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Introduction NRG1 rearrangements produce chimeric ligands that subvert the ERBB pathway to drive tumorigenesis. A better understanding of the signaling networks that mediate transformation by NRG1 fusions is needed to inform effective therapeutic strategies. Unfortunately, this has been hampered by a paucity of patient-derived disease models that faithfully recapitulate this molecularly defined cancer subset. Methods Patient-derived xenograft (PDX) and cell line models were established from NRG1-rearranged lung adenocarcinoma samples. Transcriptomic, proteomic, and biochemical analyses were performed to identify activated pathways. Efficacy studies were conducted to evaluate HER3- and MTOR-directed therapies. Results We established a pair of PDX and cell line models of invasive mucinous lung adenocarcinoma (LUAD) (LUAD-0061AS3, SLC3A2-NRG1), representing the first reported paired in vitro and in vivo model of NRG1-driven tumors. Growth of LUAD-0061AS3 models was reduced by the anti-HER3 antibody GSK2849330. Transcriptomic profiling revealed activation of the MTOR pathway in lung tumor samples with NRG1 fusions. Phosphorylation of several MTOR effectors (S6 and 4EBP1) was higher in LUAD-0061AS3 cells compared with human bronchial epithelial cells and the breast cancer cell line MDA-MB-175-VII (DOC4-NRG1 fusion). Accordingly, LUAD-0061AS3 cells were more sensitive to MTOR inhibitors than MDA-MB-175-VII cells and targeting the MTOR pathway with rapamycin blocked growth of LUAD-0061AS3 PDX tumors in vivo. In contrast, MDA-MB-175-VII breast cancer cells had higher MAPK pathway activation and were more sensitive to MEK inhibition. Conclusions We identify the MTOR pathway as a candidate vulnerability in NRG1 fusion-positive lung adenocarcinoma that may warrant further preclinical evaluation, with the eventual goal of finding additional therapeutic options for patients in whom ERBB-directed therapy fails. Moreover, our results uncover heterogeneity in downstream oncogenic signaling among NRG1-rearranged cancers, possibly tumor type-dependent, the therapeutic significance of which requires additional investigation.

Abundant phytoplankton and bacteria were identified by microscopy and high-throughput 16S rRNA tag Illumina sequencing of samples from water- and ice phases collected during winter at two central European Great Lakes, Balaton and Fertő (Neusiedlersee). Bacterial reads at all sites were dominated (>85%) by Bacteroidetes and Proteobacteria. Amongst phototrophs, microscopy and 16S sequencing revealed that both phytoplankton and cyanobacteria were represented, with a median of 1500 cyanobacterial sequence reads amongst 13 samples analyzed. The sequence analysis compared replicate Balaton and Fertő ice and water samples with an outgroup from three Hungarian soda lakes. In particular, both water and ice from Fertő contained high contributions from cyanobacteria. Two percent of total reads identified to the level of family in water at Fertő were dominated by a single operational taxonomic unit (OTU) of a cyanobacterium within the Rivulariaceae, which was largely absent from ice. Conversely, ice samples from both lakes yielded an abundant OTU assigned to a Flavobacterium sp. known to be associated with freshwater ice. Principal Coordinates Analysis (PCoA) revealed that the ice communities from all sites were similar to one another, and that the water communities did not cluster together. Fluorescence emission spectra obtained at 77 K confirmed the presence of intact cyanobacteria in Fertő water and ice. Photosynthetic characterization of phototrophs resident in water and ice analyzed by assay of acid-stable photosynthetic H14CO3– incorporation showed that communities from both phases were photosynthetically active, thus adding to growing recognition of ice-covered lakes as viable habitat for phototrophs.

This study examined vertically-resolved patterns in microbial community structure across a freshwater trophic gradient extending 1600 km from the oligotrophic waters of Lake Superior to the eutrophic waters of Lake Erie, the most anthropogenically influenced of the Laurentian Great Lakes system. Planktonic bacterial communities clustered by Principal Coordinates Analysis (PCoA) on UniFrac distance matrices into four groups representing the epilimnion and hypolimnion of the upper Great Lakes (Lakes Superior and Huron), Lake Superior's northern bays (Nipigon and Black bays), and Lake Erie. The microbes within the upper Great Lakes hypolimnion were the most divergent of these groups with elevated abundance of Planctomycetes and Chloroflexi compared to the surface mixed layer. Statistical tests of the correlation between distance matrices identified temperature and sample depth as the most influential community structuring parameters, reflecting the strong UniFrac clustering separating mixed-layer and hypolimnetic samples. Analyzing mixed-layer samples alone showed clustering patterns were correlated with nutrient concentrations. Operational taxonomic units (OTU) which were differentially distributed among these conditions often accounted for a large portion of the reads returned. While limited in coverage of temporal variability, this study contributes a detailed description of community variability that can be related to other large freshwater systems characterized by changing trophic state.

