Environmental responses of virally infected respiratory epithelial cells

Background: Rhinovirus, airborne pollution, and allergens are thought to contribute to epithelial dysfunction in chronic airway disease. Objectives were to determine whether these factors act in synergism to induce inflammation and chronic airway disease. Methods: Respiratory mucosa from chronic rhinosinusitis with nasal polyps (CRSwNP) (n=7) or healthy (n=6) patients were cultured at air-liquid interface (ALI) (culture wells n=204). Cells were infected with rhinovirus, then exposed to combinations of vehicle, diesel particulate matter (DPM), and house dust mite (HDM). Ciliary beating frequency (CBF), interleukin (IL)-6 release, and cytotoxicity were assessed by Sisson-Ammons Video Analysis (SAVA) software, flow cytometry, and LDH assays. Results: Compared with healthy cultures, CRSwNP culture groups had lower baseline CBF. The CBF of virally infected ALI cultures was higher than healthy cultures. Challenges tended to impair CBF more in cells that were also virally infected. There was an elevation in IL-6 with viral infection. Challenge combinations did not cause a different IL-6 or CBF response within groups. Conclusions: An inherent mucosal dysfunction and environmental exposures can worsen sinus disease. Synergism in CBF impairment or IL-6 release was not seen

How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a “total approach to rehabilitation”, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970’s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program

Multi-level evidence of an allelic hierarchy of USH2A variants in hearing, auditory processing and speech/language outcomes.

Language development builds upon a complex network of interacting subservient systems. It therefore follows that variations in, and subclinical disruptions of, these systems may have secondary effects on emergent language. In this paper, we consider the relationship between genetic variants, hearing, auditory processing and language development. We employ whole genome sequencing in a discovery family to target association and gene x environment interaction analyses in two large population cohorts; the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK10K. These investigations indicate that USH2A variants are associated with altered low-frequency sound perception which, in turn, increases the risk of developmental language disorder. We further show that Ush2a heterozygote mice have low-level hearing impairments, persistent higher-order acoustic processing deficits and altered vocalizations. These findings provide new insights into the complexity of genetic mechanisms serving language development and disorders and the relationships between developmental auditory and neural systems

Spatial patterns of mercury in biota of Adirondack, New York lakes

We studied the spatial distribution patterns of mercury (Hg) in lake water, littoral sediments, zooplankton, crayfish, fish, and common loons in 44 lakes of the Adirondacks of New York State, USA, a region that has been characterized as a “biological Hg hotspot”. Our study confirmed this pattern, finding that a substantial fraction of the lakes studied had fish and loon samples exceeding established criteria for human and wildlife health. Factors accounting for the spatial variability of Hg in lake water and biota were lake chemistry (pH, acid neutralizing capacity (ANC), percent carbon in sediments), biology (taxa presence, trophic status) and landscape characteristics (land cover class, lake elevation). Hg concentrations in zooplankton, fish and common loons were negatively associated with the lake water acid-base status (pH, ANC). Bioaccumulation factors (BAF) for methyl Hg (MeHg) increased from crayfish (mean log10 BAF = 5.7), to zooplankton (5.9), to prey fish (6.2), to larger fish (6.3), to common loons (7.2). MeHg BAF values in zooplankton, crayfish, and fish (yellow perch equivalent) all increased with increasing lake elevation. Our findings support the hypothesis that bioaccumulation of MeHg at the base of the food chain is an important controller of Hg concentrations in taxa at higher trophic levels. The characteristics of Adirondack lake-watersheds (sensitivity to acidic deposition; significant forest and wetland land cover; and low nutrient inputs) contribute to elevated Hg concentrations in aquatic biota

Turnip yellow mosaic virus in Chinese cabbage in Spain: Commercial seed transmission and molecular characterization

