Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “variational inference”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 217 records · Page 12Linked to original sources
PubMed2026

Spatial proteomics reveals four-stage molecular evolution in cancer immunotherapy-related gastritis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet immune-related adverse events (irAEs) including immunotherapy-related gastritis (IRAEG) pose significant clinical challenges-often necessitating treatment interruption that may compromise antitumor efficacy. IRAEG presents with atypical symptoms, lacks specific biomarkers, and shows histopathological overlap with other forms of gastritis, complicating diagnosis and management. Despite increasing clinical recognition, a systematic understanding of spatial molecular alterations across the full disease course remains limited. Here, we used spatial proteomics to map the molecular landscape of IRAEG during disease progression and to define stage-specific patterns of molecular evolution relevant to cancer immunotherapy management. METHODS: We analyzed tissue samples from seven patients, including four non-immunotherapy-related gastritis controls and three cancer patients who developed IRAEG following ICI therapy for solid tumors, sampled longitudinally across four disease stages: baseline (G1), acute severe inflammation (G2), early recovery (G3), and complete recovery (G4). Using laser capture microdissection coupled with data-independent acquisition mass spectrometry, we profiled 177 spatially resolved gastric tissue regions. Multiplex immunohistochemistry and immunofluorescence characterized features of the immune microenvironment, while Gene Ontology, KEGG pathway analysis, Gene Set Variation Analysis, and xCell inference enabled functional, metabolic, and immune profiling. Key immune and NET-related findings were further validated by multiplex immunofluorescence in an independent, expanded cohort of IRAEG and non-immunotherapy-related gastritis samples. RESULTS: IRAEG was characterized by widespread HLA molecule activation and enhanced antigen processing, resembling the immune phenotype observed in organ transplant rejection. The acute G2 stage exhibited excessive neutrophil extracellular trap formation, profound metabolic suppression, and collapse of immune homeostasis-features that may inform early intervention strategies to preserve ICI treatment continuity. During early recovery (G3), inflammatory injury transitioned toward repair, marked by activation of fatty acid metabolism and PPAR signaling. Notably, even at complete clinical recovery (G4), more than 1,000 proteins remained differentially expressed, reflecting sustained enhancement of metabolic and immune functions and establishing a distinct molecular "memory" state with implications for ICI rechallenge decisions. CONCLUSIONS: These findings define four molecularly distinct stages of IRAEG progression and recovery. The stage-specific signatures identified here serve as candidate biomarkers for diagnosis, disease staging, and therapeutic response assessment, and may guide clinical decisions regarding irAE management, treatment modification, and safe ICI rechallenge to support continued antitumor therapy.

Humans↗
PubMed2025

Advancing translational exposomics: bridging genome, exposome and personalized medicine.

Understanding the interplay between genetic predisposition and environmental and lifestyle exposures is essential for advancing precision medicine and public health. The exposome, defined as the sum of all environmental exposures an individual encounters throughout their lifetime, complements genomic data by elucidating how external and internal exposure factors influence health outcomes. This treatise highlights the emerging discipline of translational exposomics that integrates exposomics and genomics, offering a comprehensive approach to decipher the complex relationships between environmental and lifestyle exposures, genetic variability, and disease phenotypes. We highlight cutting-edge methodologies, including multi-omics technologies, exposome-wide association studies (EWAS), physiology-based biokinetic modeling, and advanced bioinformatics approaches. These tools enable precise characterization of both the external and the internal exposome, facilitating the identification of biomarkers, exposure-response relationships, and disease prediction and mechanisms. We also consider the importance of addressing socio-economic, demographic, and gender disparities in environmental health research. We emphasize how exposome data can contextualize genomic variation and enhance causal inference, especially in studies of vulnerable populations and complex diseases. By showcasing concrete examples and proposing integrative platforms for translational exposomics, this work underscores the critical need to bridge genomics and exposomics to enable precision prevention, risk stratification, and public health decision-making. This integrative approach offers a new paradigm for understanding health and disease beyond genetics alone.

Humans↗
PubMed2001

Molecular systematics of the Brassicaceae: evidence from coding plastidic matK and nuclear Chs sequences.