Toxic cyanobacterial harmful algal blooms (cyanoHABs) are one of the most significant threats to the security of Earth's surface freshwaters. In the United States, the Federal Water Pollution Control Act of 1972 (i.e., the Clean Water Act) requires that states report any waterbody that fails to meet applicable water quality standards. The problem is that for fresh waters impacted by cyanoHABs, no scientifically-based framework exists for making this designation. This study describes the development of a data-based framework using the Ohio waters of western Lake Erie as an exemplar for large lakes impacted by cyanoHABs. To address this designation for Ohio's open waters, the Ohio Environmental Protection Agency (EPA) assembled a group of academic, state and federal scientists to develop a framework that would determine the criteria for Ohio EPA to consider in deciding on a recreation use impairment designation due to cyanoHAB presence. Typically, the metrics are derived from on-lake monitoring programs, but for large, dynamic lakes such as Lake Erie, using criteria based on discrete samples is problematic. However, significant advances in remote sensing allows for the estimation of cyanoHAB biomass of an entire lake. Through multiple years of validation, we developed a framework to determine lake-specific criteria for designating a waterbody as impaired by cyanoHABs on an annual basis. While the criteria reported in this manuscript are specific to Ohio's open waters, the framework used to determine them can be applied to any large lake where long-term monitoring data and satellite imagery are available.

This study investigates the seismic collapse resistance of steel moment resisting frames equipped with superelastic viscous dampers (SVD) through incremental dynamic analysis (IDA). The SVD is a hybrid passive control device that strategically combines a viscoelastic device and shape memory alloy cables in parallel. The hybrid device exhibits improved re-centering and energy dissipating capabilities compared to only viscoelastic or only SMA-based devices. First, the design and mechanical behavior of SVDs are described. A nine-story steel frame building is selected for the numerical analyses. The building is first designed as a conventional special moment resisting frame (SMRF) to meet the strength and stiffness requirements of the design codes. Then, a reduced strength version of the fully code compliant frame is developed and upgraded with either SVDs or buckling restrained brace (BRB) system. Analytical models of the steel building for each configuration are developed to simulate global frame behavior by considering both geometric nonlinearities and cyclic strength and stiffness deterioration of structural steel components under dynamic loads. Incremental dynamic analysis is employed to assess the seismic resistance of steel frame structures up to collapse using 44 ground motion records. A sensitivity analysis is also performed to evaluate the influence of SVD design parameters on the seismic response of the frame. The results indicate that the steel frame designed with SVDs has the largest median collapse capacity and minimal residual drifts under various seismic hazard levels.

Hospital readmission in adult trauma is associated with significant morbidity, mortality, and resource utilization. In this study, we examine pediatric intensive care unit (PICU) admission as a risk factor for hospital readmission in pediatric trauma.This was a retrospective cohort study of patients aged 1 through 19 y in the Pediatric Health Information System database discharged with a trauma diagnosis. Patient and clinical variables included demographics, payer status, length of stay, chronic comorbid conditions, presence of mechanical ventilation, all-patient refined diagnosis-related group and calculated severity of illness, and discharge disposition. The main outcome variable was hospital readmission within 30 d of discharge. Odds ratios (ORs) were calculated in both univariate and multivariate analyses with corresponding 95% confidence intervals (CIs).During the 5-year study period, 90,467 patients were admitted with a trauma diagnosis, of which 16,279 (18.0%) were admitted to the PICU. Hospital readmissions occurred in 3.1% of patients. On univariate analysis, patients admitted to the PICU on the first day of hospital admission (direct PICU admission), and those first admitted to the PICU after the day of hospital admission (delayed PICU admission), had 2-3 times the risk of hospital readmission compared with those never admitted to the PICU (4.8% versus 7.2% versus 2.7%, respectively, P 0.001). On multivariate analysis, controlling for demographic and clinical variables, the adjusted ORs for hospital readmission in patients with direct and delayed PICU admission were 1.34 (95% CI 1.20-1.50) and 1.88 (95% CI 1.50-2.35) versus no PICU admission, respectively.PICU admission, either direct or delayed, during hospitalization for trauma care is an independent risk factor for hospital readmission within 30 d of discharge. Further risk stratification may help focus resources on high-risk patients to improve clinical outcomes and reduce readmissions.

