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The sustainable development of mountain regions requires inter- and transdisciplinary knowledge. The Institute for Interdisciplinary Mountain Research contributes to this global endeavor as part of the Austrian Academy of Sciences and as a member of international scientific networks, together with local partners and stakeholders. As a joint effort of individual researchers covering multiple fields, this article highlights our views on mountains as research objects, the phenomena we investigate as parts of entire mountain systems, and the synergies and differences of the disciplinary frames within which we work. Alles ist Wechselwirkung [Everything is interaction]

The sustainable development of mountain regions requires inter-and transdisciplinary knowledge. The Institute for Interdisciplinary Mountain Research contributes to this global endeavor as part of the Austrian Academy of Sciences and as a member of international scientific networks, together with local partners and stakeholders. As a joint effort of individual researchers covering multiple fields, this article highlights our views on mountains as research objects, the phenomena we investigate as parts of entire mountain systems, and the synergies and differences of the disciplinary frames within which we work.

This dissertation is an examination of the ways English teachers may be complicit in reproducing an abstinence-based sex education discourse in their own classroom practices and discussions of literature. Working from disciplinary research in sex education, sociology, English education, anthropology, and public health, I explore English teachers' experiences in negotiating the effects of, reactions to, and expectations for discussing sexuality, intimacy, and gender in a school community. Using feminist positioning theory and Bakhtin's concepts of dialogism and ventriloquism, I explore how teachers approach, grapple with, contribute to, and leverage dominant institutional discourses in their practices, thereby mediating knowledge, possibilities for conversations, and institutional norms. An amalgam of teaching philosophies, methodologies, and political ideologies underscores teachers' voicing patterns and discursive positions, helping to further inform an understanding of how contentious social issues are negotiated in the classroom. The agentic discursive positions teachers take up provide insights into teachers as mediating agents within institutional discourses, but not necessarily as change agents of institutional norms.

Over 97 years ago, the Girl Scout movement made a commitment to helping girls learn about themselves and the world around them. Today, Girl Scouts of the Missouri Heartland continues this commitment by providing leadership experiences designed to help girls develop the courage, confidence and character they need to thrive in today's ever-changing world. For example, MU professors and students volunteer each year to lead special programs such as \"Magic of Chemistry,\" \"Engineering the Future\" and \"Bridge to Music.\" Linn State Technical College staff and students collaborate with Girl Scouts to offer \"Tinker with Technology.\"

We have observed both minor‐arc (R1) and major‐arc (R2) Rayleigh waves for the largest marsquake (magnitude of 4.7 ± 0.2) ever recorded. Along the R1 path (in the lowlands), inversion results show that a simple, two‐layer model with an interface located at 21–29 km and an upper crustal shear‐wave velocity of 3.05–3.17 km/s can fit the group velocity measurements. Along the R2 path, observations can be explained by upper crustal thickness models constrained from gravity data and upper crustal shear‐wave velocities of 2.61–3.27 and 3.28–3.52 km/s in the lowlands and highlands, respectively. The shear‐wave velocity being faster in the highlands than in the lowlands indicates the possible existence of sedimentary rocks, and relatively higher porosity in the lowlands. Plain Language Summary The largest marsquake ever recorded occurred recently and waves propagating at the surface, called surface waves, have been observed. Owing to the relatively large magnitude (i.e., 4.7 ± 0.2) of this event, surface wave energy is still clearly visible after one orbit around the red planet. The shortest path taken by the wave propagating between the source and the receiver is located in the northern lowlands, near the boundary with the southern highlands (called dichotomy). The surface wave traveling in the opposite direction, following the longer distance between the quake and the seismic station, mostly passes through the highlands. Analyses of these two paths reveal that the average shear‐wave velocity is faster in the highlands than in the lowlands near the dichotomy boundary. This lower velocity in the lowlands may be due to the presence of thick accumulations of sedimentary rocks and relatively higher porosity. Key Points Analyses of the minor‐arc and major‐arc Rayleigh waves reveal different Martian crustal structures across the dichotomy boundary The average shear‐wave velocity is faster in the highlands than in the lowlands near the dichotomy boundary The lower shear‐wave velocity in the lowlands may be due to the presence of sedimentary rocks and relatively higher porosity

The Hedgehog pathway inhibitor vismodegib has shown clinical benefit in patients with advanced basal cell carcinoma and is approved for treatment of patients with advanced basal cell carcinoma for whom surgery is inappropriate. STEVIE was designed to assess the safety of vismodegib in a situation similar to routine practice, with a long follow-up. In this multicentre, open-label trial, adult patients with histologically confirmed locally advanced basal cell carcinoma or metastatic basal cell carcinoma were recruited from regional referral centres or specialist clinics. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and adequate organ function. Patients with locally advanced basal cell carcinoma had to have been deemed ineligible for surgery. All patients received 150 mg oral vismodegib capsules once a day on a continuous basis in 28-day cycles. The primary objective was safety (incidence of adverse events until disease progression or unacceptable toxic effects), with assessments on day 1 of each treatment cycle (28 days) by principal investigator and coinvestigators at the site. Efficacy variables were assessed as secondary endpoints. The safety evaluable population included all patients who received at least one dose of study drug. Patients with histologically confirmed basal cell carcinoma who received at least one dose of study drug were included in the efficacy analysis. An interim analysis was pre-planned after 500 patients achieved 1 year of follow-up. This trial is registered with ClinicalTrials.gov, number NCT01367665. The study is still ongoing. Between June 30, 2011, and Nov 6, 2014, we enrolled 1227 patients. At clinical cutoff (Nov 6, 2013), 499 patients (468 with locally advanced basal cell carcinoma and 31 with metastatic basal cell carcinoma) had received study drug and had the potential to be followed up for 12 months or longer. Treatment was discontinued in 400 (80%) patients; 180 (36%) had adverse events, 70 (14%) had progressive disease, and 51 (10%) requested to stop treatment. Median duration of vismodegib exposure was 36·4 weeks (IQR 17·7–62·0). Adverse events happened in 491 (98%) patients; the most common were muscle spasms (317 [64%]), alopecia (307 [62%]), dysgeusia (269 [54%]), weight loss (162 [33%]), asthenia (141 [28%]), decreased appetite (126 [25%]), ageusia (112 [22%]), diarrhoea (83 [17%]), nausea (80 [16%]), and fatigue (80 [16%]). Most adverse events were grade 1 or 2. We recorded serious adverse events in 108 (22%) of 499 patients. Of the 31 patients who died, 21 were the result of adverse events. As assessed by investigators, 302 (66·7%, 62·1–71·0) of 453 patients with locally advanced basal cell carcinoma had an overall response (153 complete responses and 149 partial responses); 11 (37·9%; 20·7–57·7) of 29 patients with metastatic basal cell carcinoma had an overall response (two complete responses, nine partial responses). This study assessed the use of vismodegib in a setting representative of routine clinical practice for patients with advanced basal cell carcinoma. Our results show that treatment with vismodegib adds a novel therapeutic modality from which patients with advanced basal cell carcinoma can benefit substantially. F Hoffmann-La Roche.

