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Suplemental Figure Legends for supplemental data

Supplemental Figure 1: Related to Figure 1: Characterization of Gene-Trapped Clones Supplemental Figure 2 Related to Figure 2: PINK1 alters normal astrocyte metabolism Supplemental Figure 3 Related to Figure 2: PINK1 alters normal astrocyte metabolism Supplemental Figure 4: Related to Figure 3: PINK1 alters normal astrocyte metabolism and stabilizes HIF1a Supplemental Figure 5: Related to Figure 3: PINK1 overexpression stops GBM cell growth and inhibits glycolysis. Supplemental Figure 6: Related to Figure 3: PINK1 overexpression inhibits glycolysis. Supplemental Figure 7: Related to Figure 3: PINK1 overexpression inhibits glycolysis. Supplemental Figure 8: Related to Figure 4: Selective targeting in PINK1 expressing GBM cells leads to reduced viability Supplemental Figure 9: Related to Figure 4: Targeting of PINK1 in GBM cells leads to reduced colony formation and caspase activity Supplemental Figure 10: Related to Figure 5 and 6. PINK1 expression in vivo. Supplemental Table 1: Genes identified from gene-trap screen.

Proliferating cancer cells are characterized by high rates of glycolysis, lactate production, and altered mitochondrial metabolism. This metabolic reprogramming provides important metabolites for proliferation of tumor cells, including glioblastoma. These biological processes, however, generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss-of-function screen in nontransformed human astrocytes, we demonstrate that mitochondrial PTEN-induced kinase 1 (PINK1) is a regulator of the Warburg effect and negative regulator of glioblastoma growth. We report that loss of PINK1 contributes to the Warburg effect through ROS-dependent stabilization of hypoxia-inducible factor-1A and reduced pyruvate kinase muscle isozyme 2 activity, both key regulators of aerobic glycolysis. Mechanistically, PINK1 suppresses ROS and tumor growth through FOXO3a, a master regulator of oxidative stress and superoxide dismutase 2. These findings highlight the importance of PINK1 and ROS balance in normal and tumor cells. PINK1 loss was observed in a significant number of human brain tumors including glioblastoma (n > 900) and correlated with poor patient survival. PINK1 overexpression attenuates in vivo glioblastoma growth in orthotopic mouse xenograft models and a transgenic glioblastoma model in Drosophila. Cancer Res; 76(16); 4708–19. ©2016 AACR.

Suplemental methods for experiments appearing in supplemental data and expanded details from methods in main manuscript.

Supplementary Figure S5. PDGFRÃ? pathway inhibition in foretinib treated Daoy and D425 medulloblastoma cells

Supplementary Table S1. Foretinib concentrations in mouse brain, mouse plasma and the brain-plasma ratio

Supplementary Figures 1-5 from An Epigenetic Genome-Wide Screen Identifies SPINT2 as a Novel Tumor Suppressor Gene in Pediatric Medulloblastoma

Medulloblastoma (MB) is a malignant cerebellar tumor that occurs primarily in children. The hepatocyte growth factor (HGF)/MET pathway has an established role in both normal cerebellar development as well as the development and progression of human brain tumors, including MB. To identify novel tumor suppressor genes involved in MB pathogenesis, we performed an epigenome-wide screen in MB cell lines, using 5-aza-2′deoxycytidine to identify genes aberrantly silenced by promoter hypermethylation. Using this technique, we identified an inhibitor of HGF/MET signaling, serine protease inhibitor kunitz-type 2 (SPINT2/HAI-2), as a putative tumor suppressor silenced by promoter methylation in MB. In addition, based on single nucleotide polymorphism array analysis in primary MB samples, we identified hemizygous deletions targeting the SPINT2 locus in addition to gains on chromosome 7 encompassing the HGF and MET loci. SPINT2 gene expression was down-regulated and MET expression was up-regulated in 73.2% and 45.5% of tumors, respectively, by quantitative real-time PCR. SPINT2 promoter methylation was detected in 34.3% of primary MBs examined by methylation-specific PCR. SPINT2 reexpression in MB cell lines reduced proliferative capacity, anchorage independent growth, cell motility in vitro, and increased overall survival times in vivo in a xenograft model (P < 0.0001). Taken together, these data support the role of SPINT2 as a putative tumor suppressor gene in MB, and further implicate dysregulation of the HGF/MET signaling pathway in the pathogenesis of MB. [Cancer Res 2008;68(23):9945–53]

Supplementary Methods and Figure Legends

Supplementary Figure 7 from An Epigenetic Genome-Wide Screen Identifies SPINT2 as a Novel Tumor Suppressor Gene in Pediatric Medulloblastoma