There is growing recognition that winter is an important season for growth of photoautotrophs in ice-covered freshwater environments. Exemplifying this are expansive under-ice blooms of filamentous diatoms in Lake Erie. Here we describe a metatranscriptome constructed from a phytoplankton community dominated by filamentous diatoms. As expected, a high percentage (> 73%) of the sequences with BLAST hits to nucleotides or proteins in National Center for Biotechnology Information databases were associated with photosynthetic algae of which the majority were diatoms, mainly Aulacoseira spp. and Stephanodiscus spp. which was confirmed by analysis of 18S rRNA gene transcripts and microscopy. Consistent with the winter growth environment, psychrophilic and low-light adaptations were observed. Prominent among adaptations to cold were transcripts for genes involved in biosynthesis of unsaturated fatty acids, which were consistent with expected increased membrane fluidity at low temperatures. Reflecting the combined effect of low winter insolation and high light attenuation were an abundant complement of reads for light-harvesting antennae, mainly genes encoding fucoxanthin chlorophyll a / c proteins. The presence of virulence factors originating from oomycetes offers support for new hypotheses into the eventual decline of Lake Erie's winter diatom bloom. Whereas fungi were identified both through the metatranscriptome and by microscopy, dsRNA viruses of fungi were detected that may indirectly counter against fungal infection. This study demonstrates the utility of an environmental omics approach to yield insights underlying phototrophic life as well as the interactions of the entire microbial community in an extreme environment.

The purpose of this study was to examine trends in the treatment of patients with infectious parapneumonic effusions in U.S. children's hospitals over the past decade.The PHIS database was queried for patients younger than 18years old with pneumonia and pleural effusion in three yearlong periods over the past decade. Variables included age, gender, payer, race/ethnicity, hospital region, hospital type, markers of illness severity, and treatment group (antibiotics alone, chest tube thoracostomy±thrombolytics, video-assisted thoracoscopy (VATS), or thoracotomy).5569 patients were included in the final analysis. The proportion of patients treated with antibiotics alone increased from 62% to 74% from 2004 to 2014 (p0.001). Among patients requiring pleural space drainage, the frequency of VATS peaked in 2009 (50.8%), dropping to 36.4% in 2014 (p0.001), while tube thoracostomy, usually with fibrinolytics, rose from 39.0% in 2009 to 53.2% in 2014 (p0.001).In a select cohort of free-standing, tertiary care U.S. children's hospitals, antibiotic administration alone remains the most common treatment approach to infectious parapneumonic effusions. VATS treatment for those patients requiring pleural space drainage is being gradually supplanted by thoracostomy tube placement with instillation of fibrinolytics.

In early August 2014, the municipality of Toledo, OH (USA) issued a ‘do not drink’ advisory on their water supply directly affecting over 400,000 residential customers and hundreds of businesses (Wilson, 2014). This order was attributable to levels of microcystin, a potent liver toxin, which rose to 2.5 μg L−1 in finished drinking water. The Toledo crisis afforded an opportunity to bring together scientists from around the world to share ideas regarding factors that contribute to bloom formation and toxigenicity, bloom and toxin detection as well as prevention and remediation of bloom events. These discussions took place at an NSF- and NOAA-sponsored workshop at Bowling Green State University on April 13 and 14, 2015. In all, more than 100 attendees from six countries and 15 US states gathered together to share their perspectives. The purpose of this review is to present the consensus summary of these issues that emerged from discussions at the Workshop. As additional reports in this special issue provide detailed reviews on many major CHAB species, this paper focuses on the general themes common to all blooms, such as bloom detection, modeling, nutrient loading, and strategies to reduce nutrients.