Vismodegib, a first-in-class Hedgehog-pathway inhibitor, is approved for use in adults with advanced basal-cell carcinoma. Patients with multiple basal-cell carcinomas, including those with basal-cell nevus (Gorlin) syndrome, need extended treatment. We assessed the safety and activity of two long-term intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas. In this randomised, regimen-controlled, double-blind, phase 2 trial, we enrolled adult patients with multiple basal-cell carcinomas, including those with basal-cell nevus syndrome, who had one or more histopathologically confirmed and at least six clinically evident basal-cell carcinomas. From a centralised randomisation schedule accessed via an interactive voice or web-based response system, patients were randomly assigned (1:1) to treatment group A (150 mg oral vismodegib per day for 12 weeks, then three rounds of 8 weeks of placebo daily followed by 12 weeks of 150 mg vismodegib daily) or treatment group B (150 mg oral vismodegib per day for 24 weeks, then three rounds of 8 weeks of placebo daily followed by 8 weeks of 150 mg vismodegib daily). Treatment assignment was stratified by diagnosis of basal-cell nevus syndrome, geographical region, and immunosuppression status. The primary endpoint was percentage reduction from baseline in the number of clinically evident basal-cell carcinomas at week 73. The primary analysis was by intention to treat. The safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01815840, and the study is ongoing. Between April 30, 2013, and April 9, 2014, 229 patients were randomly assigned treatment, 116 in treatment group A and 113 in treatment group B. The mean number of basal-cell carcinoma lesions at week 73 was reduced from baseline by 62·7% (95% CI 53·0–72·3) in treatment group A and 54·0% (43·6–64·4) in treatment group B. 216 (95%) of 227 patients included in the safety analysis had at least one treatment-emergent adverse event deemed to be related to study treatment (107 [94%] of 114 in treatment group A and 109 [97%] of 113 in treatment group B). The most common grade 3 or worse treatment-related adverse events were muscle spasms (four [4%] patients in treatment group A vs 12 [11%] in treatment group B), increased blood creatine phosphokinase (one [1%] vs four [4%]), and hypophosphataemia (zero vs three [3%]). Serious treatment-emergent events were noted in 22 (19%) patients in treatment group A and 19 (17%) patients in treatment group B. Four (2%) patients died from adverse events; one (pulmonary embolism in treatment group A) was possibly related to treatment. Both intermittent dosing schedules of vismodegib seemed to show good activity in long-term regimens in patients with multiple basal-cell carcinomas. Further study is warranted. F Hoffmann-La Roche.

Neurofibromatosis involves activation of the RAS pathway. Inhibition of MEK, a component of the pathway, with selumetinib was performed in 50 children with inoperable disease. A total of 70% had a response, which was maintained in the majority for more than a year. Pain relief, improved function, and higher quality of life were also observed.

Cystic fibrosis (CF) is a lethal autosomal recessive disorder that afflicts more than 70,000 people. People with CF experience multi-organ dysfunction resulting from aberrant electrolyte transport across polarized epithelia due to mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene. CF-related lung disease is by far the most important determinant of morbidity and mortality. Here we report results from a multi-institute consortium in which single-cell transcriptomics were applied to define disease-related changes by comparing the proximal airway of CF donors ( n  = 19) undergoing transplantation for end-stage lung disease with that of previously healthy lung donors ( n  = 19). Disease-dependent differences observed include an overabundance of epithelial cells transitioning to specialized ciliated and secretory cell subsets coupled with an unexpected decrease in cycling basal cells. Our study yields a molecular atlas of the proximal airway epithelium that will provide insights for the development of new targeted therapies for CF airway disease. Single-cell RNA profiling of human cystic fibrosis proximal airway tissue reveals an overabundance of epithelial cells transitioning to specialized ciliated and secretory cells coupled with a decrease in cycling basal cells.

We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP–CpG associations (methylation quantitative trait loci (meQTL), P  < 10 −14 ), including 467,915 meQTL that operate in trans . The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKBIE (rheumatoid arthritis) , MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961 , chromatin immunoprecipitation followed by sequencing (ChIP–seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1 , with the strongest effect in CD8 + T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype. Genome-wide association analyses of DNA methylation in peripheral blood from 3,799 Europeans and 3,195 South Asians identify unique SNP–CpG associations (meQTL), providing insights into molecular mechanisms and the potential links to phenotypic variation.