Supplementary Figure 6 from An Epigenetic Genome-Wide Screen Identifies SPINT2 as a Novel Tumor Suppressor Gene in Pediatric Medulloblastoma

In 2015, Wisconsin began mandating the ACT college entrance exam and the WorkKeys career readiness assessment. With population-level data and several quasi-experimental designs, we assess how this policy affected college attendance. We estimate a positive policy effect for middle/high-income students, no effect for low-income students, and greater effects at high schools that had lower ACT participation before the policy. We further find little evidence that being deemed college-ready by one’s ACT scores or career-ready by one’s WorkKeys scores affects college attendance probabilities. Pragmatically, the findings highlight the policy’s excellence and equity consequences, which are complex given that the policy has principally helped advantaged students. Theoretically, the findings shed light on students’ (dis)inclinations to update educational beliefs in light of new signals.

Racialized tracking is central to sociological explanations for racially stratified educational outcomes. However, school officials’ decision-making is of debated importance for explaining racialized tracking. We contribute to this literature by examining the effects of schools’ enrollment policies for Advanced Placement (AP) courses. Using a unique combination of school survey data and administrative data from Wisconsin, we examine what happens to racial inequality in AP participation when school officials enforce performance-based selection criteria, which we call “course gatekeeping.” We find that course gatekeeping has racially disproportionate effects. Although racialized differences in prior achievement partially explain the especially large negative effects among students of color, course gatekeeping producesBlack-white and Hispanic-white disparities in participation even among students with similar, relatively low prior achievement. We further find that course gatekeeping has longer-run effects, particularly discouraging Black and Asian or Pacific Islander students from attending highly selective four-year colleges.

For decades, cell biologists and cancer researchers have taken advantage of non-murine species to increase our understanding of the molecular processes that drive normal cell and tissue development, and when perturbed, cause cancer. The advent of whole-genome sequencing has revealed the high genetic homology of these organisms to humans. Seminal studies in non-murine organisms such as Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio identified many of the signaling pathways involved in cancer. Studies in these organisms offer distinct advantages over mammalian cell or murine systems. Compared to murine models, these three species have shorter lifespans, are less resource intense, and are amenable to high-throughput drug and RNA interference screening to test a myriad of promising drugs against novel targets. In this review, we introduce species-specific breeding strategies, highlight the advantages of modeling brain tumors in each non-mammalian species, and underscore the successes attributed to scientific investigation using these models. We conclude with an optimistic proposal that discoveries in the fields of cancer research, and in particular neuro-oncology, may be expedited using these powerful screening tools and strategies.

Recent work has broadened the scope of school effectiveness research to consider not only academic achievement but also other outcomes, especially college attendance. This literature has argued that high schools are an important determinant of college attendance, with some contending that high schools matter more for college attendance than for academic achievement. A separate branch of research has illustrated how place-based opportunities facilitate college attendance. We merge these two literatures by asking if schools’ geographic context can explain apparent variation in effectiveness among Wisconsin high schools. We find that geographic context explains nearly a third of the variance in traditional estimates of school effectiveness on college attendance, because factors like proximity to colleges are strongly associated with college attendance. Accounting for geography is therefore important in order not to overstate high schools’ role in higher education outcomes. In contrast, geographic context explains little of the variance in academic achievement growth. Thus, if high schools seem to matter more for college attendance than for academic achievement under traditional estimates, schools’ apparent importance for the two outcomes converge upon adjusting for differences in geographic context. Results are based on multilevel models applied to rich administrative data on every Wisconsin public high school entrant between 2006 and 2011.

Terrorism is a major problem worldwide, causing thousands of fatalities and billions of dollars in damage every year. Toward the end of better understanding and mitigating these attacks, we present a set of machine learning models that learn from localized news data in order to predict whether a terrorist attack will occur on a given calendar date and in a given state. The best model--a Random Forest that learns from a novel variable-length moving average representation of the feature space--achieves area under the receiver operating characteristic scores $> .667$ on four of the five states that were impacted most by terrorism between 2015 and 2018. Our key findings include that modeling terrorism as a set of independent events, rather than as a continuous process, is a fruitful approach--especially when the events are sparse and dissimilar. Additionally, our results highlight the need for localized models that account for differences between locations. From a machine learning perspective, we found that the Random Forest model outperformed several deep models on our multimodal, noisy, and imbalanced data set, thus demonstrating the efficacy of our novel feature representation method in such a context. We also show that its predictions are relatively robust to time gaps between attacks and observed characteristics of the attacks. Finally, we analyze factors that limit model performance, which include a noisy feature space and small amount of available data. These contributions provide an important foundation for the use of machine learning in efforts against terrorism in the United States and beyond.