Background The revised 2014 American College of Cardiology (ACC)/American Heart Association valvular heart disease guidelines provide evidenced-based recommendations for the management of mitral regurgitation (MR). However, knowledge gaps related to our evolving understanding of critical MR concepts may impede their implementation. Methods The ACC conducted a multifaceted needs assessment to characterize gaps, practice patterns, and perceptions related to the diagnosis and treatment of MR. A key project element was a set of surveys distributed to primary care and cardiovascular physicians (cardiologists and cardiothoracic surgeons). Survey and other gap analysis findings were presented to a panel of 10 expert advisors from specialties of general cardiology, cardiac imaging, interventional cardiology, and cardiac surgeons with expertise in valvular heart disease, especially MR, and cardiovascular education. The panel was charged with assessing the relative importance and potential means of remedying identified gaps to improve care for patients with MR. Results The survey results identified several knowledge and practice gaps that may limit implementation of evidence-based recommendations for MR care. Specifically, half of primary care physicians reported uncertainty regarding timing of intervention for patients with severe primary or functional MR. Physicians in all groups reported that quantitative indices of MR severity were frequently not reported in clinical echocardiographic interpretations, and that these measurements were not consistently reviewed when provided in reports. In the treatment of MR, nearly 30% of primary care physician and general cardiologists did not know the volume of mitral valve repair surgeries by their reference cardiac surgeons and did not have a standard source to obtain this information. After review of the survey results, the expert panel summarized practice gaps into 4 thematic areas and offered proposals to address deficiencies and promote better alignment with the 2014 ACC/American Heart Association valvular disease guidelines. Conclusion Important knowledge and skill gaps exist that may impede optimal care of the patient with MR. Focused educational and practice interventions should be developed to reduce these gaps.

Oligotrophic Lake Superior and mesotrophic Lake Erie are trophic end members of the hydrologically connected Laurentian Great Lakes system, and as such exhibit different profiles of dissolved nitrogen species. Nitrification in Lake Superior has led to increasing nitrate concentrations over the past century, as opposed to Erie, where nitrate inventories have declined due to denitrification. In this study, we examined the abundance and diversity of nitrifying microbes involved in the oxidation of ammonia to nitrite, and nitrite to nitrate. By in situ hybridization methods, we enumerated the major planktonic ammonia oxidizing bacteria (AOB) and archaea (AOA) during a July 2011 cruise from Lake Superior to Lake Erie. In Lake Superior, AOA dominated compared to AOB, typically exceeding 5 × 103 mL− 1, whereas in Erie, AOB were more abundant than AOA. These data parallel prior work on Lake Superior and Lake Erie sediments, in which AOA are far more abundant in Superior, but AOB dominate in Erie. The lakes were sampled during stratification, and AOA and AOB were largely restricted to the hypolimnion, consistent with the observation that ammonia oxidizers are photoinhibited in surface waters. In Lakes Superior and Erie, we also detected nitrite oxidizing bacteria (NOB) in a pattern paralleling AOA/AOB abundance. Phylogenetic analysis of archaeal 16S rRNA revealed that the planktonic archaea of Lake Superior are members of the ammonia oxidizing Group I.1a Thaumarchaeota most closely related to Nitrosoarchaeum limnia. These AOA are distinct from the Group I.1a AOA in Lake Superior sediments. The major AOB of Lake Erie form a subcluster within the genus Nitrosospira.

This study proposes a hybrid passive control device and investigates its performance in improving response of steel frame structures subjected to multi-level seismic hazards. The proposed superelastic viscous damper (SVD) relies on shape memory alloy (SMA) cables for re-centering capability and employs a viscoelastic (VE) damper that consists of two layers of a high damped (HD) blended butyl elastomer compound to augment its energy dissipation capacity. First, experimental tests are conducted to characterize behavior of SMA cables and VE damper and to assess the influence of various parameters such as displacement amplitude and loading frequency on their mechanical response. Then, an analytical model of a six-story steel special moment frame building with the installed SVDs is developed to determine the dynamic response of the structure. Nonlinear response history analyses are conducted to evaluate the behavior of controlled and uncontrolled buildings under 44 ground motion records. Results shows that SVDs can effectively mitigate dynamic response of steel frame structures at different seismic hazard levels and enhance their post-earthquake functionality.

The bifurcation of river flow around large stable islands, also known as anabranching, represents a distinctive form of river adjustment that is uncommon in the Appalachian Piedmont province of the eastern U.S. Within this province, highly localized river branching similar to classical anabranching forms exists in one area near the foot of the Blue Ridge Escarpment. This paper examines channel form and processes along a reach of the upper Yadkin River in North Carolina (USA) before and after a flood-induced division of its flow into two subparallel branches, both of which remain active 35 years later. The research draws on aerial photograph analyses, channel surveying, and observations of inset channel benches, flood frequency analysis, and discharge monitoring and modeling to analyze planform history and to track and explain changes in newly excised and losing channels along the bifurcated reach. The characterization of this branched reach resembles some descriptions of gravel-dominated laterally active anabranching, although the match is imperfect. Reductions in valley slope and confinement and the presence of local valley constrictions near the base of the escarpment steeplands have been conducive to long-term sedimentation and a greater likelihood of branching. A period of relatively rapid cross section adjustment occurred on both branches soon after bifurcation, and this may have permitted the losing branch to remain open. Well-stratified benches currently observed along the losing branch are interpreted to be largely the late product of a waning early major adjustment phase and moderate, recent, and perhaps ongoing variations in flow division and appear to be not fully adjusted to prevailing discharges. Coarse benches along the newly excised branch are better-adjusted inset floodplain fragments created primarily by lateral migration and point accretion. Patterns of benchfull flow frequency variation are interpreted to indicate that the flow bifurcation ratio has been neither static nor monotonically changing in recent decades. Further exploration of branching in this environment, otherwise dominated by single-thread meandering patterns, is of importance for a variety of management and ecological concerns.

