Seeing It, Knowing It

In When Obscenity Discriminates, I argued that the First Amendment’s obscenity doctrine has generated discriminatory collateral effects against gays and lesbians, and that those collateral effects generate a need to refine the obscenity doctrine in light of the Supreme Court’s decision in Lawrence v. Texas. In his response, If Obscenity Were to Discriminate, Professor Barry McDonald agrees with my essay’s “core insight—that the Miller obscenity test should be applied in a manner that is neutral as to the sexual orientation of the pertinent actors,” and notes that this insight “appears to have substantial support in basic principles of the Court’s equal protection and First Amendment jurisprudence.” McDonald builds from that “core insight” by “tak[ing] the liberty of recasting these arguments as more modest claims that the obscenity doctrine needs to be modified in light of Lawrence in order to achieve a principled and coherent constitutional jurisprudence as it relates to the Court’s treatment of gay sex.” However, the “more modest claim[]” that McDonald purports to make is, in fact, the claim made in my essay, namely, to “refin[e]—but not overturn[]—the obscenity test set forth in Miller” so that it distinguishes between sex and sexual orientation. Thus, despite Professor McDonald’s perception to the contrary, he and I are in closer agreement about the doctrine’s needed changes. On some points, however, we do divide, and our division derives from two sources. First, and most fundamentally, we disagree about how to measure doctrinal effect. Although McDonald and I agree that the obscenity doctrine should not be applied in a way that is biased toward homosexual content, he and I part ways on the issue of determining when to measure the effects of a biased obscenity test. For McDonald, unless and until the obscenity test is applied in a court of law in a biased manner—that is, unless and until a work which would not constitute obscenity but for its homosexual content is held to be unprotected—the obscenity test has not generated any discriminatory effect. This source of disagreement is fundamental because it divides McDonald and me on the question of implementation and, ultimately, on whether the obscenity doctrine merits refinement. To McDonald, the obscenity doctrine is fine as is unless and until it is misapplied in court; I believe, on the other hand, that the doctrine’s discriminatory effects are inherent to the test used and thus the doctrine merits refinement even absent “misapplication” in court. Part II of this Reply responds to McDonald’s objections that derive from our disagreement on measuring doctrinal effect

Hepatic metabolite profiling of polychlorinated biphenyl (PCB)-resistant and sensitive populations of Atlantic killifish (Fundulus heteroclitus)

Author Posting. © The Author(s), 2018. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in Aquatic Toxicology (2018), doi:10.1016/j.aquatox.2018.10.007.Atlantic killifish inhabiting polluted sites along the east coast of the U.S. have evolved resistance to toxic effects of contaminants. One such contaminated site is the Acushnet River estuary, near New Bedford Harbor (NBH), Massachusetts, which is characterized by very high PCB concentrations in the sediments and in the tissues of resident killifish. Though killifish at this site appear to be thriving, the metabolic costs of survival in a highly contaminated environment are not well understood. In this study we compared the hepatic metabolite profiles of resistant (NBH) and sensitive populations (Scorton Creek (SC), Sandwich, MA) using a targeted metabolomics approach in which polar metabolites were extracted from adult fish livers and quantified. Our results revealed differences in the levels of several metabolites between fish from the two sites. The majority of these metabolites are associated with one-carbon metabolism, an important pathway that supports multiple physiological processes including DNA and protein methylation, nucleic acid biosynthesis and amino acid metabolism. We measured the gene expression of DNA methylation (DNA methyltransferase 1, dnmt1) and demethylation genes (Ten-Eleven Translocation (TET) genes) in the two populations, and observed lower levels of dnmt1 and higher levels of TET gene expression in the NBH livers, suggesting possible differences in DNA methylation profiles. Consistent with this, the two populations differed significantly in the levels of 5-methylcytosine and 5-hydroxymethylcytosine nucleotides. Overall, our results suggest that the unique hepatic metabolite signatures observed in NBH and SC reflect the adaptive mechanisms for survival in their respective habitats.This work was supported by the Joint Initiative Awards Fund from the Andrew W. Mellon Foundation (NA and EBK) and National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program (P42ES007381) at Boston University. LG was supported by the Postdoctoral Scholar Program at the Woods Hole Oceanographic Institution (with funding provided by the Townsend Postdoctoral Scholarship Fund, and the John H. Steele Endowment in support of Postdoctoral Research)

Bringing Upstairs Care Downstairs; Integration of Rehabilitation Medicine, Care Management, and the Hospital Elder Life Program (HELP) into an Emergency Department.

Introduction: Services such as physical therapy (PT), occupational therapy (OT), speech-language pathology (SLP), social work (SW), care management, and elder life specialists have long been an established part of care for patients admitted to Maine Medical Center (MMC) but not for patients in the Emergency Department (ED). Methods and Results: Driven in part by changes in Medicare reimbursement models, care management established a presence in the Emergency Department (ED) in 2003 with a focus on care planning and cost avoidance. In recent years PT, OT, SLP, SW, and the Hospital Elder Life Program (HELP) have increased their ED involvement substantially. These services not only support care management decisions but have become an invaluable part of the ED team. The timing, staffing models, and roles of these services in our emergency department are described. Discussion: There was strong leadership support to create these positions in the ED. Increased patient volume hospital wide has required staffing flexibility. Initial concerns for slowing the ED where anecdotally resolved. Other hospitals in our system are interested in this approach. Conclusions: While the value of this work feels self-evident and is already established for admitted patients, descriptive and outcome-oriented studies for ED patients would be enlightening

Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Genome-Wide Association Study of Retinopathy in Individuals without Diabetes

10.1371/journal.pone.0054232PLoS ONE82

Genetic loci for retinal arteriolar microcirculation.

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4-2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in genera