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Selinexor is a first-in-class inhibitor of the nuclear exportin XPO1 that was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma. In relapsed/refractory acute myeloid leukemia (AML), selinexor has shown promising activity, suggesting that selinexor-based combination therapies may have clinical potential. Here, motivated by the hypothesis that selinexor's nuclear sequestration of diverse substrates imposes pleiotropic fitness effects on AML cells, we systematically catalog the pro- and anti-fitness consequences of selinexor treatment. We discover that selinexor activates PI3Kγ-dependent AKT signaling in AML by upregulating the purinergic receptor P2RY2. Inhibiting this axis potentiates the anti-leukemic effects of selinexor in AML cell lines, patient-derived primary cultures and multiple mouse models of AML. In a syngeneic, MLL-AF9-driven mouse model of AML, treatment with selinexor and ipatasertib outperforms both standard-of-care chemotherapy and chemotherapy with selinexor. Together, these findings establish drug-induced P2RY2-AKT signaling as an actionable consequence of XPO1 inhibition in AML.

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.

Knowledge of the distribution of genetic resources within and among taxa is prerequisite for development of management strategies which facilitate conservation of those resources. We used restriction-site associated DNA (RAD) sequencing to survey genetic variation in Alvord Chub and Borax Lake Chub from the Alvord Basin in southeastern Oregon and northern Nevada, USA. Our specific goals were to gain an understanding of the population genetic structure of Alvord Chub and the relationship between this species and Borax Lake Chub. Despite the fact that our collections were taken from ponds and streams, isolated from one another by kilometers of desert, our results revealed that diversity in Alvord Chub was primarily distributed among two regional groupings, which we hypothesize to be related to habitat changes following the end of the most recent glaciation event, approximately 10 thousand years ago. Our results further revealed that Alvord Chub and Borax Lake Chub shared common ancestors during that glaciation event, and that divergence between the two may have been sympatric. Finally, we observed evidence that the clade containing Alvord Chub and Borax Lake Chub was isolated from its closest extant relative, the Tui chub, during the Miocene Epoch, when volcanic flows were forming the mountains surrounding what became the Alvord Basin. These results will be useful for informing conservation strategies for Alvord Chub, and provide new insights regarding the role of these species in the evolutionary legacy of the region.

In this paper, we look closely at two events selected through event-oriented inquiry that were part of a classroom presentation on race. The first event was a provocative discussion about Mark Twain’s (Pudd’nhead Wilson, Harper, New York, 1899) and passing for being White. The other was a discussion on the use of the N-word. Grounded in authentic inquiry, we use ethnographic narrative, cogenerative dialogues, and video and oximeter data analyses as part of a multi-ontological approach for studying emotions. Statistical analysis of oximeter data shows statistically significant heart rate synchrony among two of the coteachers during their presentations, providing evidence of emotional synchrony, resonance, and social and emotional contagion.

Protecting genetic diversity throughout the range of a species is important for conservation, as doing so provides for long-term evolutionary potential and persistence under a changing environment. Conservation of diversity at the intraspecific level requires identification of all genetically distinct population segments within species; i.e., conservation units (CUs). Silene spaldingii occurs in grasslands of the Columbia Plateau region of western North America and is listed as threatened under the Federal Endangered Species Act. The recovery plan identified five physiographic regions across the range of the species to use as surrogates for genetic CUs. We collected leaf samples from an average of 26 plants from each of 19 of the largest populations across all five physiographic regions and used variable microsatellite and chloroplast DNA markers to determine how genetic variation is distributed across the range of the species and how well physiographic regions reflect population structure within this species. Results of several multivariate analyses clustered our samples into four genetic groups which did not correspond well with the physiographic regions. We observed little genetic differentiation among populations in the main range of the species which encompasses nearly all of four contiguous physiographic regions. However, three other distinct genetic groups were identified: two in the disjunct northeast corner and one at the southeast edge of the main range. Modification of the CUs to reflect the genetic groups rather than the physiographic regions would result in CUs which better reflect historical patterns of population structure. Moreover, use of the genetic units to inform translocation and genetic rescue efforts could improve our ability to mimic natural patterns of gene flow. Our results suggest that physiographic regions may not always be an accurate reflection of population structure for threatened or endangered species.