In Norway, onomastic fieldwork and the study of place names have a tradition back to the 19th c. In 20th c. numerous field work campaigns were undertaken and extensive collections were created. The last large project ended almost 40 years ago. This fact and the Norwegian ratification of the UNESCO charter for the protection of intangible cultural heritage in 2007, prompted the Norwegian Cultural Ministry to launch a funding scheme for the collection of local place names. The paper discusses the context for this decision. A digital registration system was ready in 2016 and in the same year, the first projects were funded. In the paper, the registered data are analysed and the experiences with the system are discussed. The database currently contains 126 000 detailed registrations. This is a substantial number, and the project can be considered a success. On the other hand, the number could have been higher. A reason for this is the lack of a good and user-friendly search interface and a nationwide organization taking care of datasets from onomastic fieldwork.

Bolstering low-income students’ postsecondary participation is important to remediate these students’ disadvantages and to improve society’s overall level of education. Recent research has demonstrated that secondary schools vary considerably in their tendencies to send students to postsecondary education, but existing research has not systematically identified the school characteristics that explain this variation. Identifying these characteristics can help improve low-income students’ postsecondary outcomes. We identify relevant characteristics using population-level data from Wisconsin, a mid-size state in the United States. We first show that Wisconsin’s income-based disparities in postsecondary participation are wide, even net of academic achievement. Next, we show that several geographic characteristics of schools help explain between-secondary school variation in low-income students’ postsecondary outcomes. Finally, we test whether a dense set of school organisational features explain any remaining variation. We find that these features explain virtually no variation in secondary schools’ tendencies to send low-income students to postsecondary education.

Public wildlife management in the United States is transforming as agencies seek relevancy to broader constituencies. State agencies in the United States, while tasked with conserving wildlife for all beneficiaries of the wildlife trust, have tended to manage for a limited range of benefits in part due to a narrow funding model heavily dependent on hunting, fishing, and trapping license buyers. To best meet the needs, interests, and concerns of a broader suite of beneficiaries, agencies will need to reconsider how priorities for management are set. This presents an opportunity for conservation program design and evaluation to be elevated in importance. We argue that success in wildlife conservation in the U.S. requires assessment of both decision-making processes and management results in relation to four questions: conservation of what, under what authority, for what purposes, and for whom?

Studying 380,000 criminal cases in federal district courts from 2006 to 2019, we replicate previous findings that aggregate, conditional racial disparities in sentence lengths are large. We further show that estimated racial disparities in sentencing vary considerably across judges. Results suggest that judges assign white defendants sentences that are conditionally 13% shorter than Black defendants’ and 19% shorter than Hispanic defendants’, on average. A judge who is one standard deviation above average in terms of estimated Black-white disparity gives Black defendants sentences that are conditionally 39% longer than white defendants’, compared to the average disparity of 13%. A judge who is one standard deviation above average in terms of estimated Hispanic-white disparity gives Hispanic defendants sentences that are conditionally 49% longer than white defendants’, compared to the average disparity of 19%.

The five most common species of Pacific salmon, Rainbow Trout (steelhead) Oncorhynchus spp., and Atlantic Salmon Salmo salar intermingle in the North Pacific Ocean and its freshwater tributaries. Efficient morphological methods for distinguishing among these species are sometimes limited by condition of the specimen (degraded or missing morphology), life history stage, or training of the observer. Researchers have successfully applied various genetic methods to distinguish among these species when morphological analyses are not possible, but they cannot easily incorporate these methods into standard fish and wildlife population monitoring analysis workflows. Here we test five 5′–3′ exonuclease (TaqMan) assays developed from mitochondrial genes and provide novel methods that take advantage of TaqMan output to distinguish among these species. We found that combinations of as few as two of the five assays were adequate to distinguish all species. TaqMan chemistry is designed to interrogate a single nucleotide locus. We also explore the basis for the variation in the observed scatter plot distributions (variation in florescent signals) and show that this variation is due to nucleotide diversity in and near the probe site. Because the SNPs underlying the assays developed here are all physically close to one another along the mitochondrial genome, the potential exists to develop a single DNA sequence-based assay to discriminate among salmon species. This single assay can be added to a genotyping-by-sequencing panel to identify and exclude nontarget species from analyses.

