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Background Liquid biopsy assays using cerebrospinal fluid (CSF) can revolutionize care for children with central nervous system (CNS) tumors by enabling precise monitoring of therapeutic responses and detecting recurrence or measurable residual disease (MRD). These assays can detect cell-free, circulating tumor DNA (ctDNA) via somatic alterations, though accurately measuring low-abundance ctDNA in CSF is challenging. Methods Our research focused on the optimization of next-generation sequencing library preparation from cell-free DNA (cfDNA), evaluating four commercial kits to address the low nucleic acid yield in CSF-derived cfDNA. The selected kit minimized false positives and detected somatic variants at 5% variant allele frequency using 0.1 ng input of synthetic cfDNA, suitable for low-volume CSF samples. Results We then applied our optimized workflow to six children with CNS tumors using a personalized hybrid-capture sequencing strategy (“MRD4U”), in which individualized panels were designed based on each patient’s tumor sequencing. Using MRD4U, we identified ctDNA in two samples, even though neither patient had radiographic or clinical evidence of disease at the time of liquid biopsy. Notably, one ctDNA-positive patient developed radiographic recurrence four months later, demonstrating the assay’s potential to detect molecular relapse ahead of conventional clinical measures. Conclusions These findings demonstrate applicability of our personalized MRD4U assay in early detection of disease recurrence. Unlike non-targeted or tumor-agnostic CSF liquid biopsy approaches, MRD4U leverages patient-specific genomic information to enable sensitive, tumor-informed monitoring that can be deployed across a wide range of pediatric CNS tumors. Our approach is broadly applicable to any tumor type with existing genomic data, enabling ctDNA detection across diverse diagnoses. Ultimately, this strategy may inform clinical decision-making and enable earlier therapeutic intervention.

Microsatellites occur in all plant genomes and provide useful markers for studies of genetic diversity and structure. Chloroplast microsatellites (cpSSRs) are frequently targeted because they are more easily isolated than nuclear microsatellites. Here, we quantified the frequency and uses of cpSSRs based on a literature review of over 400 studies published 1995–2013. These markers are an important and economical tool for plant biologists and continue to be used alongside modern genomics approaches to study genetic diversity and structure, evolutionary history, and hybridization in native and agricultural species. Studies using species-specific primers reported a greater number of polymorphic loci than those employing universal primers. A major disadvantage to cpSSRs is fragment size homoplasy; therefore, we documented its occurrence at several cpSSR loci within and between species of Acmispon (Fabaceae). Based on our empirical data set, we recommend targeted sequencing of a subset of samples combined with fragment genotyping as a cost-efficient, data-rich approach to the use of cpSSRs and as a test of homoplasy. The availability of genomic resources for plants aids in the development of primers for new study systems, thereby enhancing the utility of cpSSRs across plant biology.

Carnivorous plants are striking examples of evolutionary convergence, displaying complex and often highly similar adaptations despite lack of shared ancestry. Using available carnivorous plant genomes along with non-carnivorous reference taxa, this study examines the convergence of functional overrepresentation of genes previously implicated in plant carnivory. Gene Ontology (GO) coding was used to quantitatively score functional representation in these taxa, in terms of proportion of carnivory-associated functions relative to all functional sequence. Statistical analysis revealed that, in carnivorous plants as a group, only two of the 24 functions tested showed a signal of substantial overrepresentation. However, when the four carnivorous taxa were analyzed individually, 11 functions were found to be significant in at least one taxon. Though carnivorous plants collectively may show overrepresentation in functions from the predicted set, the specific functions that are overrepresented vary substantially from taxon to taxon. While it is possible that some functions serve a similar practical purpose such that one taxon does not need to utilize both to achieve the same result, it appears that there are multiple approaches for the evolution of carnivorous function in plant genomes. Our approach could be applied to tests of functional convergence in other systems provided on the availability of genomes and annotation data for a group.