Being in the moment, showing compassion, being non-judgmental, acknowledging deep emotional challenges without getting stuck: these are mindfulness characteristics important to us as teachers, yet not often included in teacher preparation. These concerns become magnified when we focus on difficult knowledge and thorny issues, like topics related to gender and race. Using a sociocultural framework, we address how mindfulness, heuristics, and other contemplative practices can be adopted to create safe, supporting, and healing spaces for such complex, often emotionally painful discussions. Participant narratives are used extensively to provide a voice to those marginalized or hurt. Drawing from these narratives and their experience in discussing thorny issues, we put forth possible solutions and interventions that can create spaces that encourage and support critical discourse through mindful practices. The development of a heuristic for discussing thorny issues whose characteristics can be adopted by interested teachers and educators to help frame and mediate this type of difficult discussion is an outcome of this research.

Urbanization presents numerous challenges to aquatic species. For fish, typical threats include altered flow dynamics, poor water quality, and degraded food webs. These threats can be detrimental to fish and whether urban environments can support healthy populations is unclear. Tryon Creek is one of the largest urban watersheds in Portland, Oregon where developed land accounts for 55.6% of total land use. We used demographic, life history, disease, and genetic indices to assess the overall health of the Coastal Cutthroat Trout (Oncorhynchus clarkii) population in Tryon Creek. Results of these population indicators were within ranges for streams with Coastal Cutthroat Trout populations not influenced by urbanization and considered healthy. Coastal Cutthroat Trout in Tryon Creek exhibited a mean condition factor of 1.07 (95% CI 0.95–1.19, range 0.94–1.24), four size-classes, an estimated density of 0.01–0.03 individuals/m2, and migratory behavior. The population did not exhibit excessive deviation from Hardy–Weinberg equilibrium. Genetic diversity in Tryon Creek (He = 0.76; allelic richness = 6.6) was comparable to that observed in non-urbanized streams in the Mt. Hood National Forest (He = 0.72; allelic richness = 5.6). Moreover, allele frequencies appeared stable, and no genetic divergence was detected among generations (F ST ~0.00; non-significant allele frequency heterogeneity tests). The population tested negative for 12 different pathogens and results for Renibacterium salmoninarum were inconclusive. The characteristics of Coastal Cutthroat Trout in Tryon Creek were similar to populations not influenced by urbanization which suggests an urban stream can support a healthy fish population.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Dysregulation of WNT signaling occurs in up to 20% of cases. Using a genome-wide approach, we identified the secreted frizzled-related protein 1, 2 and 3 (SFRP1, SFRP2 and SFRP3) family of WNT inhibitors as putative tumor suppressor genes silenced by promoter region methylation in MB. SFRP1, SFRP2 and SFRP3 expression increased after 5-aza-2′-deoxycytidine treatment. SFRP1, SFRP2 and SFRP3 methylation was identified in 23.5, 3.9 and 15.7% of primary MB specimens, respectively, by methylation-specific PCR. Stable SFRP1, SFRP2 and SFRP3 expression reduced phospho-DVL2 levels and hindered MB cell proliferation and colony formation in soft agar in vitro. In 60% of primary tumors, SFRP1 was expressed at levels twofold lower than that in normal cerebellum. SFRP1 expression impaired tumor formation in vivo in flank and orthotopic intracerebellar xenograft models and conferred a significant survival advantage (P