Phylogenetic relationships were inferred using nucleotide sequence variation of the nuclear-encoded chalcone synthase gene (Chs) and the chloroplast gene matK for members of five tribes from the family Brassicaceae to analyze tribal and subtribal structures. Phylogenetic trees from individual data sets are mostly in congruence with the results from a combined matK-Chs analysis with a total of 2721 base pairs, but with greater resolution and higher statistical support for deeper branching patterns. The analysis indicates that tribes Lepidieae, Arabideae, and Sisymbrieae are not monophyletic. Among taxa under study four different lineages each were detected in tribes Arabideae and Lepidieae, interspersed with taxa from tribes Sisymbrieae, Hesperideae, and Brassiceae. It is concluded that tribe Brassiceae might be the only monophyletic group of the traditional tribes. From our data we estimated several divergence times for different lineages among cruciferous plants: 5.8 mya (million years ago) for the Arabidopsis-Cardaminopsis split, 20 mya for the Brassica-Arabidopsis split, and ∼40 mya for the age of the deepest split between the most basal crucifer Aethionema and remaining cruciferous taxa.

Journal Article↗
PubMed1994

A general approach for PCR-amplification and sequencing of chloroplast DNA from crude vascular plant and algal tissue.

A universal and reliable sequencing approach suitable for evolutionary and phylogenetic studies of most plant species has been developed. The initial step in the approach is PCR with primers from conserved regions in the chloroplast genome. Prior to PCR a simple DNA extraction is carried out where lysed tissue is embedded in agarose and dialyzed. Due to the use of one biotinylated primer in the PCR, the PCR products can be bound to magnetic streptavidin-coated beads and then sequenced directly by the solid-phase approach. The regions used for sequencing and subsequent analyses are the intron of the trnL gene and the intergenic spacer between the trnL and the trnF genes in the chloroplast DNA. Comparisons of the sequences obtained from closely and distantly related species show that the different chloroplast DNA regions harbor variations suitable for phylogenetic inference from the subspecific to the interfamiliar level. The strategy can be used both for manual and automated sequencing.

Autoanalysis↗
PubMed1997

Phylogeographic analysis of pigtail macaque populations (Macaca nemestrina) inferred from mitochondrial DNA.

Mitochondrial DNA variation was surveyed in nine populations of the pigtail macaque (Macaca nemestrina), covering all three recognized subspecies in Southeast Asia. To do this, a 2,300 base pair fragment spanning the mitochondrial NAD 3 and NAD 4 genes and flanking tRNA subunits leucine and glycine was targeted for amplification and digested with a battery of 16 restriction endonucleases. Out of a total of 107 individuals, 32 unique haplotypes could be distinguished. Parsimony and neighbor-joining analyses grouped the haplotypes into five strongly supported assemblages representing China/Thailand, Malaysia, Sumatra, Borneo, and Siberut. These results indicate that the mainland and island mtDNA haplotypes are strictly and uniquely limited to the geographic ranges of the recognized morphological subspecies. Cladistic and neighbor-joining analyses indicate that inferred phylogenies of mtDNA haplotypes are congruent with subspecies designations. Furthermore, in support of morphological studies, results indicate that the Mentawai macaque is most likely not a distinct species but a subspecies of M. nemestrina.

Animals↗
PubMed2002

Diverse supernova sources of pre-solar material inferred from molybdenum isotopes in meteorites.

Variations in the isotopic composition of some components in primitive meteorites demonstrate that the pre-solar material was not completely homogenized, nor was it processed at sufficiently high temperatures to erase the signatures of the diverse stellar sources. This is in accord with the observation that accretion disks of young stellar objects are at relatively low temperatures. Carbonaceous chondrites are considered to represent the 'average' Solar System composition; the rare pre-solar grains in the matrixes of carbonaceous chondrites have been used to identify some sources of the pre-solar material. Here we report that the molybdenum isotopic composition of bulk carbonaceous chondrites is distinctly different from the accepted average solar value. We show that the Mo data require the presence of material produced in at least two different r-processes, and that the contribution from the p-process material is decoupled from the r-process, all occurring in supernova explosions. This is consistent with the emerging picture of diverse sources inferred from short-lived isotopes in the early Solar System and elemental analyses of metal-poor stars.