Mutations that provide environment-dependent selective advantages drive adaptive divergence among species. Many phenotypic differences among related species are more likely to result from gene expression divergence rather than from non-synonymous mutations. In this regard, cis-regulatory mutations play an important part in generating functionally significant variation. Some proposed mechanisms that explore the role of cis-regulatory mutations in gene expression divergence involve microsatellites. Microsatellites exhibit high mutation rates achieved through symmetric or asymmetric mutation processes and are abundant in both coding and non-coding regions in positions that could influence gene function and products. Here we tested the hypothesis that microsatellites contribute to gene expression divergence among species with 50 individuals from five closely related Helianthus species using an RNA-seq approach. Differential expression analyses of the transcriptomes revealed that genes containing microsatellites in non-coding regions (UTRs and introns) are more likely to be differentially expressed among species when compared to genes with microsatellites in the coding regions and transcripts lacking microsatellites. We detected a greater proportion of shared microsatellites in 5′UTRs and coding regions compared to 3′UTRs and non-coding transcripts among Helianthus spp. Furthermore, allele frequency differences measured by pairwise FST at single nucleotide polymorphisms (SNPs), indicate greater genetic divergence in transcripts containing microsatellites compared to those lacking microsatellites. A gene ontology (GO) analysis revealed that microsatellite-containing differentially expressed genes are significantly enriched for GO terms associated with regulation of transcription and transcription factor activity. Collectively, our study provides compelling evidence to support the role of microsatellites in gene expression divergence.

PREMISE OF THE STUDY: Taxa inhabiting the California Channel Islands exhibit variation in their degree of isolation, but few studies have considered patterns across the entire archipelago. We studied phylogeography of insular Acmispon argophyllus and A. dendroideus to determine whether infraspecific taxa are genetically divergent and to elucidate patterns of diversification across these islands. METHODS: DNA sequences were collected from nuclear (ADH) and plastid genomes (rpL16, ndhA, psbD‐trnT) from >450 samples on the Channel Islands and California. We estimated population genetic diversity and structure, phylogenetic patterns among populations, and migration rates, and tested for population growth. KEY RESULTS: Populations of northern island A. argophyllus var. niveus are genetically distinct from conspecific populations on southern islands. On the southern islands, A. argophyllus var. argenteus populations on Santa Catalina are phylogenetically distinct from populations of var. argenteus and var. adsurgens on the other southern islands. For A. dendroideus, we found the varieties to be monophyletic. Populations of A. dendroideus var. traskiae on San Clemente are genetically differentiated from other conspecific populations, whereas populations on the northern islands and Santa Catalina show varying degrees of gene flow. Evidence of population growth was found in both species. CONCLUSIONS: Oceanic barriers between islands have had a strong influence on population genetic structure in both Acmispon species, although the species have differing phylogeographic patterns. This study provides a contrasting pattern of dispersal on a near island system that does not follow a strict stepping‐stone model, commonly found on isolated island systems.

• Premise of the study: To estimate genetic structure, chloroplast loci containing length-variable regions were developed for two legumes, Acmispon argophyllus and A. dendroideus.• Methods and Results: Primers for 14 chloroplast loci containing repeat regions were developed from the chloroplast genome sequence of the legume Lotus japonicus and tested in Acmispon. Nine loci exhibited polymorphism in Acmispon, with up to six alleles per locus. Gene diversity ranged from 0 to 0.775 in A. argophyllus and 0.142 to 0.766 in A. dendroideus. The primers also amplified in other Acmispon species. Sequencing of the fragments revealed discordance between fragment sizes and underlying sequence for three loci containing complex repeat regions.• Conclusions: Although genotypes were easily generated and sized, sequencing may be more informative of genetic variation in loci with complex repeat regions. These loci exhibit substantial variation and should be useful for understanding genetic structure associated with seed dispersal in Acmispon.

