Community Voices: Lessons for National Health Policy

Highlights successful models that were designed to improve access to health care for vulnerable populations, describes ways that government can support local communities, and emphasizes the need for fundamental reform of the U.S. healthcare system

Genomic and transcriptomic signals of thermal tolerance in heat-tolerant corals (Platygyra daedalea) of the Arabian/Persian Gulf

© 2018 John Wiley & Sons Ltd Scleractinian corals occur in tropical regions near their upper thermal limits and are severely threatened by rising ocean temperatures. However, several recent studies have shown coral populations can harbour genetic variation in thermal tolerance. Here, we have extended these approaches to study heat tolerance of corals in the Persian/Arabian Gulf, where heat-tolerant local populations experience extreme summer temperatures (up to 36°C). To evaluate whether selection has depleted genetic variation in thermal tolerance, estimate potential future adaptive responses and understand the functional basis for these corals’ unusual heat tolerance, we conducted controlled crosses in the Gulf coral Platygyra daedalea. Heat tolerance is highly heritable in this population (h 2 = 0.487–0.748), suggesting substantial potential for adaptive responses to selection for elevated temperatures. To identify genetic markers associated with this variation, we conducted genomewide SNP genotyping in parental corals and tested for relationships between paternal genotype and offspring thermal tolerance. Resulting multilocus SNP genotypes explained a large fraction of variation in thermal tolerance in these crosses (69%). To investigate the functional basis of these differences in thermal tolerance, we profiled transcriptional responses in tolerant and susceptible families, revealing substantial sire effects on transcriptional responses to thermal stress. We also studied sequence variation in these expressed sequences, identifying alleles and functional groups of differentially expressed genes associated with thermal tolerance. Our findings demonstrate that corals in this population harbour extensive genetic variation in thermal tolerance, and heat-tolerant phenotypes differ in both gene sequences and transcriptional stress responses from their susceptible counterparts

Enhancing the heat tolerance of reef-building corals to future warming

Reef-building corals thriving in extreme thermal environments may provide genetic variation that can assist the evolution of populations to rapid climate warming. However, the feasibility and scale of genetic improvements remain untested despite ongoing population declines from recurrent thermal stress events. Here, we show that corals from the hottest reefs in the world transfer sufficient heat tolerance to a naïve population sufficient to withstand end-of-century warming projections. Heat survival increased up to 84% when naïve mothers were selectively bred with fathers from the hottest reefs because of strong heritable genetic effects. We identified genomic loci associated with tolerance variation that were enriched for heat shock proteins, oxidative stress, and immune functions. Unexpectedly, several coral families exhibited survival rates and genomic associations deviating from origin predictions, including a few naïve purebreds with exceptionally high heat tolerance. Our findings highlight previously uncharacterized enhanced and intrinsic potential of coral populations to adapt to climate warming

Rab4 Orchestrates a Small GTPase Cascade for Recruitment of Adaptor Proteins to Early Endosomes

SummaryBackgroundEarly, sorting endosomes are a major crossroad of membrane traffic, at the intersection of the endocytic and exocytic pathways. The sorting of endosomal cargo for delivery to different subcellular destinations is mediated by a number of distinct coat protein complexes, including adaptor protein 1 (AP-1), AP-3, and Golgi-localized, gamma adaptin ear-containing, Arf-binding (GGAs) protein. Ultrastructural studies suggest that these coats assemble onto tubular subdomains of the endosomal membrane, but the mechanisms of coat recruitment and assembly at this site remain poorly understood.ResultsHere we report that the endosomal Rab protein Rab4 orchestrates a GTPase cascade that results in the sequential recruitment of the ADP-ribosylation factor (Arf)-like protein Arl1; the Arf-specific guanine nucleotide exchange factors BIG1 and BIG2; and the class I Arfs, Arf1 and Arf3. Knockdown of Arf1, or inhibition of BIG1 and BIG2 activity with brefeldin A results in the loss of AP-1, AP-3, and GGA-3, but not Arl1, from endosomal membranes and the formation of elongated tubules. In contrast, depletion of Arl1 randomizes the distribution of Rab4 on endosomal membranes, inhibits the formation of tubular subdomains, and blocks recruitment of BIG1 and BIG2, Arfs, and adaptor protein complexes to the endosome.ConclusionsTogether these findings indicate that Arl1 links Rab4-dependent formation of endosomal sorting domains with downstream assembly of adaptor protein complexes that constitute the endosomal sorting machinery

Scanning Angle Raman Spectroscopy of Poly(3-hexylthiophene)-Based Films on Indium Tin Oxide, Gold, and Sapphire Surfaces

