strictly sequential contributions from ancestral populations, thereby limiting their applicability to realistic scenarios. Here, we introduce HiMWA, a computational framework based on a hierarchical multiple-wave admixture model for reconstructing complex admixture histories involving multiple ancestral populations. HiMWA characterizes both hierarchical admixture, in which ancestral populations first admix to form intermediate populations, and subsequent multiple-wave admixture that shapes the final admixed population. The framework integrates model selection based on ancestry switch counts with parameter estimation using the length distribution of ancestral tracts. Extensive simulations demonstrate that HiMWA is accurate and robust across diverse admixture scenarios, including those affected by genetic drift and local ancestry inference errors. Applying HiMWA to Kazakhs and Uyghurs revealed a shared hierarchical admixture structure. In both populations, West European and South Asian ancestries first admixed to form a West Eurasian intermediate population, while East Asian and Siberian ancestries formed an East Eurasian intermediate population. These two intermediates subsequently contributed to present-day populations through multiple waves of admixture. Our results highlight the prevalence of hierarchical multiple-wave admixture in Central Asia and provide insights into the region's complex demographic history. HiMWA offers a powerful and flexible framework for disentangling complex admixture histories and reconstructing realistic population genetic histories from genomic data. The HiMWA software, documentation, and example datasets are publicly available at https://github.com/Shuhua-Group/HiMWA and https://ngdc.cncb.ac.cn/biocode/tool/BT008069.
The treehopper Spissistilus festinus [Say, 1830] (Hemiptera: Membracidae) is not a direct pest of winegrapes (Vitis vinifera) but poses a threat to vineyards as a vector of grapevine red blotch virus (GRBV). While previous no-choice assays suggested a preference for Fabaceae for feeding and reproduction, recent gut content analyses revealed frequent feeding of S. festinus on Vitaceae, particularly free-living V. californica and its hybrids, within northern California vineyards. To better understand host selection and feeding behaviors of S. festinus, we conducted choice assays using excised leaves of Fabaceae (snap bean, alfalfa) and Vitaceae (winegrape, V. californica, V. californica hybrid). In two-choice assays, S. festinus more often visited snap bean, though Vitis species were also attractive when present. In four-choice contexts, snap bean remained a preferred host, followed by V. californica and winegrapes. These results confirmed the polyphagous tendencies of S. festinus and provided new insights into the feeding behaviors of this treehopper species.
In this work, we evaluate the biomolecular dynamics behaviors when conventionally iterating between all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) simulations over multiple cycles. We implemented the workflow to iterate between AA and CG in OpenMM, namely the iterative multiscale MD (iMMD) simulation workflow. In particular, we aim to identify practical applications for iterating between AA and CG simulations in a conventional manner without any constraints or model modifications. We evaluate the iMMD workflow on four representative systems, spanning folding of two soluble proteins and protein-protein as well as protein-lipid interactions of two membrane proteins. We observe that iteration between AA and CG representations could help the soluble proteins exit undesirable metastable states to fold, resulting from random protein structural distortions due to cycling. Consequently, the most reliable use of iterative AA and CG simulations appears to be to accelerating complex lipid mixing for membrane-bound protein systems rather than sampling protein conformational space. Our work explores the practical usages and limitations for iterative AA and CG simulations using readily available AA and CG force fields. The evaluated iMMD workflow in OpenMM is made available at https://github.com/lanl/iMMD.
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SEMPLR is an R package that predicts transcription factor binding and variant effects using SNP Effect Matrices (SEMs), providing efficient, genome-wide scoring, enrichment testing, and visualization tools for comprehensive analysis of regulatory sequences. Available on GitHub at https://github.com/grkenney/SEMPLR and on Bioconductor at https://bioconductor.org/packages/release/bioc/html/SEMPLR.html. Supplementary data are available at Bioinformatics online.
The majority of intestinal tumors harbor mutations in canonical Wnt pathway genes such as APC, whereas the lack of such alterations in a subset of tumors implies alternative tumorigenic routes. Here we identify recurrent in-frame deletion in COPA, frequently co-occurring with USP9X-truncating mutation, in small intestinal adenoma and adenocarcinoma. Patient-derived and CRISPR-engineered small intestinal organoids carrying COPA in-frame deletions exhibit R-spondin-independent yet Wnt ligand-dependent growth, maintaining LGR5 expression without canonical Wnt drivers. Mechanistically, COPA mutation stabilizes the Frizzled coreceptor LRP6 irrespective of R-spondin, sustaining Wnt pathway activation under growth factor-restricted conditions. USP9X loss further potentiates this phenotype. Unlike canonical Wnt pathway members, COPA encodes the α-subunit of coatomer complex I, which engages in vesicle trafficking with little prior linkage to intestinal tumorigenesis. Our findings establish COPA mutation as a unique and atypical intestinal tumor driver and implicate USP9X loss as a cooperating lesion.