Patient-derived xenografts retain the genotype of the parent tumors more readily than tumor cells maintained in culture. The two previously reported clival chordoma xenografts were derived from recurrent tumors after radiation. To study the genetics of clival chordoma in the absence of prior radiation exposure we established a patient-derived xenograft at primary resection of a clival chordoma. Epicranial grafting of clival chordoma collected during surgery was performed. Tumor growth was established in a nonobese diabetic/severe combined immunodeficiency mouse and tumors have been passaged serially for seven generations. Physaliferous cell architecture was shown in the regenerated tumors, which stained positive for Brachyury, cytokeratin, and S100 protein. The tumors showed bone invasion. Single-nucleotide polymorphism analysis of the tumor xenograft was compared with the parental tumor. Copy number gain of the T gene (brachyury) and heterozygous loss of cyclin dependent kinase inhibitor 2A (CDKN2A) was observed. Heterozygous loss of the tumor-suppressor fragile histidine triad (FHIT) gene also was observed, although protein expression was preserved. Accumulation of copy number losses and gains as well as increased growth rate was observed over three generations. The patient-derived xenograft reproduces the phenotype of clival chordoma. This model can be used in the future to study chordoma biology and to assess novel treatments.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, with a median survival of just over one year. The failure of available treatments to achieve remission in patients with GBM has been attributed to the presence of cancer stem cells (CSCs), which are thought to play a central role in tumor development and progression and serve as a treatment-resistant cell repository capable of driving tumor recurrence; in fact, the property of “stemness” itself may be responsible for treatment resistance. In this study, we identify a novel lncRNA, Cancer stem cell associated distal enhancer of SOX2 (CASCADES) that functions as an epigenetic regulator in glioma CSCs (GSCs). CASCADES is expressed in IDH-wild type GBM and significantly enriched in GSCs. Knockdown of CASCADES in GSCs results in differentiation towards a neuronal lineage in a cell- and cancer-specific manner. Bioinformatics analysis reveals that CASCADES functions as a super-enhancer associated lncRNA epigenetic regulator of SOX2. Our findings identify CASCADES as a critical regulator of stemness in GSCs and represent a novel epigenetic and therapeutic target for disrupting the cancer stem cell compartment in GBM.

In the Unites States, the public has a constitutional right to access criminal trial proceedings. In practice, it can be difficult or impossible for the public to exercise this right. We present JUSTFAIR: Judicial System Transparency through Federal Archive Inferred Records, a database of criminal sentencing decisions made in federal district courts. We have compiled this data set from public sources including the United States Sentencing Commission, the Federal Judicial Center, the Public Access to Court Electronic Records system, and Wikipedia. With nearly 600,000 records from the years 2001 - 2018, JUSTFAIR is the first large scale, free, public database that links information about defendants and their demographic characteristics with information about their federal crimes, their sentences, and, crucially, the identity of the sentencing judge.

In this paper we present our study how to use the Meta Dictionary of the Norwegian Language Collections to measure lexical stability in standard dictionaries across a timespan. The Meta Dictionary uses the lexical item as its core unit, expressing each lexical unit in a separate Meta Dictionary entry. The success of this model rests on having access to electronic versions of major and generally accepted dictionaries from the different stages of the orthography of a language. With this documentation it is possible to see, for instance, how much and which parts of the 1873 lexicon (Norwegian vernacular) is present in modern Nynorsk and Bokmål respectively, and whether this lexicon is present in its original orthography or not. This method for studies of the lexical development is comparable to remote sensing in archaeology and distant reading in literary studies. As an extended example of the application of the method we study a few issues related to the position of the pioneering lexicographers Ivar Aasen (1813-1896) and Hans Ross (1831-1912) in the description of Nynorsk, as shown in more recent lexicographical works, and in particular in two school dictionaries from 1954 and 1970 which border on being spellers. publishedVersion

In its December 2019 edition, the \textit{Notices of the American Mathematical Society} published an essay critical of the use of diversity statements in academic hiring. The publication of this essay prompted many responses, including three public letters circulated within the mathematical sciences community. Each letter was signed by hundreds of people and was published online, also by the American Mathematical Society. We report on a study of the signatories' demographics, which we infer using a crowdsourcing approach. Letter A highlights diversity and social justice. The pool of signatories contains relatively more individuals inferred to be women and/or members of underrepresented ethnic groups. Moreover, this pool is diverse with respect to the levels of professional security and types of academic institutions represented. Letter B does not comment on diversity, but rather, asks for discussion and debate. This letter was signed by a strong majority of individuals inferred to be white men in professionally secure positions at highly research intensive universities. Letter C speaks out specifically against diversity statements, calling them "a mistake," and claiming that their usage during early stages of faculty hiring "diminishes mathematical achievement." Individuals who signed both Letters B and C, that is, signatories who both privilege debate and oppose diversity statements, are overwhelmingly inferred to be tenured white men at highly research intensive universities. Our empirical results are consistent with theories of power drawn from the social sciences., 21 pages, 2 tables, 2 figures; minor textual edits made to previous version