Interest in realizing conjugated polymer-based films with controlled morphology for efficient electronic devices, including photovoltaics, requires a parallel effort to characterize these films. Scanning angle (SA) Raman spectroscopy is applied to measure poly(3-hexylthiophene) (P3HT):phenyl–C61–butyric acid methyl ester (PCBM)-blend morphology on sapphire, gold, and indium tin oxide interfaces, including functional organic photovoltaic devices. Nonresonant SA Raman spectra are collected in seconds with signal-to-noise ratios that exceed 80, which is possible due to the reproducible SA signal enhancement. Raman spectra are collected as the incident angle of the 785 nm excitation laser is precisely varied upon a prism/sample interface from approximately 35 to 70°. The width of the ∼1447 cm–1 thiophene C═C stretch is sensitive to P3HT order, and polymer order varied depending on the underlying substrate. This demonstrates the importance of performing the spectroscopic measurements on substrates and configurations used in the functioning devices, which is not a common practice. The experimental measurements are modeled with calculations of the interfacial mean square electric field to determine the distance dependence of the SA Raman signal. SA Raman spectroscopy is a versatile method applicable whenever the chemical composition, structure, and thickness of interfacial polymer layers need to be simultaneously measured

Intracranial mesenchymal tumor with FET-CREB fusion - A unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms

Intracranial mesenchymal tumors with FET-CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here we studied twenty patients with intracranial mesenchymal tumors proven to harbor FET-CREB fusion by next-generation sequencing (NGS). The 16 female and 4 male patients had a median age of 14 years (range 4-70). Tumors were uniformly extra-axial or intraventricular and located at the cerebral convexities (n=7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that 8 tumors harbored EWSR1-ATF1 fusion, 7 had EWSR1-CREB1, 4 had EWSR1-CREM, and 1 had FUS-CREM. Tumors were uniformly well-circumscribed and typically contrast-enhancing with solid and cystic growth. Tumors with EWSR1-CREB1 fusions more often featured stellate/spindle cell morphology, mucin-rich stroma, and hemangioma-like vasculature compared to tumors with EWSR1-ATF1 fusions that most often featured sheets of epithelioid cells with mucin-poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression-free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1-ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET-CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma-like neoplasms

Subseafloor microbial communities in hydrogen-rich vent fluids from hydrothermal systems along the Mid-Cayman Rise

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Environmental Microbiology 18 (2016): 1970–1987, doi:10.1111/1462-2920.13173.Warm fluids emanating from hydrothermal vents can be used as windows into the rocky subseafloor habitat and its resident microbial community. Two new vent systems on the Mid-Cayman Rise each exhibits novel geologic settings and distinctively hydrogen-rich vent fluid compositions. We have determined and compared the chemistry, potential energy yielding reactions, abundance, community composition, diversity, and function of microbes in venting fluids from both sites: Piccard, the world's deepest vent site, hosted in mafic rocks; and Von Damm, an adjacent, ultramafic-influenced system. Von Damm hosted a wider diversity of lineages and metabolisms in comparison to Piccard, consistent with thermodynamic models that predict more numerous energy sources at ultramafic systems. There was little overlap in the phylotypes found at each site, although similar and dominant hydrogen-utilizing genera were present at both. Despite the differences in community structure, depth, geology, and fluid chemistry, energetic modelling and metagenomic analysis indicate near functional equivalence between Von Damm and Piccard, likely driven by the high hydrogen concentrations and elevated temperatures at both sites. Results are compared with hydrothermal sites worldwide to provide a global perspective on the distinctiveness of these newly discovered sites and the interplay among rocks, fluid composition and life in the subseafloor.National Aeronautics and Space Administration Grant Number: NNX09AB756; Alfred P. Sloan Foundation; NSF Grant Number: OCE10618

DNA methylation of the allergy regulatory gene interferon gamma varies by age, sex, and tissue type in asthmatics

Background Asthma is associated with allergic sensitization in about half of all cases, and asthma phenotypes can vary by age and sex. DNA methylation in the promoter of the allergy regulatory gene interferon gamma (IFNγ) has been linked to the maintenance of allergic immune function in human cell and mouse models. We hypothesized that IFNγ promoter methylation at two well-studied, key cytosine phosphate guanine (CpG) sites (-186 and -54), may differ by age, sex, and airway versus systemic tissue in a cohort of 74 allergic asthmatics. Results After sampling buccal cells, a surrogate for airway epithelial cells, and CD4+ lymphocytes, we found that CD4+ lymphocyte methylation was significantly higher in children compared to adults at both CpG sites (P <0.01). Buccal cell methylation was significantly higher in children at CpG -186 (P = 0.03) but not CpG -54 (P = 0.66). Methylation was higher in males compared to females at both CpG sites in CD4+ lymphocytes (-186: P <0.01, -54: P = 0.02) but not buccal cells (-186: P = 0.14, -54: P = 0.60). In addition, methylation was lower in CD4+ lymphocytes compared to buccal cells (P <0.01) and neighboring CpG sites were strongly correlated in CD4+ lymphocytes (r = 0.84, P <0.01) and weakly correlated in buccal cells (r = 0.24, P = 0.04). At CpG -186, there was significant correlation between CD4+ lymphocytes and buccal cells (r = 0.24, P = 0.04) but not at CpG -54 (r = -0.03, P = 0.78). Conclusions These findings highlight significant age, sex, and tissue-related differences in IFNγ promoter methylation that further our understanding of methylation in the allergic asthma pathway and in the application of biomarkers in clinical research