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PubMed2025

MRDagent: iterative and adaptive parameter optimization for stable ctDNA-based MRD detection in heterogeneous samples.

MOTIVATION: Minimal residual disease (MRD) as critical biomarker for cancer prognosis and management plays a crucial role in improving patient outcomes. However, detecting MRD via next-generation sequencing-based circulating tumor DNA variant calling remains unstable due to the extremely low variant allele frequency and significant inter- and intra-sample heterogeneity. Although parameter optimization can theoretically enhance the detection performance of variants, achieving stable MRD detection remains challenging due to three key factors: (i) the necessity for individualized parameter tuning across numerous heterogeneous genomic intervals within each sample, (ii) the tightly interdependent parameter requirements across different stages of variant detection workflows, and (iii) the limitations of current automated parameter optimization methods. RESULTS: In this study, we propose MRDagent, a novel variant detection tool designed specifically for MRD detection. MRDagent incorporates an iterative and self-adaptive optimization framework capable of handling unknown objectives, varying constraints, and highly coupled parameters across stages. A key innovation of MRDagent is the integration of a convolutional neural network-based meta-model, trained on historical data to enable rapid parameter prediction. This significantly enhances computational efficiency and generalization performance. Extensive evaluations on simulated and real-world datasets demonstrate MRDagent's superior and stable performance, providing an efficient, reliable solution for MRD detection in clinical and high-throughput research applications. AVAILABILITY AND IMPLEMENTATION: MRDagent is freely available at https://github.com/aAT0047/MRDagent.git. The corresponding dataset and software archive are available at Zenodo: https://doi.org/10.5281/zenodo.15458496.

Circulating Tumor DNA↗
PubMed2025

LYCEUM: learning to call copy number variants on low-coverage ancient genomes.

MOTIVATION: Copy number variants (CNVs) are pivotal in driving phenotypic variation that facilitates species adaptation. They are significant contributors to various disorders, making ancient genomes crucial for uncovering the genetic origins of disease susceptibility across populations. However, detecting CNVs in ancient DNA (aDNA) samples poses substantial challenges due to several factors: (i) aDNA is often highly degraded; (ii) contamination from microbial DNA and DNA from closely related species introduces additional noise into sequencing data; and finally, (iii) the typically low-coverage of aDNA renders accurate CNV detection particularly difficult. Conventional CNV calling algorithms, which are optimized for high-coverage read-depth signals, underperform under such conditions. RESULTS: To address these limitations, we introduce LYCEUM, the first machine learning-based CNV caller for aDNA. To overcome challenges related to data quality and scarcity, we employ a two-step training strategy. First, the model is pre-trained on whole genome sequencing data from the 1000 Genomes Project, teaching it CNV-calling capabilities similar to conventional methods. Next, the model is fine-tuned using high-confidence CNV calls derived from only a few existing high-coverage aDNA samples. During this stage, the model adapts to making CNV calls based on the downsampled read depth signals of the same aDNA samples. LYCEUM achieves accurate detection of CNVs even in typically low-coverage ancient genomes. We also observe that the segmental deletion calls made by LYCEUM show correlation with the demographic history of the samples and exhibit patterns of negative selection inline with natural selection. AVAILABILITY AND IMPLEMENTATION: LYCEUM is available at https://github.com/ciceklab/LYCEUM.

DNA Copy Number Variations↗
PubMed1977

Osmotic adaptation to rigid contact lenses.

Using a precision thermocouple hygrometer, requiring just 5 microliters of sample, the tear osmotic pressures of 6 subjects were monitored throughout their adaptation to rigid contact lenses. Relative to the prefitting baselines established for each previous to this study, these subjects showed a range of hypotonic shifts on initially receiving their lenses, but this imbalance was rectified by the end of the first wearing week and a new relatively hypertonic level of tear osmotic pressure was commonly established. This new baseline was reflected in the pre-insertion samples of several of the subjects as well once adaptation was advanced.