Journal Article↗
PubMed2006

Bathymetric and geographic population structure in the pan-Atlantic deep-sea bivalve Deminucula atacellana (Schenck, 1939).

The deep-sea soft-sediment environment hosts a diverse and highly endemic fauna of uncertain origin. We know little about how this fauna evolved because geographic patterns of genetic variation, the essential information for inferring patterns of population differentiation and speciation are poorly understood. Using formalin-fixed specimens from archival collections, we quantify patterns of genetic variation in the protobranch bivalve Deminucula atacellana, a species widespread throughout the Atlantic Ocean at bathyal and abyssal depths. Samples were taken from 18 localities in the North American, West European and Argentine basins. A hypervariable region of mitochondrial 16S rDNA was amplified by polymerase chain reaction (PCR) and sequenced from 130 individuals revealing 21 haplotypes. Except for several important exceptions, haplotypes are unique to each basin. Overall gene diversity is high (h = 0.73) with pronounced population structure (Phi(ST) = 0.877) and highly significant geographic associations (P < 0.0001). Sequences cluster into four major clades corresponding to differences in geography and depth. Genetic divergence was much greater among populations at different depths within the same basin, than among those at similar depths but separated by thousands of kilometres. Isolation by distance probably explains much of the interbasin variation. Depth-related divergence may reflect historical patterns of colonization or strong environmental selective gradients. Broadly distributed deep-sea organisms can possess highly genetically divergent populations, despite the lack of any morphological divergence.

Animals↗
PubMed1997

Testing homogeneity of intra-run variance parameters in immunoassay.

A common assumption in the analysis of immunoassay data is a similar pattern of within-run variation across runs of the assays. One makes this assumption without formal investigation of its validity, despite the widely acknowledged fact that accurate understanding of intra-run variation is critical to reliable calibration inference. We propose a simple procedure for a formal test of the assumption of the homogeneity of parameters that characterize intra-run variation based on representation of standard curve data from multiple assay runs by a non-linear mixed effects model. We examine the performance of the procedure and investigate the robustness of calibration inference to incorrect assumptions about the pattern of intra-run variation.

Calibration↗
PubMed2000

Changes in deep-water formation during the Younger Dryas event inferred from 10Be and 14C records.

Variations in atmospheric radiocarbon (14C) concentrations can be attributed either to changes in the carbon cycle--through the rate of radiocarbon removal from the atmosphere--or to variations in the production rate of 14C due to changes in solar activity or the Earth's magnetic field. The production rates of 10Be and 14C vary in the same way, but whereas atmospheric radiocarbon concentrations are additionally affected by the carbon cycle, 10Be concentrations reflect production rates more directly. A record of the 10Be production-rate variations can therefore be used to separate the two influences--production rates and the carbon cycle--on radiocarbon concentrations. Here we present such an analysis of the large fluctuations in atmospheric 14C concentrations, of unclear origin, that occurred during the Younger Dryas cold period. We use the 10Be record from the GISP2 ice core to model past production rates of radionuclides, and find that the largest part of the fluctuations in atmospheric radiocarbon concentrations can be attributed to variations in production rate. The residual difference between measured 14C concentrations and those modelled using the 10Be record can be explained with an additional change in the carbon cycle, most probably in the amount of deep-water formation.

Journal Article↗
PubMed2000

Inferring the location and effect of tumor suppressor genes by instability-selection modeling of allelic-loss data.

Cancerous tumor growth creates cells with abnormal DNA. Allelic-loss experiments identify genomic deletions in cancer cells, but sources of variation and intrinsic dependencies complicate inference about the location and effect of suppressor genes; such genes are the target of these experiments and are thought to be involved in tumor development. We investigate properties of an instability-selection model of allelic-loss data, including likelihood-based parameter estimation and hypothesis testing. By considering a special complete-data case, we derive an approximate calibration method for hypothesis tests of sporadic deletion. Parametric bootstrap and Bayesian computations are also developed. Data from three allelic-loss studies are reanalyzed to illustrate the methods.

Adenocarcinoma↗
PubMed1993

DNA sequence variation and phylogenetic relationships among strains of Pseudomonas syringae pv. syringae inferred from restriction site maps and restriction fragment length polymorphism.