Atypical Teratoid/Rhabdoid Tumours (ATRT) are highly malignant neoplasms arising primarily in the CNS of children. They are defined by loss of function mutations in smarcb1, a gene serving a vital role in neurogenesis and differentiation. In order to recapitulate ATRT in the mouse, we used a Cre-Lox recombination system to conditionally knockout smarcb1 in specific cell compartments. Loss of smarcb1 in BLBP-expressing cells of the developing brain led to severe neurologic defects. Mice exhibited seizures, ataxia, and median 12-day survival. Histological analysis revealed severe thinning of the cerebral cortex and cerebellum. Temporally-targeted smarcb1 loss in BLBP/Nestin-expressing embryonic compartments did not result in tumour formation. Similarly, BLBP-expressing, smarcb1-deficient neural stem/progenitor cells (NSC/NPCs) were isolated and allografted but did not form tumours. These cells demonstrated decreased proliferation, higher apoptosis, and upregulation of p53, CDKN1A, and CDKN2A. In contrast, ubiquitous smarcb1 loss at the earlier embryonic day 6.5 produced widespread tumorigenicity in the forebrain, hindbrain, skullbase, and spine; each with unique phenotypes, survival, and morphology. We employed a clinically-relevant Nanostring gene-panel screen to stratify tumours into genetically distinct subgroups. Our findings indicate that smarcb1 plays an important role in CNS development. Loss of smarcb1 in NSC/NPCs is lethal, and its developmental context influences cell fate. Targeted smarcb1 loss likely plays a tumorigenic role at an earlier developmental stage than previously determined, in a diverse array of primitive stem cells. These data support the generation of a murine ATRT model capable of producing distinct tumour entities that recapitulate the human disease.

Past research finds that the effect of socioeconomic origin on the probability of making educational transitions decreases for successively higher educational transitions, suggesting for example that one’s family of origin matters less for college entry than it does for high school completion. This pattern of waning effects could well be the result of selective attrition, since those of modest social origins who make a given transition may have unobserved characteristics, such as cognitive or noncognitive skills, that help them make the next transition, while better off individuals may be less steeply selected on these characteristics. I study a sample of American 10th graders from 1980 to assess how much the pattern of waning effects is due to selective attrition along academic and noncognitive skills for this cohort. I find that controlling for academic skills makes the effect of socioeconomic status more stable across transitions, but controlling for noncognitive skills does not. Socioeconomic advantage does not decline uniformly across transitions, and it appears most pronounced at the transition into college. These results do not support a claim that late transitions are egalitarian.

Sampling is a fundamental aspect of any implementation of compressive sensing. Typically, the choice of sampling method is guided by the reconstruction basis. However, this approach can be problematic with respect to certain hardware constraints and is not responsive to domain-specific context. We propose a method for defining an order for a sampling basis that is optimal with respect to capturing variance in data, thus allowing for meaningful sensing at any desired level of compression. We focus on the Walsh-Hadamard sampling basis for its relevance to hardware constraints, but our approach applies to any sampling basis of interest. We illustrate the effectiveness of our method on the Physical Sciences Inc. Fabry-P\'{e}rot interferometer sensor multispectral dataset, the Johns Hopkins Applied Physics Lab FTIR-based longwave infrared sensor hyperspectral dataset, and a Colorado State University Swiss Ranger depth image dataset. The spectral datasets consist of simulant experiments, including releases of chemicals such as GAA and SF6. We combine our sampling and reconstruction with the adaptive coherence estimator (ACE) and bulk coherence for chemical detection and we incorporate an algorithmic threshold for ACE values to determine the presence or absence of a chemical. We compare results across sampling methods in this context. We have successful chemical detection at a compression rate of 90%. For all three datasets, we compare our sampling approach to standard orderings of sampling basis such as random, sequency, and an analog of sequency that we term `frequency.' In one instance, the peak signal to noise ratio was improved by over 30% across a test set of depth images., Comment: 15 pages