Adaptation, Physiological↗
PubMed2025

Harnessing Landscape Genomics to Evaluate Genomic Vulnerability and Future Climate Resilience in an East Asia Perennial.

In this era of rapid climate change, understanding the adaptive potential of organisms is imperative for buffering biodiversity loss. Genomic forecasting provides invaluable insights into population vulnerability and adaptive potential under diverse climatic conditions, thereby facilitating management interventions and bolstering shaping species-specific germplasm conservation strategies. We primarily employed landscape genomics approaches, leveraging single-nucleotide polymorphisms obtained through whole-genome resequencing of 201 individuals across 43 Rheum palmatum complex populations, to pinpoint adaptive variation and its significance in the context of future climates, delineate seed zones, and establish guidelines for ex situ germplasm conservation. The species complex exhibited strong signatures of local adaptation and differential genomic vulnerabilities across its distribution range, with eastern lineage populations facing significant maladaptation risks under future climate scenarios. Using diverse datasets of putatively adaptive loci and climate change scenarios, we delineated three distinct seed zones within the species' range, estimated varying sample sizes per zone to capture most adaptive diversity, and predicted shifts in seed zone centroids ranging from 48.3 to 359.3 km from historical distributions to mitigate climate change impacts. Collectively, our findings underscore the importance of integrating genomic and environmental data to forecast the adaptive trajectory of an East Asian perennial under anticipated climate changes, guide seed zone delineation for germplasm conservation and enhance population resilience. These results provide a blueprint for designing targeted conservation strategies and restoration plans in other imperilled species.

Climate Change↗
PubMed1979

The eye of the soldier beetle Chauliognathus pulchellus (Cantharidae).

The soldier beetle eye is unusual in having large optically isotropic corneal cones which project inwards from a thick isotropic cornea. Refraction is mainly at the corneal surface. Calculation shows that the first focal plane is near the tip of the cone, from which the optical pathway continues as a crystalline tract. At the distal end of the crystalline tract, 3 micrometer in diameter, the four cone cells enclose the proximal tip of the corneal cone; at the proximal end they enclose the distal tip of a long fused rhabdom rod. The eye is remarkable in that there are two classes of retinula cells; four cells contribute to the long thin axial rhabdom, 2 micrometer in diameter and 120 micrometer long, and the other four cells form two rounded rhabdoms, 10 x 4 micrometer in cross-section and 20 micrometer deep, which lie to one side of the optical axis. The physiological properties of individual retinula cells were measured by intracellular recording. The retinula cells are of three spectral types with peaks near 360, 450 and 520--530 nm. Except by the criterion of spectral sensitivity, the retinula cells sampled could not be sorted into more than one class. The measured value of the acceptance angle, near 3 degrees in the dark-adapted state, is consistent with the hypothesis that all sampled cells were of the anatomical type that participate in the central rhabdom rod. A calculation of the theoretical field size of individual retinula cells from measurments of refractive index and lens dimensions predicts that cells which participate in the central rhabdom will have acceptance angles near 3 degrees. The conclusion, therefore, is that only one anatomical type of cell has so far been sampled.

Adaptation, Physiological↗
PubMed2026

Haplotype Blocks Are Associated With Rapid Local Adaptation to Environmental Shifts in Wild Barley.

Genomic mechanisms of local adaptation must be highly responsive in geographic regions where climate is changing rapidly. The Levant region is a critical biodiversity hotspot and the distribution edge for many species, including the wild ancestor of domesticated barley. This region is under an accelerated desertification process, thus enforcing a rapid genomic response to the projected environmental changes. To elucidate the genomic basis of rapid local adaptation, we studied wild barley populations using an ecological-genetic sampling design that decouples environmental variation from demographic background. We collected and sequenced 300 wild barley individuals and evaluated the phenotypes of 3600 progeny plants over 3 years. Our genomic analyses revealed that local adaptation is associated with clusters of candidate genes forming haplotype blocks. These clusters are enriched with environment and stress responsive genes, including flowering time regulators, drought and heat responsive genes. We identified six candidate adaptive haplotype blocks which span 1-8 Mbp and are distributed across chromosomes 1H, 2H, 4H and 5H, each segregating as two major haplotypes. Additionally, we integrated over 2600 occurrence records into ecological and evolutionary modelling to assess the genomic vulnerability of populations to projected future climates. Our study identifies candidate genomic regions and environmental drivers of local adaptation in wild barley and highlights the advantage of haplotype blocks architecture in orchestrating an efficient response to rapid environmental change. We highlight the ecological factors most strongly associated with the observed evolutionary responses and provide insights and guidelines for biodiversity conservation and implementation of crop wild relatives in breeding.