WNT proteins have been recognized as key regulators of skeletal health. However, developing WNT-associated bone anabolic agents is clinically challenging and expensive. Here we identify the reconstructed thumb and index domains of WNT7B (WNT7BRTID) as a WNT-derived bone anabolic peptide via Alphafold-empowered sequence prediction and in silico docking screening. In aged mice and pigs models of osteoporosis, WNT7BRTID peptides demonstrate therapeutic potential by improving the osteogenic potential of mesenchymal stromal/stem cells (MSCs) and enhancing bone regeneration. Using single-cell sequencing, transgenic lineage tracking and biochemical approaches, we show that WNT7BRTID harnesses the function and osteogenic lineage generation of intrinsic tissue-residual MSCs without needing MSC transplantation to repair a critical-sized defect effectively. Mechanistically, WNT7BRTID activates non-canonical Ca2+-NFAT signalling through RECK/GPR124 to drive its bone anabolic effects, independent of canonical Wnt/β-catenin signalling known for its oncogenic effects. Our results suggest that WNT7BRTID could work as bone anabolic agent for alleviating bone loss in aging and for fracture repair by promoting MSC function via Ca2+-NFAT signalling.
Pharmacogenetics uses genetic testing to improve the safety and effectiveness of prescribed medicines, yet implementation at scale remains limited due to the absence of interoperable health IT solutions that integrate results into prescribing workflows. This study aimed to develop and validate open data standards for pharmacogenetic results to enable interoperability across healthcare systems. A baseline data model was constructed using the open standard openEHR by synthesising literature, genomic sequencing outputs, and international data specifications, and refined through iterative workshops with the Global Alliance for Genomics and Health. The model underwent two rounds of structured peer review involving 24 experts from 10 countries. Mapping to HL7 FHIR was evaluated using both manual and automated approaches, including the FHIR-Connect tool. The resulting standardised pharmacogenetic data model separates test results from therapeutic implications and incorporates recognised terminologies such as SNOMED CT and HGNC. It achieved international consensus and is published on the openEHR Clinical Knowledge Manager platform. Mapping to HL7 FHIR demonstrated bidirectional information flow within healthcare systems, with automated mapping enabling scalable and reusable transformations. This work provides a framework for storing and exchanging pharmacogenetic test results, supporting semantic harmonisation, interoperability, and integration with clinical decision support systems. Open data standards for pharmacogenetic test results therefore offer a foundation for scalable implementation of pharmacogenetics in routine clinical practice.
Social determinants of health-such as socioeconomic status (SES) and race and ethnicity-strongly shape health. Individuals with lower SES or marginalized identities experience earlier onset of disease and shorter lifespans. 'Epigenetic clocks' measure biological ageing and are increasingly used to study healthy ageing, yet it remains unclear which clocks are most sensitive to social inequality. Here we conducted an Open Science Framework-pre-registered systematic review and meta-analysis of 140 studies (N = 65,919; 1,065 effect sizes) testing associations of SES and race and ethnicity with three generations of clocks. PubMed, PsycINFO, Web of Science, medRxiv and bioRxiv were searched from February 2024 to September 2025. Eligible studies included empirical articles in English published since 2013 on non-clinical populations reporting at least one relevant association. Associations between SES and biological ageing varied across different generations of epigenetic clocks (F(2) = 178,10, P < 0.001), with the weakest effects for first-generation clocks (r = -0.03, 95% confidence intervaI (CI) [-0.04, -0.01], P < 0.001) and stronger effects for second- (r = -0.11, 95% CI [-0.12, -0.09], P < 0.001) and third-generation clocks (r = -0.13, 95% CI [-0.15, -0.11], P < 0.001]). Sex, tissue and array minimally modified results, and publication bias was negligible. Limitations include inconsistent reporting of technicalities and overrepresentation of data from high-income countries. The findings indicate that newer clocks are more responsive to social inequality.