GDF15 is a dynamic biomarker of the integrated stress response in the central nervous system.

Aim: Characterize Growth Differentiation Factor 15 (GDF15) as a secreted biomarker of the integrated stress response (ISR) within the central nervous system (CNS).

Methods: We determined GDF15 levels utilizing in vitro and in vivo neuronal systems wherein the ISR was activated. Primarily, we used the murine model of vanishing white matter disease (VWMD), a neurological disease driven by persistent ISR in the CNS, to establish a link between levels of GDF15 in the cerebrospinal fluid (CSF) and ISR gene expression signature in the CNS.

Temporal Patterns of Behavioral and Psychological Symptoms of Dementia and Caregiver Distress: Associated Daily and Individual Factors.

This study examined daily occurrences of behavioral and psychological symptoms of dementia (BPSD) and whether caregivers' perceived distress towards BPSD varies throughout four phases of the day (i.e., morning, daytime, evening, and night).

PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPr (Ptgfr) are implicated as a TGF-β1-independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER-SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene.

Disruption of Prostaglandin F Receptor Signaling Attenuates Fibrotic Remodeling and Alters Fibroblast Population Dynamics in A Preclinical Murine Model of Idiopathic Pulmonary Fibrosis.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2, and its cognate receptor FPr () are implicated as a TGF1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (I - ) expressing a disease-associated missense mutation in the surfactant protein C () gene.

Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients.

Colorectal cancer (CRC) is increasingly appreciated as a heterogeneous disease, with factors such as microsatellite instability (MSI), cancer subsite within the colon versus rectum, and age of diagnosis associated with specific disease course and therapeutic response. Activating oncogenic mutations in KRAS and NRAS are common in CRC, driving tumor progression and influencing efficacy of both cytotoxic and targeted therapies. The RAS mutational spectrum differs substantially between tumors arising from distinct tissues.

Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer.

Purpose: The incidence rates of colorectal cancers are increasing in young adults. The objective of this study was to investigate genomic differences between tumor samples collected from younger and older patients with colorectal cancer.

Experimental Design: DNA was extracted from 18,218 clinical specimens, followed by hybridization capture of 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer.

Prevalence of PDL1 Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors.

Importance: Copy number alterations in programmed cell death ligand 1 (PDL1 or CD274), programmed cell death 1 ligand 2 (PDCD1LG2 or PDL2), and Janus kinase 2 (JAK2) genes (chromosome 9p24.1) characterize Hodgkin lymphoma, resulting in high response rates to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade. The prevalence and utility of PDL1 amplification as a response biomarker to PD-1/PD-L1 blockade are unknown in other tumors.

A synthetic biology approach to probing nucleosome symmetry.

The repeating subunit of chromatin, the nucleosome, includes two copies of each of the four core histones, and several recent studies have reported that asymmetrically-modified nucleosomes occur at regulatory elements in vivo. To probe the mechanisms by which histone modifications are read out, we designed an obligate pair of H3 heterodimers, termed H3X and H3Y, which we extensively validated genetically and biochemically. Comparing the effects of asymmetric histone tail point mutants with those of symmetric double mutants revealed that a single methylated H3K36 per nucleosome was sufficient to silence cryptic transcription in vivo.

Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.

Background: High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types.

Methods: In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome.

Evolution and genetic architecture of chromatin accessibility and function in yeast.

Chromatin accessibility is an important functional genomics phenotype that influences transcription factor binding and gene expression. Genome-scale technologies allow chromatin accessibility to be mapped with high-resolution, facilitating detailed analyses into the genetic architecture and evolution of chromatin structure within and between species. We performed Formaldehyde-Assisted Isolation of Regulatory Elements sequencing (FAIRE-Seq) to map chromatin accessibility in two parental haploid yeast species, Saccharomyces cerevisiae and Saccharomyces paradoxus and their diploid hybrid.

Integrative phenomics reveals insight into the structure of phenotypic diversity in budding yeast.