Medulloblastoma is the most common pediatric primary malignant intracranial neoplasm. The 5-year survival rates vary from 40% to 70% depending on clinical prognostic criteria, and many of the patients who survive exhibit long-term neurocognitive and/or neuroendocrine sequelae. Because of these results, research is required to increase our understanding of the basic biology of medulloblastoma, helping to refine patient stratification, decrease side effects of treatments, identify novel prognostic markers, and discover new less toxic therapies. The recognition that some medulloblastomas occur in familial cancer syndromes has led to some important discoveries in the molecular pathogenesis of medulloblastoma. These syndromes provide us with clues regarding alterations in key signaling or growth factor activation pathways that contribute to medulloblastoma formation. A better understanding of the molecular pathways involved in medulloblastoma formation may allow the discovery of new drugs that act on specific targets, yet many steps must still be taken before clinical use of new drugs. In addition, the identification of a novel signaling pathways in medulloblastoma is often accompanied by the quest for novel pharmacotherapeutics that have the potential to act favorably on this disease.

The intentional introduction of red king crab, Paralithodes camtschatica (Tilesius, 1815) in the Barents Sea represent one of a few successful cases and one that now supports a commercial fishery. Introductions of alien species into new environments are often associated with genetic bottlenecks, which cause a reduction in the genetic variation, and this could be important for the spreading potential of the species in the Atlantic Ocean. Red king crab samples collected in the Varangerfjord located on the Barents Sea (northern Norway) were compared with reference crab samples collected from the Bering Sea and Kamchatka regions in the Pacific Ocean. All samples were screened for eleven microsatellite loci, based on the development of species-specific primers. The observed number of alleles per locus was similar, and no reduction in genetic variation, including gene diversity and allelic richness, was detected between the Varangerfjord sample and the reference sample from Okhotsk Sea near Kamchatka, indicating no genetic bottlenecking at least for the microsatellite loci investigated. The same results were found in comparison with the sample from Bering Sea. The level of genetic differentiation among the samples, measured as overall F ST across all loci, was relatively low (0.0238) with a range of 0.0035–0.1000 for the various loci investigated. The largest pairwise F ST values were found between the Bering Sea and Varangerfjord/Barents Sea samples, with a value of 0.0194 across all loci tested. The lowest value (0.0101) was found between the Varangerfjord and Kamchatka samples. Genetic differentiation based on exact tests on allele frequencies revealed highly significant differences between all pairwise comparisons. The high level of genetic variation found in the Varangerfjord/Barents Sea sample could be of significance with respect to further spreading of the species to other regions in the North Atlantic Ocean.

The apical transmembrane protein Crumbs is a central regulator of epithelial apical-basal polarity in Drosophila. Loss-of-function mutations in the human homologue of Crumbs, CRB1 (RP12), cause recessive retinal dystrophies, including retinitis pigmentosa. Here we show that Crumbs and CRB1 localize to corresponding subdomains of the photoreceptor apical plasma membrane: the stalk of the Drosophila photoreceptor and the inner segment of mammalian photoreceptors. These subdomains support the morphogenesis and orientation of the photosensitive membrane organelles: rhabdomeres and outer segments, respectively. Drosophila Crumbs is required to maintain zonula adherens integrity during the rapid apical membrane expansion that builds the rhabdomere. Crumbs also regulates stalk development by stabilizing the membrane-associated spectrin cytoskeleton, a function mechanistically distinct from its role in epithelial apical-basal polarity. We propose that Crumbs is a central component of a molecular scaffold that controls zonula adherens assembly and defines the stalk as an apical membrane subdomain. Defects in such scaffolds may contribute to human CRB1-related retinal dystrophies.

Infrared absorbance and visible/near-IR excited plasmon resonances are investigated in gold-black, a porous nano-structured conducting film. Polymer infusion (for hardening) generally reduced absorbance in the long wave IR but has little effect at THz wavelengths. The characteristic length scales of the structured films vary considerably as a function of deposition parameters, but the absorbance is found to be only weakly correlated with these distributions. Initial investigations of gold-black by photoelectron emission microscopy (PEEM) reveal plasmon resonances, which have potential to enhance the efficiency of thin film solar cells. For films with different characteristic length scales, the plasmon resonances appear in structures with similar length scales.