We evaluated the restriction fragment length polymorphism of genomic DNA among 53 strains of the phytopathogenic bacterium Pseudomonas syringae pv. syringae. Twenty-nine strains were isolated from beans, and the rest were isolated from 11 other hosts. Southern blots of DNA digested with EcoRI or HindIII were hybridized to two random probes from a cosmid library of P. syringae pv. syringae and a hrp (hypersensitive reaction and pathogenicity) cluster cloned from P. syringae pv. syringae. The size of hybridizing fragments was determined, and a similarity matrix was constructed by comparing strains on a pairwise basis for the presence or absence of fragments. The proportion of shared fragments was then used to estimate sequence divergence. Dendrograms were produced by using the unweighted pair group method with averages and the neighbor-joining method. For the hrp region, BamHI, EcoRI, EcoRV, and HindIII restriction sites were mapped for six representative bean strains and used to construct EcoRI and HindIII restriction maps for all 30 strains pathogenic on beans. Restriction mapping revealed the presence of a 3-kb insertion in nine bean strains and a probable second insertion or deletion event on the left-hand side of the hrp cluster that biased estimates of nucleotide sequence divergence from fragment comparisons. This demonstrated that the determination of phylogenetic relationships among bacteria by using restriction fragment length polymorphism data requires mapping restriction sites to remove the effect of insertion or deletion events on the analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

DNA, Bacterial↗
PubMed1996

Migration and evolution of lesser long-nosed bats Leptonycteris curasoae, inferred from mitochondrial DNA.

We used sequence variation within 297 bp of control region mitochondrial DNA (mtDNA) amplified from 53 lesser long-nosed bats, Leptonycteris curasoae (Phyllostomidae: Glossophaginae) captured at 13 locations in south-western United States and Mexico and one site in Venezuela to infer population structure and possible migration routes of this endangered nectar- and fruit-eating species. Phylogenetic analysis using maximum parsimony and UPGMA confirmed species and subspecies distinctions within Leptonycteris and revealed two clades exhibiting 3% sequence divergence within the Mexican subspecies, L. c. yerbabuenae. Even though many roots contained L. c. yerbabuenae from both clades, weak population structure was detected both by a correlation between genetic differentiation, F(st), and geographical distance and by a cladistic estimate of the number of migration events required to align bat sequences with geographical location on maximum parsimony, as compared to random, trees. Three results suggest that L. c. yerbabuenae are more likely to migrate between sites along the Pacific coast of Mexico or along the foothills of the Sierra Madre Occidental than between these regions. (1) Seventeen of 20 bats which shared an identical sequence were captured up to 1800 km apart but within the same putative migration corridor. (2) Residuals from a regression of F(st) on distance were greater between than within these regions. (3) Fewer migration events were required to align bats with these two groups than expected from random assignment. We recommend analysing independent genetic data and monitoring bat visitation to roost sites during migration to confirm these postulated movements.

Animals↗
PubMed2005

Genetic diversity among barley cultivars assessed by sequence-specific amplification polymorphism.

We analyzed the genetic structure and relationships among barley cultivars (Hordeum vulgare L.) with sequence-specific amplification polymorphisms (S-SAPs). Polymorphisms were identified in 824 individual barley plants representing 103 cultivars (eight plants per cultivar) widely grown in Canada and the United States, using PCR primers designed from the long terminal repeat of the barley retrotransposon BARE-1 and a subset of four selective MseI primers. From the 404 bands scored, 150 were polymorphic either within or between cultivars. Genetic structure assessed with analysis of molecular variance attributed the largest component of variation to the within groups of cultivars (69-86%). Within-cultivar genetic variation was estimated as average gene diversity over loci and ranged from 0 (completely homogenous) to 0.076 (most heterogeneous cultivar). Only 17 out of 103 cultivars (16%) were judged to be homogenous by this criterion. Relationships among cultivars were analyzed by cluster analysis using unweighted pair-groups using arithmetic averages and found groups similar to those determined by agriculturally significant phenotypic traits such as spike morphology (two-rowed or six-rowed), cultivar type (malting or feed), seed characteristic (hull-less or hulled), and growth habit (winter or spring), with minor overlaps. Discriminant analysis of groups determined by these phenotypic traits fully supported the different groups with minor overlaps between the malting/feed. S-SAP markers generated from retrotransposons such as BARE-1 are invaluable tools for the study of genetic diversity in organisms with a narrow genetic base such as barley. In this study, S-SAP analysis revealed significant amounts of cryptic variation in closely related cultivars including somaclonal variation, which could not be inferred by the pedigree analysis.