To better understand the quantitative characteristics and structure of phenotypic diversity, we measured over 14,000 transcript, protein, metabolite, and morphological traits in 22 genetically diverse strains of Saccharomyces cerevisiae. More than 50% of all measured traits varied significantly across strains [false discovery rate (FDR) = 5%]. The structure of phenotypic correlations is complex, with 85% of all traits significantly correlated with at least one other phenotype (median = 6, maximum = 328).

Population genomics and transcriptional consequences of regulatory motif variation in globally diverse Saccharomyces cerevisiae strains.

Noncoding genetic variation is known to significantly influence gene expression levels in a growing number of specific cases; however, the patterns of genome-wide noncoding variation present within populations, the evolutionary forces acting on noncoding variants, and the relative effects of regulatory polymorphisms on transcript abundance are not well characterized. Here, we address these questions by analyzing patterns of regulatory variation in motifs for 177 DNA binding proteins in 37 strains of Saccharomyces cerevisiae. Between S.

On the prospects of whole-genome association mapping in Saccharomyces cerevisiae.

Advances in sequencing technology have enabled whole-genome sequences to be obtained from multiple individuals within species, particularly in model organisms with compact genomes. For example, 36 genome sequences of Saccharomyces cerevisiae are now publicly available, and SNP data are available for even larger collections of strains. One potential use of these resources is mapping the genetic basis of phenotypic variation through genome-wide association (GWA) studies, with the benefit that associated variants can be studied experimentally with greater ease than in outbred populations such as humans.

Clusters of adaptive evolution in the human genome.

Considerable work has been devoted to identifying regions of the human genome that have been subjected to recent positive selection. Although detailed follow-up studies of putatively selected regions are critical for a deeper understanding of human evolutionary history, such studies have received comparably less attention. Recently, we have shown that ALMS1 has been the target of recent positive selection acting on standing variation in Eurasian populations.

Highly punctuated patterns of population structure on the X chromosome and implications for African evolutionary history.

It is well known that average levels of population structure are higher on the X chromosome compared to autosomes in humans. However, there have been surprisingly few analyses on the spatial distribution of population structure along the X chromosome. With publicly available data from the HapMap Project and Perlegen Sciences, we show a strikingly punctuated pattern of X chromosome population structure.

Tracking footprints of artificial selection in the dog genome.

The size, shape, and behavior of the modern domesticated dog has been sculpted by artificial selection for at least 14,000 years. The genetic substrates of selective breeding, however, remain largely unknown. Here, we describe a genome-wide scan for selection in 275 dogs from 10 phenotypically diverse breeds that were genotyped for over 21,000 autosomal SNPs.

An ortholog of MIXTA-like2 controls epidermal cell shape in flowers of Thalictrum.

Here, we investigated the genetic underpinnings of pollination-related floral phenotypes in Thalictrum, a ranunculid with apetalous flowers. The variable presence of petaloid features in other floral organs correlates with distinct adaptations to insect vs. wind pollination.

Population genomic analysis of ALMS1 in humans reveals a surprisingly complex evolutionary history.

Mutations in the human gene ALMS1 result in Alström Syndrome, which presents with early childhood obesity and insulin resistance leading to Type 2 diabetes. Previous genomewide scans for selection in the HapMap data based on linkage disequilibrium and population structure suggest that ALMS1 was subject to recent positive selection. Through a detailed population genomic analysis of existing genomewide data sets and new resequencing data obtained in geographically diverse populations, we find that the signature of selection at ALMS1 is considerably more complex than what would be expected for an idealized model of a selective sweep acting on a newly arisen advantageous mutation.

Population genomics of intron splicing in 38 Saccharomyces cerevisiae genome sequences.

Introns are a ubiquitous feature of eukaryotic genomes, and the dynamics of intron evolution between species has been extensively studied. However, comparatively few analyses have focused on the evolutionary forces shaping patterns of intron variation within species. To better understand the population genetic characteristics of introns, we performed an extensive population genetics analysis on key intron splice sequences obtained from 38 strains of Saccharomyces cerevisiae.