Hordeum↗
PubMed2026

Genetic diversity, phylogenetic relationships, and marker development between Hydrangea serrata and H. macrophylla based on plastome and 45S nrDNA.

Ornamental hydrangeas (genus Hydrangea) are cultivated worldwide for their diverse flower colors and attractive morphology. Here, we assembled the complete plastid genome (plastome) and 45S nuclear ribosomal DNA (45S nrDNA) sequences of 22 individuals representing H. serrata, H. macrophylla, and related species (H. arborescens, H. paniculata, H. petiolaris, and H. hydrangeoides). The plastomes contained up to 2,344 single-nucleotide polymorphisms (SNPs) and 367 insertions/deletions (InDels) within the genus, whereas the assembled 45S nrDNA sequences showed 119 SNPs and 10 InDels. Phylogenetic analyses based on plastome and 45S nrDNA sequences clearly separated H. serrata and H. macrophylla from the other Hydrangea species. In the plastome-based tree, H. petiolaris was placed in the same clade as H. arborescens, whereas in the 45S nrDNA-based tree it showed a close relationship to H. hydrangeoides. The H. serrata and H. macrophylla samples were not always separated according to their species boundaries, as observed in samples Hse8-Hse12. Notably, one H. serrata sample (Hse8), collected from a wild mountainous region of Japan, exhibited a closer genetic relationship to H. macrophylla samples, indicating that cultivated hydrangeas may have originated from a specific wild lineage of H. serrata adapted to mountainous habitats. Using plastome-derived molecular markers, 66 Hydrangea samples were further classified into five groups, with Group II comprising both cultivated H. macrophylla and a subset of wild H. serrata samples, suggesting a close genetic affinity between this group and the ancestral gene pool of cultivated H. macrophylla. Based on these genomic resources, eight plastome-derived molecular markers were developed to differentiate cultivated hydrangeas from wild genotypes and to assess genetic diversity within H. serrata and H. macrophylla, providing practical tools for germplasm identification, breeding, and genetic resource management of Hydrangea species.

hydrangea↗
PubMed2026

Population Genomics of Almond (Prunus dulcis) Reveals Region-Specific Selection and a Complex History of Domestication.

The domestication of perennial crops in the Mediterranean Basin remains unclear, particularly regarding the genomic consequences of human-mediated demographic shifts and selection. We analysed 8.1 million single nucleotide polymorphisms from 96 cultivated almond (Prunus dulcis) accessions from Europe, North America, Central Asia, and New Zealand, alongside four wild relatives. Population structure analyses revealed four geographically differentiated cultivated groups (Central Asian, North American, and two European) and three wild populations (P. spinosissima, P. orientalis, and P. fenzliana). Cultivated almonds retained high genetic diversity, consistent with weak domestication bottlenecks typical of outcrossing perennials. Elevated diversity and private allele counts in Central Asian cultivars, together with limited evidence of crop-wild gene flow, support Central Asia as an important reservoir of ancestral cultivated diversity that may have played a major role during the early stages of almond domestication. In contrast, allele sharing consistent with historical wild-to-crop introgression-especially involving P. orientalis-has contributed to the genomic composition of European and North American almonds. Genome-wide scans for selective sweeps showed most genes overlapping candidate sweep regions were population-specific, though often associated with similar biological functions, including stress responses and agronomic traits. This suggests repeated targeting of comparable pathways during and post-domestication, despite distinct selection histories. Notably, a subset of candidate genes detected in cultivated populations also occurs in wild relatives, particularly P. orientalis. This overlap is consistent with shared ancestral variation, introgression/gene flow between wild and cultivated lineages, and/or parallel adaptation. Altogether, our results support a complex domestication and diversification history for almonds, shaped by geographic expansion, gene flow with wild relatives, and recurrent selection acting in different regions. This study highlights wild relatives as important reservoirs of genetic diversity and emphasises the need for broader geographic sampling to clarify their contributions to almond domestication and adaptation.