The AURORA US Metastasis Project was established with the goal to identify molecular features associated with metastasis. We assayed 55 females with metastatic breast cancer (51 primary cancers and 102 metastases) by RNA sequencing, tumor/germline DNA exome and low-pass whole-genome sequencing and global DNA methylation microarrays. Expression subtype changes were observed in ~30% of samples and were coincident with DNA clonality shifts, especially involving HER2. Downregulation of estrogen receptor (ER)-mediated cell–cell adhesion genes through DNA methylation mechanisms was observed in metastases. Microenvironment differences varied according to tumor subtype; the ER + /luminal subtype had lower fibroblast and endothelial content, while triple-negative breast cancer/basal metastases showed a decrease in B and T cells. In 17% of metastases, DNA hypermethylation and/or focal deletions were identified near HLA-A and were associated with reduced expression and lower immune cell infiltrates, especially in brain and liver metastases. These findings could have implications for treating individuals with metastatic breast cancer with immune- and HER2-targeting therapies.

Microsatellites are common in most species. While an adaptive role for these highly mutable regions has been considered, little is known concerning their contribution towards phenotypic variation. We used populations of the common sunflower (Helianthus annuus) at two latitudes to quantify the effect of microsatellite allele length on phenotype at the level of gene expression. We conducted a common garden experiment with seed collected from sunflower populations in Kansas and Oklahoma followed by an RNA-Seq experiment on 95 individuals. The effect of microsatellite allele length on gene expression was assessed across 3325 microsatellites that could be consistently scored. Our study revealed 479 microsatellites at which allele length significantly correlates with gene expression (eSTRs). When irregular allele sizes not conforming to the motif length were removed, the number of eSTRs rose to 2379. The percentage of variation in gene expression explained by eSTRs ranged from 1 - 86% when controlling for population and allele-by-population interaction effects at the 479 eSTRs. Of these, 70.4% are in untranslated regions (UTRs). A Gene Ontology (GO) analysis revealed that eSTRs are significantly enriched for GO terms associated with cis- and trans-regulatory processes. These findings suggest that a substantial number of transcribed microsatellites can influence gene expression.

Nature underpins human well-being in critical ways, especially in health. Nature provides pollination of nutritious crops, purification of drinking water, protection from floods, and climate security, among other well-studied health benefits. A crucial, yet challenging, research frontier is clarifying how nature promotes physical activity for its many mental and physical health benefits, particularly in densely populated cities with scarce and dwindling access to nature. Here we frame this frontier by conceptually developing a spatial decision-support tool that shows where, how, and for whom urban nature promotes physical activity, to inform urban greening efforts and broader health assessments. We synthesize what is known, present a model framework, and detail the model steps and data needs that can yield generalizable spatial models and an effective tool for assessing the urban nature–physical activity relationship. Current knowledge supports an initial model that can distinguish broad trends and enrich urban planning, spatial policy, and public health decisions. New, iterative research and application will reveal the importance of different types of urban nature, the different subpopulations who will benefit from it, and nature’s potential contribution to creating more equitable, green, livable cities with active inhabitants.

Thiazolidinedione (TZD) insulin sensitizers have the potential to effectively treat a number of human diseases, however the currently available agents have dose-limiting side effects that are mediated via activation of the transcription factor PPARγ. We have recently shown PPARγ-independent actions of TZD insulin sensitizers, but the molecular target of these molecules remained to be identified. Here we use a photo-catalyzable drug analog probe and mass spectrometry-based proteomics to identify a previously uncharacterized mitochondrial complex that specifically recognizes TZDs. These studies identify two well-conserved proteins previously known as brain protein 44 (BRP44) and BRP44 Like (BRP44L), which recently have been renamed Mpc2 and Mpc1 to signify their function as a mitochondrial pyruvate carrier complex. Knockdown of Mpc1 or Mpc2 in Drosophila melanogaster or pre-incubation with UK5099, an inhibitor of pyruvate transport, blocks the crosslinking of mitochondrial membranes by the TZD probe. Knockdown of these proteins in Drosophila also led to increased hemolymph glucose and blocked drug action. In isolated brown adipose tissue (BAT) cells, MSDC-0602, a PPARγ-sparing TZD, altered the incorporation of (13)C-labeled carbon from glucose into acetyl CoA. These results identify Mpc1 and Mpc2 as components of the mitochondrial target of TZDs (mTOT) and suggest that understanding the modulation of this complex, which appears to regulate pyruvate entry into the mitochondria, may provide a viable target for insulin sensitizing pharmacology.