[EN] Seed transmission of Turnip yellow mosaic virus (TYMV, genus Tymovirus) was evaluated in the whole seeds and seedlings that emerged from three commercial Chinese cabbage (Brassica pekinensis) seed batches. Seedlings in the cotyledon stage and adult plants were assayed for TYMV by DAS-ELISA and confirmed by RT-PCR. The proportion of whole seeds infected with TYMV was at least 0.15 %. The seeds of the three seed batches were grown in Petri dishes, and surveyed in the cotyledon stage in trays that contained a peat:sand mixture grown in greenhouses or growth chambers, which were analysed in the cotyledon and adult stages. The seed-to-seedling transmission rate ranged from 2.5 % to 2.9 % in two different seed batches (lot-08 and lot-09, respectively). Spanish isolates derived from turnip (Sp-03) and Chinese cabbage (Sp-09 and Sp-13), collected in 2003, 2009 and 2013 in two different Spanish regions, were molecularly characterised by analysing the partial nucleotide sequences of three TYMV genome regions: partial RNA-dependent RNA polymerase (RdRp), methyltransferase (MTR) and coat protein (CP) genes. Phylogenetic analyses showed that the CP gene represented two different groups: TYMV-1 and TYMV-2. The first was subdivided into three subclades: European, Australian and Japanese. Spanish isolate Sp-03 clustered together with European TYMV group, whereas Sp-09 and Sp-13 grouped with the Japanese TYMV group, and all differed from group TYMV-2. The sequences of the three different genomic regions examined clustered into the same groups. The results suggested that Spanish isolates grouped according to the original hosts from which they were isolated. The inoculation of the Spanish TYMV isolates to four crucifer plants species (turnip, broccoli, Brunswick cabbage and radish) revealed that all the isolates infected turnip with typical symptoms, although differences were observed in other hosts.Alfaro Fernández, AO.; Serrano, A.; Tornos, T.; Cebrian Mico, MC.; Córdoba-Sellés, MDC.; Jordá, C.; Font San Ambrosio, MI. (2016). Turnip yellow mosaic virus in Chinese cabbage in Spain: Commercial seed transmission and molecular characterization. EUROPEAN JOURNAL OF PLANT PATHOLOGY. 146(2):433-442. doi:10.1007/s10658-016-0929-3S4334421462Assis Filho, M., & Sherwood, J. L. (2000). Evaluation of seed transmission of Turnip yellow mosaic virus and Tobacco mosaic virus in Arabidopsis thaliana. Phytopathology, 90, 1233–1238.Benetti, M. P., & Kaswalder, F. (1983). Trasmisione per seme del virus del mosaico giallo rapa. Annali dell Istituto Sperimentale per la Patologia Vegetale, 8, 67–70.Blok, J., Mackenzie, A., Guy, P., & Gibbs, A. (1987). 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The use of a multiple-transfer method in plant virus transmission studies: some statistical points arising in the analysis of results. Annals of Applied Biology, 48, 75–83.Hayden, C. M., Mackenzie, A. M., & Gibbs, A. J. (1998a). Virion protein sequence variation among Australian isolates of turnip yellow mosaic tymovirus. Archives of Virology, 143, 191–201.Hayden, C. M., Mackenzie, A. M., Skotnicki, M. L., & Gibbs, A. (1998b). Turnip yellow mosaic virus isolates with experimentally produced recombinant virion proteins. Journal of General Virology, 79, 395–403.Hein, A. (1984). Transmission of Turnip yellow mosaic virus through seed of Camelina sativa gold of pleasure. Journal of Plant Diseases and Protection, 91, 549–551.Herrera-Vásquez, J. A., Córdoba-Sellés, M. C., Cebrián, M. C., Alfaro-Fernández, A., & Jordá, C. (2009). Seed transmission of Melon necrotic spot virus and efficacy of seed-disinfection treatments. Plant Pathology, 58, 436–452.Hull, R. (2002). Matthews’ plant virology (4a ed.1001 pp). San Diego: Academic Press.Johansen, E., Edwards, M. C., & Hampton, R. O. (1994). Seed transmission of viruses: current perspectives. Annual Review of Phytopathology, 32, 363–386.Kirino, N., Inoue, K., Tanina, K., Yamazaki, Y., & Ohki, S. T. (2008). Turnip yellow mosaic virus isolated from Chinese cabbage in Japan. Journal of General Plant Pathology, 74, 331–334.Markham, R., & Smith, K. S. (1949). Studies on the virus of turnip yellow mosaic. Parasitology, 39, 330–342.Mathews, R. E. F. (1980). Turnip yellow mosaic virus, CMI/AAB Descriptions of plant virus No. 230 (No. 2 revised). Kew: Commonwealth Mycology Institute/Association of Applied Biologists.Mitchell, E. J., & Bond, J. M. (2005). Variation in the coat protein sequence of British isolates of Turnip yellow mosaic virus and comparison with previously published isolates. Archives of Virology, 150, 2347–2355.Pagán, I., Fraile, A., Fernández-Fueyo, E., Montes, N., Alonso-Blanco, C., & García-Arenal, F. (2010). Arabidopsis thaliana as a model for the study of plant-virus co-evolution. Philosophical Transations of the Royal Society Biological Sciences, 365, 1983–1995.Paul, H. L., Gibbs, A., & Wittman-Liebold, B. (1980). The relationships of certain Tymoviruses assessed from the amino acid composition of their coat proteins. Intervirology, 13, 99–109.Pelikanova, J. (1990). Garlic mustard a spontaneous host of TYMV. Ochrana Rostlin, 26, 17–22.Procházková, Z. (1980). Host range and symptom differences between isolates of Turnip mosaic virus obtained from Sisymbrium loeselii. Biologia Plantarum, 22, 341–347.Rimmer, S. R., Shtattuck, V. I., & Buchwaldt, L. (2007). Compendium of brassica diseases (1ª Edición ed.p. 117). USA: APS press.Rot, M. E., & Jelkman, W. (2001). 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Convergent recombination suppression suggests role of sexual selection in guppy sex chromosome formation.