Background Pathological gambling (PG) is a heterogeneous disorder. The identification and characterization of PG subtypes could lead to tailored treatment approaches, which may, in turn, improve treatment outcomes. Objective To investigate PG subtypes based on personality traits across two different cultural and clinical settings. Consistent with the Pathways Model, we hypothesized the presence of three subtypes (behaviorally conditioned — BC, emotionally vulnerable — EV, and antisocial impulsivist — AI). Methods 140 PG adults from Sao Paulo, Brazil (SP sample) and 352 adults with PG ( n = 214) or sub-clinical PG ( n = 138) from Toronto, Canada (TO sample) completed the Temperament and Character Inventory (TCI). Latent-class analysis was used to investigate subtypes. Results A 2-class solution was the best model for the pooled SP and TO samples. Class 1 presented a normative personality profile and was composed exclusively of participants from Toronto (BC subtype). Class 2 was characterized by high novelty seeking, high harm avoidance, and low self-directedness, and included participants from both SP and TO (EV subtype). When sub-clinical PGs were excluded from the analysis, a single-class solution better characterized the SP and TO samples. Conclusions Our results suggest that PG severity, rather than community or clinical settings, may have an effect on PG subtypes. The generalizability of the results is limited by the demographic and clinical features of the selected samples. Future neurobiological studies may contribute to the categorization of subjects into PG subtypes based on different underlying biological pathways.

Grand Lake St. Marys (Ohio, USA) is a hypereutrophic reservoir prone to persistent toxic cyanobacterial blooms fueled by agricultural nutrient runoff. The pervasive and highly toxic 2010 bloom led to the collapse of the local tourism industry, with microcystin concentrations exceeding 2000 μg mL −1 at some locations during the peak of the bloom. Sampling from a location adjacent to the intake to the Celina Water Treatment Plant, chlorophyll a levels remained above 25 μg L −1 from June to September, reaching a maximum in excess of 100 μg L −1 in July. Molar ratios of dissolved inorganic nitrogen (DIN) to dissolved inorganic phosphorus (DIP) declined below 16 in July and August, suggesting the cyanobacterial population became N-limited during the bloom peak. Cyanobacterial biomass was dominated by Planktothrix spp. throughout late summer 2010, but phylogenetic analysis of mcyA sequences revealed the presence of toxic Microcystis spp. during July that coincided with the highest toxin measurements. August and September samples indicated the community shifted to yield Planktothrix spp. as the major toxic genus. Community shifts of this nature may impede targeted remediation efforts, and therefore a thorough understanding of the taxa involved is necessary prior to implementing strategies to limit bloom formation.

The pelagic regions of Lake Superior and eastern Lake Erie (Laurentian Great Lakes) are typically phosphorus (P)-limited environments, and picocyanobacteria of the genus Synechococcus spp. are prominent primary producers during the summer. As a proxy for their utilization of organic P, the expression of two genes, phnD and phoX , was monitored. The phnD gene encodes the phosphonate binding protein of the ABC-type phosphonate transporter, whereas the phoX gene encodes a calcium-dependent alkaline phosphatase. Furthermore, to assess the ability of freshwater Synechococcus spp. to substitute sulfolipids for phospholipids, sqdX gene (cyanobacterial sulfolipid synthase) expression was examined. We employed PCR primers to detect the presence of all three genes in the endemic Synechococcus spp., and RT-PCR assays of cultured freshwater strains and environmental samples to assess the degree of P-stress in the phytoplankton. We show that the phnD gene was constitutively expressed, suggesting that freshwater picocyanobacteria were metabolizing exogenous phosphonate compounds in Lakes Erie and Superior. By contrast, phoX was regulated by P bioavailability. We also provide evidence that sqdX is expressed during increased growth rates in phosphorus-replete conditions, suggesting that sulfolipid synthesis is not a P conservation mechanism for freshwater Synechococcus spp.