Diffuse intrinsic pontine glioma (DIPG) is a surgically unresectable and devasting tumor in children. To date, there have been no effective chemotherapeutics despite a myriad of clinical trials. The intact blood-brain barrier (BBB) in part is responsible for the limited clinical response to chemotherapy. MRI guided focused ultrasound (MRgFUS) is a promising non-invasive tissue ablative method for CNS tumors. Moreover, MRgFUS allows for the temporary disruption of BBB. Our first objective was to determine the feasibility and safety of temporary BBB disruption within the brainstem using MRgFUS following intravenous (IV) administration of microbubbles in vivo. Our second objective was to select effective chemotherapeutics against DIPG cell lines, and to examine their therapeutic effects with MRgFUS in a mouse model of DIPG which exhibits an intact BBB. The non-invasive opening of the BBB was determined in the brainstem of normal rodents using physiological monitoring and histological analysis. Doxorubicin was selected from a drug screen consisting of conventional chemotherapeutics using SU-DIPG4 and SU-DIPG17 cell lines. We established SU-DIPG17 xenografts which demonstrated diffusely infiltrative tumor growth similar to human DIPG. By LC-MS/MS analysis, MRgFUS led to a 4-fold increase in doxorubicin concentrations within the brainstem tumors following IV administration when compared to IV administration alone, We demonstrated feasibility and safety of MRgFUS in the rodent brainstem and have shown that MRgFUS increases doxorubicin uptake in the brainstem of a rodent model of DIPG. These preclinical data will be helpful in designing clinical trials of BBB disruption using MRgFUS for DIPG in children.

Proliferating cancer cells are characterized by high rates of glycolysis, lactate production, and altered mitochondrial metabolism. This metabolic reprogramming provides important metabolites for proliferation of tumor cells, including glioblastoma. These biological processes, however, generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss-of-function screen in nontransformed human astrocytes, we demonstrate that mitochondrial PTEN-induced kinase 1 (PINK1) is a regulator of the Warburg effect and negative regulator of glioblastoma growth. We report that loss of PINK1 contributes to the Warburg effect through ROS-dependent stabilization of hypoxia-inducible factor-1A and reduced pyruvate kinase muscle isozyme 2 activity, both key regulators of aerobic glycolysis. Mechanistically, PINK1 suppresses ROS and tumor growth through FOXO3a, a master regulator of oxidative stress and superoxide dismutase 2. These findings highlight the importance of PINK1 and ROS balance in normal and tumor cells. PINK1 loss was observed in a significant number of human brain tumors including glioblastoma (n > 900) and correlated with poor patient survival. PINK1 overexpression attenuates in vivo glioblastoma growth in orthotopic mouse xenograft models and a transgenic glioblastoma model in Drosophila. Cancer Res; 76(16); 4708–19. ©2016 AACR.

Wildlife conservation is losing ground in the U.S. for many reasons. The net effect is declines in species and habitat. To address this trend, the wildlife conservation institution (i.e., all customs, practices, organizations and agencies, policies, and laws with respect to wildlife) must adapt to contemporary social–ecological conditions. Adaptation could be supported by clear guidelines reflecting contemporary expectations for wildlife governance. We combine elements of public trust thinking and good governance to produce a broad set of wildlife governance principles. These principles represent guidance for ecologically and socially responsible wildlife conservation. They address persistent, systemic problems and, if adopted, will bring the institution into line with modern expectations for governance of public natural resources. Implementation will require changes in values, objectives, and processes of the wildlife conservation institution. These changes may be difficult, but promise improved wildlife conservation outcomes and increased support for conservation. We introduce challenges and opportunities associated with the principles, and encourage dialogue about them among scientists, practitioners, and other leaders in U.S. wildlife conservation. The principles alone will not change the course of conservation for the better, but may be necessary for such change to occur.

We study, by numerical simulations and experimentally, the resonant diffraction by metal (Ag) gratings in the mid-IR ( $\sim 10~\mu \text{m}$ ) spectral range. The excitation of surface plasmon-polaritons facilitates narrow-band resonantly enhanced diffraction into symmetry-prohibited diffraction orders. We show that, even though the propagation losses for plasmonic modes are greatly reduced at longer wavelengths, the magnitude of the resonant diffraction peak remains limited due to diffraction into other, normally allowed, diffraction orders. The grating depth dependence of the resonant diffraction spectra indicates that with shallower gratings, the $Q$ -factor of the resonance may become as large as $10^{3}$ – $10^{4}$ , while the magnitude of the peak is reduced.