Prunus dulcis↗
PubMed2025

Genetic Adaptation to Brackish Water and Spawning Season in European Cisco.

How species adapt to diverse environmental conditions is essential for understanding evolution and the maintenance of biodiversity. The European cisco (Coregonus albula) is a salmonid that occurs in both fresh and brackish water, and this together with the presence of sympatric spring- and autumn-spawning lacustrine populations provides an opportunity for studying the genetics of adaptation in relation to salinity and timing of reproduction. Here, we present a high-quality reference genome of the European cisco based on PacBio HiFi long read sequencing and HiC-directed scaffolding. We generated low-coverage whole-genome sequencing data from 336 individuals across 12 population samples to explore population structure and genetics of ecological adaptation. We found a major subdivision between two groups of populations most likely reflecting colonisation from different glacial refugia. Within the two major groups, we detected further genetic differentiation between spring- and autumn-spawning populations and between populations from freshwater lakes, rivers and brackish water (Bothnian Bay). A genome-wide screen for genetic differentiation among populations identified a set of outlier SNPs strongly correlated with spawning timing and salinity. Several of the genes associated with spawning time, including BHLHE40, TIMELESS and CPT1A, have previously been shown to have a role in circadian rhythm biology. As many as 17 loci were associated with genetic differentiation between populations reproducing in fresh and brackish water. This study provides insights into the genomic basis of ecological adaptation in European cisco with implications for sustainable fishery management.

Animals↗
PubMed1979

Inhibition of aspartate release from the retina of the anaesthetised rabbit by stimulation with light flashes.

Rabbits were anaesthetised and the cornea, iris, lens and vitreous were removed from eyes to form an eye-cup which was filled with Krebs-bicarbonate Ringer. The medium in the eye-cup was replaced at 10-min intervals and the amino acids in each resulting sample were assayed. Exposure of the dark-adapted retina to flashes of light (3 Hz) did not alter the efflux of glutamate glutamine, alanine, glycine or GABA. The efflux of taurine and ACh was greatly increased by light flashes, but in contrast, the release of aspartate was reduced by more than 50%, a result consistent with the suggestion that aspartate may be a photoreceptor transmitter substance.

Anesthesia, General↗
PubMed2026

Evaluation and Optimization of Different Digestion Strategies for In-Depth Proteomic Characterization of Residual Host Cell Proteins in rAAV-Based Gene Therapy Products.

Recombinant adeno-associated virus vectors (rAAVs) are the most important vectors for in vivo gene therapies, yet their safety relies on low levels of residual host cell proteins (HCPs). While mass spectrometry-based proteomics enables sensitive and untargeted HCP profiling, it faces challenges with matrix interferences from purification buffers and the high dynamic range between abundant viral capsids and trace HCPs. Although sample preparation methods that address these challenges are well-established for antibody products, their adaptation to rAAV purification stages and products remains largely unexplored. In this study, we systematically evaluated three widely used proteomic sample preparation workflows─In-Solution, FASP, and SP3─across different stages of rAAV purification. In addition, each workflow was tested under both standard denatured digestion conditions and a "native" digestion strategy designed to reduce dynamic range by preserving capsid integrity while selectively digesting HCPs. This comparison identified the native FASP protocol as the most effective sample preparation method for overcoming matrix interference and dynamic range challenges, consistently outperforming other workflows in HCP identification across purification stages. Further optimization of the native FASP workflow enhanced its performance, achieving the highest host cell (HC) proteome depth, particularly in highly purified drug substance samples. This optimized sample preparation strategy provides a robust and easy-to-use framework for deep characterization of the host cell proteome in rAAV samples. By enabling deeper insights into the HCP profile, this approach supports improved understanding of the rAAV purification process and facilitates the development of targeted strategies to enhance product quality and safety.