Sex chromosomes evolve once recombination is halted between a homologous pair of chromosomes. The dominant model of sex chromosome evolution posits that recombination is suppressed between emerging X and Y chromosomes in order to resolve sexual conflict. Here we test this model using whole genome and transcriptome resequencing data in the guppy, a model for sexual selection with many Y-linked colour traits. We show that although the nascent Y chromosome encompasses nearly half of the linkage group, there has been no perceptible degradation of Y chromosome gene content or activity. Using replicate wild populations with differing levels of sexually antagonistic selection for colour, we also show that sexual selection leads to greater expansion of the non-recombining region and increased Y chromosome divergence. These results provide empirical support for longstanding models of sex chromosome catalysis, and suggest an important role for sexual selection and sexual conflict in genome evolution

Transabdominal Preperitoneal Repair for Obturator Hernia

信州大学博士（医学）・学位論文・平成23年3月31日授与（甲第889号）・横山隆秀Background A laparoscopic surgical approach for obturator hernia (OH) repair is uncommon. The aim of the present study was to assess the effectiveness of laparoscopic transabdominal preperitoneal (TAPP) repair for OH. Methods From 2001 to May 2010, 659 patients with inguinal hernia underwent TAPP repair at in our institutes. Among these, the eight patients with OH were the subjects of this study. Results Three of the eight patients were diagnosed as having occult OH, and the other five were diagnosed preoperatively, by ultrasonography and/or computed tomography, as having strangulated OH. Bilateral OH was found in five patients (63%), and combined groin hernias, either unilaterally or bilaterally, were observed in seven patients (88%), all of whom had femoral hernia. Of the five patients with bowel obstruction at presentation, four were determined not to require resection after assessment of the intestinal viability by laparoscopy. There was one case of conversion to a two-stage hernia repair performed to avoid mesh contamination: addition of mini-laparotomy, followed by extraction of the gangrenous intestine for resection and anastomosis with simple peritoneal closure of the hernia defect in the first stage, and a Kugel hernia repair in the second stage. There was no incidence of postoperative morbidity, mortality, or recurrence. Conclusions Because TAPP allows assessment of not only the entire groin area bilaterally but also simultaneous assessment of the viability of the incarcerated intestine with a minimum abdominal wall defect, we believe that it is an adequate approach to the treatment of both occult and acutely incarcerated OH. Two-stage hernia repair is technically feasible in patients requiring resection of the incarcerated intestine.ArticleWORLD JOURNAL OF SURGERY. 35(10):2323-2327 (2011)journal articl

Exploiting evolutionary steering to induce collateral drug sensitivity in cancer

Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using 'evolutionary steering' to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 108-109 cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance

The scaffold protein KSR1, a novel therapeutic target for the treatment of Merlin-deficient tumors

Merlin has broad tumor-suppressor functions as its mutations have been identified in multiple benign tumors and malignant cancers. In all schwannomas, the majority of meningiomas and 1/3 of ependymomas Merlin loss is causative. In neurofibromatosis type 2, a dominantly inherited tumor disease because of the loss of Merlin, patients suffer from multiple nervous system tumors and die on average around age 40. Chemotherapy is not effective and tumor localization and multiplicity make surgery and radiosurgery challenging and morbidity is often considerable. Thus, a new therapeutic approach is needed for these tumors. Using a primary human in vitro model for Merlin-deficient tumors, we report that the Ras/Raf/mitogen-activated protein, extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) scaffold, kinase suppressor of Ras 1 (KSR1), has a vital role in promoting schwannomas development. We show that KSR1 overexpression is involved in many pathological phenotypes caused by Merlin loss, namely multipolar morphology, enhanced cell-matrix adhesion, focal adhesion and, most importantly, increased proliferation and survival. Our data demonstrate that KSR1 has a wider role than MEK1/2 in the development of schwannomas because adhesion is more dependent on KSR1 than MEK1/2. Immunoprecipitation analysis reveals that KSR1 is a novel binding partner of Merlin, which suppresses KSR1's function by inhibiting the binding between KSR1 and c-Raf. Our proteomic analysis also demonstrates that KSR1 interacts with several Merlin downstream effectors, including E3 ubiquitin ligase CRL4DCAF1. Further functional studies suggests that KSR1 and DCAF1 may co-operate to regulate schwannomas formation. Taken together, these findings suggest that KSR1 serves as a potential therapeutic target for Merlin-deficient tumors