Introduction: Osteoporosis remains an undertreated disease entity causing substantial morbidity and mortality. Proximal humerus fractures are a common sentinel fracture, providing an opportunity to intervene with antiresorptive therapy before more subsequent fractures occur. Despite the success of programs aimed to improve postfracture osteoporosis recognition and management, less than 30% of patients presenting with a fragility fracture are diagnosed or treated for osteoporosis nationally. Further elucidation of diagnosis and management of osteoporosis following humerus fracture is warranted. Methods: This study is a retrospective cohort review intended to demonstrate the current state and clinical import of osteoporosis diagnosis and management following a humerus fracture at a large academic tertiary care center without an established secondary fracture prevention program. All patients 50 years of age or older who presented with a new humerus fracture between 2008 and 2014 were included. Outcome measures included: The initiation of antiresorptive therapy or screening before fracture, within the year following fracture, or not at all. Results: One thousand seven hundred unique geriatric patients were seen for humerus fractures. Nineteen percent of these patients (n = 324) were already on an antiresorptive medication. Three percent of previously untreated patients were started on antiresorptive therapy during the year after their fracture, with 31 or 2% of untreated patients starting at any subsequent point. Seventy-six percent of patients (n = 1301) were never prescribed antiresorptive therapy. Discussion and Conclusion: In the absence of a dedicated program to improve secondary fracture prevention following minimal trauma spinal fractures, recognition and treatment of osteoporosis in patients remained inadequate over time despite numerous calls to action on the topic in the orthopedic literature and public health initiatives. Undertreatment of osteoporosis puts patients at increased risk for additional fractures. This study underscores an opportunity to improve bone health by aggressively screening for and treating osteoporosis in geriatric humerus fracture patients.

Studies in social stratification have used siblings as a tool to learn about the intergenerational transmission of advantage but less often have asked how siblings impact one another’s life chances. The author draws on social capital theory and hypothesizes that when youths attend college, they increase the probability that their siblings attend college. The author further hypothesizes that this effect is strongest among youths whose parents do not have college degrees. Findings from a U.S. national probability sample support both hypotheses. Although it is possible that confounding factors drive the estimates, the author conducts robustness checks that show that confounding would need to be very atypically strong to invalidate a causal interpretation. The positive main effect suggests that an intragenerational transmission of educational advantage exists alongside the intergenerational transmission that receives more attention. Effect heterogeneity points to the potential redundancy of college-educated siblings’ benefits when youths already receive similar benefits from college-educated parents.

Bokmål og nynorsk gir som skriftmål hver sin innfallsport til norsk språkbruk og skriftkultur. Enten en ser bokmål og nynorsk som to ulike skriftmål eller som to ulike skriftlige uttrykk for norsk talemål, så er de nærstående skriftspråkstandarder, og utgjør til sammen den skriftspråklige rammen som folk i Norge lever innenfor, med et historisk spenn fra dansk (før 1907) til Aasen-normalen (uttrykt i oppslagsordformen i Aasens Norsk Ordbog fra 1873). Formålet med arbeidet som er beskrevet i denne artikkelen, er å legge til rette for en systematisk undersøkelse av skriftmålsutviklingen i norsk på 1900-tallet. Dersom en skal kunne uttale seg med en rimelig grad av sikkerhet om resultatene av norsk språkpolitikk etter 1900, må det foreligge språksamlinger som samordner både primærkilder og sekundærkilder for begge målformer på ordnivå.

The conference theme of CAA2016 was “Exploring Oceans of Data”, hinting at the vast amount of digital data resulting from digitisation projects and from all kind of electronic measuring gadgets used to document excavations and surveys. The digital data are much more fragile than paper and can easily evaporate. The last decade we have been told to avoid information islands and the slogan has been “Open the data silos”. Is it easier to find a needle in an enormous haystack than in many small? If we are satisfied with the result lists of the google-type answer, it is a clear yes. If we want to build scientific data sets which may be aggregated into larger data sets, we need common authority systems and ontologies for data integration. Archaeology is neither library nor archival science, but methods for construction, curation and reuse of archaeological data sets must be the main focus. Standardised conceptual data models can ease curation and secure long term reusability and will not impose a straitjacket on research.

Genotypic sex identification assays can provide valuable information about fish populations when phenotypic sex determination is difficult. Here we describe the development of a TaqMan® assay (Ots_SexID) designed to identify the genotypic sex by targeting a region previously examined in the growth hormone pseudogene for winter-run Chinook salmon (Oncorhynchus tshawytscha) collected from the Sacramento River and spawned at the Livingston Stone National Fish Hatchery. Accuracy of the marker was assessed by comparing genotypic sex assignments for Chinook salmon spawned at Livingston Stone National Fish hatchery in 2012 (n = 84) with phenotypic sex recorded during spawning. Genotypic sex was observed to be concordant with phenotypic sex identified using Ots_SexID in 83/84 individuals, suggesting that the assay could be used to predict phenotypic sex with ∼︀99% accuracy. To evaluate the utility of the TaqMan assay in other parts of the species’ range, we examined collections from 29 other populations ranging from Alaska to California. Genotypic sex assignments based on the assay were generally concordant with observed phenotypes, but there were some strong exceptions. These results suggest that the new assay will be very useful for Sacramento River winter-run Chinook salmon, but also highlight the importance of thoroughly testing any genotypic sex identification assay before application in a population of interest.