Dependovirus↗
PubMed2025

The Relationship Among Range Adaptation, Social Anhedonia, and Social Functioning: A Combined Magnetic Resonance Spectroscopy and Resting-State fMRI Study.

BACKGROUND AND HYPOTHESIS: Social anhedonia is a core feature of schizotypy and correlates significantly with social functioning and range adaptation. Range adaptation refers to representing a stimulus value based on its relative position in the range of pre-experienced values. This study aimed to examine the resting-state neural correlates of range adaptation and its associations with social anhedonia and social functioning. STUDY DESIGN: In study 1, 60 participants completed resting-state magnetic resonance spectroscopy and fMRI scans. Range adaptation was assessed by a valid effort-based decision-making paradigm. Self-reported questionnaires was used to measure social anhedonia and social functioning. Study 2 utilized 26 pairs of participants with high (HSoA) and low levels of social anhedonia (LSoA) to examine the group difference in range adaptation's neural correlates and its relationship with social anhedonia and social functioning. An independent sample of 40 pairs of HSoA and LSoA was used to verify the findings. STUDY RESULTS: Study 1 showed that range adaptation correlated with excitation-inhibition balance (EIB) and ventral prefrontal cortex (vPFC) functional connectivity, which in turn correlating positively with social functioning. Range adaptation was specifically determined by the EIB via mediation of ventral-medial prefrontal cortex functional connectivities. Study 2 found HSoA and LSoA participants exhibiting comparable EIB and vPFC connectivities. However, EIB and vPFC connectivities were negatively correlated with social anhedonia and social functioning in HSoA participants. CONCLUSIONS: EIB and vPFC functional connectivity is putative neural correlates for range adaptation. Such neural correlates are associated with social anhedonia and social functioning.

Humans↗
PubMedDate not supplied

A technique for isolating turkey respiratory adenoviruses.

Several turkey respiratory adenoviruses were isolated in turkey embryonic liver cells from nasal turbinate filtrate collected from clinically ill turkey poults during postmortem examination. Suspect adenovirus inoculum had to remain in cell culture for 5 to 7 days, and 9 blind passages were required before a sample was declared negative. Once isolated, the turkey adenoviruses adapted rapidly to turkey kidney cells.

Adenoviridae↗
PubMed2026

Pathogenic properties of myasthenia gravis AChR autoantibodies associate with clinical response to efgartigimod.

BACKGROUND: Efgartigimod, a neonatal Fc receptor (FcRn) blocker, effectively reduces total IgG, including pathogenic acetylcholine receptor (AChR) autoantibodies in myasthenia gravis (MG); however, clinical responses vary. To investigate this variability, we studied how efgartigimod impacts AChR-specific autoantibody profiles and associated pathogenic mechanisms, including complement activation, AChR internalisation and ACh-binding site blockade. METHODS: Serum samples (N=150) were sourced from 50 AChR autoantibody-positive generalised MG patients participating in the phase 3 ADAPT study, randomised to receive efgartigimod (N=40) or placebo (N=10) in cycles of 4-weekly infusions. Samples were collected at baseline, day 29 and day 57 during the first cycle. Live cell-based assays quantified AChR-specific IgG subclasses and isotypes and assessed their capacity to mediate pathomechanisms. RESULTS: Efgartigimod decreased all detectable AChR-specific IgG subclasses. At baseline, AChR autoantibody-mediated C3b deposition, AChR internalisation and ACh-binding site blockade were detected in 42 (84%), 41 (82%) and 10 (20%) patients, respectively. After 4-weekly infusions of efgartigimod, the magnitude of all three pathomechanisms was significantly decreased. However, the extent of this reduction varied across individuals. Double responders on both MG-activities of daily living and quantitative MG scores demonstrated a greater reduction in complement activity and AChR internalisation compared with patients who responded on only one score or were double non-responders. In addition, efgartigimod reduced IgG-dependent IgM binding to AChR. CONCLUSIONS: These findings suggest that clinical efficacy may be more closely associated with functional modulation of the AChR-specific autoantibodies than with their absolute quantity alone. These results support the evaluation of mechanistic pathway monitoring as a potential strategy to predict or guide efgartigimod treatment response.