Analysis of Variance↗
PubMed2003

A software package for cDNA microarray data normalization and assessing confidence intervals.

DNA microarray data are affected by variations from a number of sources. Before these data can be used to infer biological information, the extent of these variations must be assessed. Here we describe an open source software package, lcDNA, that provides tools for filtering, normalizing, and assessing the statistical significance of cDNA microarray data. The program employs a hierarchical Bayesian model and Markov Chain Monte Carlo simulation to estimate gene-specific confidence intervals for each gene in a cDNA microarray data set. This program is designed to perform these primary analytical operations on data from two-channel spotted, or in situ synthesized, DNA microarrays.

Bayes Theorem↗
PubMed2004

Evolution of the RNA polymerase B' subunit gene (rpoB') in Halobacteriales: a complementary molecular marker to the SSU rRNA gene.

Many prokaryotes have multiple ribosomal RNA operons. Generally, sequence differences between small subunit (SSU) rRNA genes are minor (<1%) and cause little concern for phylogenetic inference or environmental diversity studies. For Halobacteriales, an order of extremely halophilic, aerobic Archaea, within-genome SSU rRNA sequence divergence can exceed 5%, rendering phylogenetic assignment problematic. The RNA polymerase B' subunit gene (rpoB') is a single-copy conserved gene that may be an appropriate alternative phylogenetic marker for Halobacteriales. We sequenced a fragment of the rpoB' gene from 21 species, encompassing 15 genera of Halobacteriales. To examine the utility of rpoB' as a phylogenetic marker in Halobacteriales, we investigated three properties of rpoB' trees: the variation in resolution between trees inferred from the rpoB' DNA and RpoB' protein alignment, the degree of mutational saturation between taxa, and congruence with the SSU rRNA tree. The rpoB' DNA and protein trees were for the most part congruent and consistently recovered two well-supported monophyletic groups, the clade I and clade II haloarchaea, within a collection of less well resolved Halobacteriales lineages. A comparison of observed versus inferred numbers of substitution revealed mutational saturation in the rpoB' DNA data set, particularly between more distant species. Thus, the RpoB' protein sequence may be more reliable than the rpoB' DNA sequence for inferring Halobacteriales phylogeny. AU tests of tree selection indicated the trees inferred from rpoB' DNA and protein alignments were significantly incongruent with the SSU rRNA tree. We discuss possible explanations for this incongruence, including tree reconstruction artifact, differential paralog sampling, and lateral gene transfer. This is the first study of Halobacteriales evolution based on a marker other than the SSU rRNA gene. In addition, we present a valuable phylogenetic framework encompassing a broad diversity of Halobacteriales, in which novel sequences can be inserted for evolutionary, ecological, or taxonomic investigations.

Base Sequence↗
PubMed2001

Identifying main evolutionary mechanisms shaping genetic variation of Leuciscus cephalus L. 1758 (Cyprinidae) in western Greece: discordance between methods.

Numerous methods can be used in intraspecific phylogeographic studies to infer the evolutionary mechanisms that shaped observed genetic variation in populations. However, these methods are scarcely used jointly, and the evolutionary outcomes they could propose are not fully compared. In this study, using a chub (Leuciscus cephalus; Cyprinidae) mitochondrial DNA data set (13 populations in Western Greece, 14 haplotypes), we compare three distinct 'historical' methods that could possibly infer relative importance of basic evolutionary mechanisms (isolation vs migration) shaping genetic variation: the nested clade analysis, the psi-test and the 'mismatch distributions'. Taking together, interpretations of these analyses allow to draw a picture of the evolutionary history of chub in Western Greece based on isolation and genetic drift for higher clades. However, results issued each method can differ for low differentiated clades. We discuss such differences and suggest that methods should be used jointly in phylogeographic studies for a better evaluation of the evolutionary mechanisms that shaped genetic variation.

Animals↗