Magnetic Resonance Image-guided Focused Ultrasound (MRgFUS) has been used to achieve transient blood brain barrier (BBB) opening without tissue injury. Delivery of a targeted ultrasonic wave causes an interaction between administered microbubbles and the capillary bed resulting in enhanced vessel permeability. The use of MRgFUS in the brainstem has not previously been shown but could provide value in the treatment of tumours such as Diffuse Intrinsic Pontine Glioma (DIPG) where the intact BBB has contributed to the limited success of chemotherapy. Our primary objective was to determine whether the use of MRgFUS in this eloquent brain region could be performed without histological injury and functional deficits. Our secondary objective was to select an effective chemotherapeutic against patient derived DIPG cell lines and demonstrate enhanced brainstem delivery when combined with MRgFUS in vivo. \ud \ud \ud \ud Female Sprague Dawley rats were randomised to one of four groups: 1) Microbubble administration but no MRgFUS treatment; 2) MRgFUS only; 3) MRgFUS + microbubbles; and 4) MRgFUS + microbubbles + cisplatin. Physiological assessment was performed by monitoring of heart and respiratory rates. Motor function and co-ordination were evaluated by Rotarod and grip strength testing. Histological analysis for haemorrhage (H & E), neuronal nuclei (NeuN) and apoptosis (cleaved Caspase-3) was also performed. A drug screen of eight chemotherapy agents was conducted in three patient-derived DIPG cell lines (SU-DIPG IV, SU-DIPG XIII and SU-DIPG XVII). Doxorubicin was identified as an effective agent. NOD/SCID/GAMMA (NSG) mice were subsequently administered with 5 mg/kg of intravenous doxorubicin at the time of one of the following: 1) Microbubbles but no MRgFUS; 2) MRgFUS only; 3) MRgFUS + microbubbles and 4) no intervention. Brain specimens were extracted at 2 h and doxorubicin quantification was conducted using liquid chromatography mass spectrometry (LC/MS). \ud \ud \ud \ud BBB opening was confirmed by contrast enhancement on T1-weighted MR imaging and positive Evans blue staining of the brainstem. Normal cardiorespiratory parameters were preserved. Grip strength and Rotarod testing demonstrating no decline in performance across all groups. Histological analysis showed no evidence of haemorrhage, neuronal loss or increased apoptosis. \ud \ud \ud \ud Doxorubicin demonstrated cytotoxicity against all three cell lines and is known to have poor BBB permeability. Quantities measured in the brainstem of NSG mice were highest in the group receiving MRgFUS and microbubbles (431.5 ng/g). This was significantly higher than in mice who received no intervention (7.6 ng/g). \ud \ud \ud \ud Our data demonstrates both the preservation of histological and functional integrity of the brainstem following MRgFUS for BBB opening and the ability to significantly enhance drug delivery to the region, giving promise to the treatment of brainstem-specific conditions.

Patient-derived xenografts (PDXs) retain the genotype of the parental tumors more readily than tumor cells maintained in culture. In order to study the genetics of clival chordoma in the absence of prior radiation we sought to establish a PDX following the primary resection of a clival chordoma. Epicranial grafting of a primary clival chordoma was performed in NOD/SCID mice. Tumors have been passaged serially in mice for 7 generations. Physaliferous cell architecture was demonstrated in the regenerated tumors, which stained positive for Brachyury, Cytokeratin, and S100. The tumors demonstrated bone invasion. Single-nucleotide polymorphism analysis of the tumor xenograft was compared to the parental tumor. We identified homozygous amplification of the T-gene (brachury) and heterozygous loss of CDKN2A. We also identified heterozygous loss of the tumor suppressor FHIT gene, although protein expression was preserved. Accumulation of copy number losses and gains over three generations showed for the first time that there is inherent genomic instability in chordoma. In conclusion, this PDX reproduces the phenotype of clival chordoma. This study is the first to show chromosomal genomic instability in a chordoma that is serially propagated through multiple generations. The genomic instability observed in chordoma may serve as the biological basis for resistance to chemotherapy as is observed for other forms of cancer.