Humans↗
PubMed2026

Quantitative RNA modification mapping by mass spectrometry with isobaric tags and nucleobase fragment analysis.

RNA modifications regulate RNA stability, translation, stress responses, and disease processes, yet their function remains poorly understood due to technical limitations in sequence analysis. Here, we present an RNA-specific isobaric tandem mass tagging (RMT) platform for omic-scale quantitative mapping of RNA modifications. The platform combines RNA-specific tags adapted from proteomics with an end-to-end workflow spanning sample preparation through data processing. Validation using synthetic oligonucleotides and total tRNA from Pseudomonas aeruginosa yielded reproducible quantification, with coefficients of variation below 5%. Together with nucleobase fragment analysis, we identified and quantified 24 RNA modifications in PA14 tRNAs, including previously undescribed m2A38 and Gm/Cm39, and assigned their corresponding writer enzymes. Further analyses of tRNAs from writer knockout strains and stressed cells revealed dynamic modification patterns, modification interdependencies, and their potential roles in stress adaptation. This method provides a robust, cost-effective platform for quantitative RNA modification mapping, enabling deeper biological insights.

RNA, Transfer↗
PubMed1979

Liquid-chromatographic determination of acetaminophen in serum.

We describe a sensitive and precise "high-pressure" liquid-chromatographic method for determining acetaminophen in serum. The 2-acetaminophenol and 3-acetaminophenol structural isomers of acetaminophen are used as internal standards. The method, which involves solvent extraction and adsorption chromatography on silica, provides excellent sensitivity, accuracy, and selectivity. The standard curve is linear over the range of acetaminophen concentrations of 0.5 to 300 mg/L, which makes the method useful for both pharmacokinetic studies and overdose monitoring. Analytical recovery is 97% for acetaminophen concentrations ranging from 5 to 300 mg/L. Many commonly used drugs were tested and found not to interfere. The procedure has been successfully adapted as a microscale method requiring only 50 microL of sample. The microscale method is particularly useful for pediatric and neonatal patients for whom sample size is a major concern.

Acetaminophen↗
PubMed1975

Plasma proteins in canine gastric lymph.

Because it has not been possible to collect gastric lymph by cannulation of lymph vessels, the methods of renal micropuncture were adapted to collection and analysis of 0.5- to 3-mu samples obtained by puncturing lymph vessels on or immediately adjacent to the ventral surface of the dog's stomach. Samples of gastric lymph collected immediately after completion of surgical exposure of the stomach were subjected to acrylamide gel electrophoresis, and they were found to show all the protein bands exhibited by simultaneously collected samples of plasma. Quantitative analysis of similar samples by cellulose acetate electrophoresis gave the following ratios of protein concentration in gastric lymph to plasma: total protein, 0.51; albumin, 0.68; total globulins, 0.42; alpha1-globulin, 0.49; alpha2-globulin, 0.62; beta-globulin, 0.35; fibrinogen, 0.39; and gamma-globulin, 0.46. When samples were collected over 4 hr the concentrations of all proteins in lymph increased, and an argument is presented that this was not the result of increasing small pore size as the result of injury. When the mucosa was irrigated with solutions of dithiothreitol, a substance causing plasma shedding, the concentrations of proteins in gastric lymph over a 4-hr period were similar to those found in control experiments. Gastric lymph mixed with 100 mN HCl was found to have proteolytic activity.

Alpha-Globulins↗