WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma.

Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by populations of cancer stem cells (CSCs). However, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy-resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1 family-mediated Lys4 methylation of histone H3 (H3K4me), associated with positive regulation of transcription. In GBM CSCs, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, including the POU5F1(OCT4)::SOX2 motif. Use of a SOX2/OCT4 reporter demonstrated that WDR5 inhibitor treatment diminished cells with high reporter activity. Furthermore, WDR5 inhibitor treatment and WDR5 knockdown altered the stem cell state, disrupting CSC in vitro growth and self-renewal, as well as in vivo tumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.

Associations between Parental Engagement in the Neonatal Intensive Care Unit and Neighborhood-Level Socioeconomic Status.

OBJECTIVE: This study aimed to (1) determine the effect of neighborhood-level socioeconomic status (SES), which considers the social and physical environment where a person lives, on parental engagement in the Neonatal Intensive Care Unit (NICU) and (2) compare the relationships between parental engagement and individual versus neighborhood-level measures of SES. STUDY DESIGN: In this cohort study, parents (n = 45) of premature neonates ≤34 weeks' gestation were assessed at 2 and 6 weeks after birth from December 2017 to October 2019. Neighborhood-level SES was determined using census data per the Association of Maternal and Child Health Programs' methodology, and parents self-reported their education level as an individual-level measure of SES. Data on frequency of engagement in NICU activities, including telephone updates, visitation, providing expressed breastmilk, and participating in kangaroo care, were collected from the electronic medical record. Parent psychosocial factors were assessed using validated surveys. Statistical analysis was performed using Fisher's exact test, t-test, and logistic regression. RESULTS: In multivariate regression analysis, disadvantaged neighborhood-level SES was associated with decreased odds of kangaroo care (OR = 0.16, 95% CI: [0.03-0.89]) and visitation (OR = 0.14, 95% CI: [0.02-0.87]), while lower individual-level SES was not significantly associated with kangaroo care, visiting, calling, or pumping (p > 0.05). CONCLUSION: Parental engagement was more consistently and significantly associated with neighborhood-level SES than with individual-level SES. Therefore, neighborhood-level SES measures may be more explanatory than individual-level SES measures. Further studies and targeted interventions are needed to address disparities in the frequency of kangaroo care and visitation according to SES. KEY POINTS: · Parents from disadvantaged neighborhoods are less likely to do kangaroo care and visit the NICU.. · Parent engagement was more significantly associated with neighborhood than with parent education.. · Neighborhood-level SES measures may be more explanatory than individual-level SES measures.. · Interventions are needed to address SES-related disparities in NICU kangaroo care and visitation..

Transcription elongation factors represent in vivo cancer dependencies in glioblastoma.

Glioblastoma is a universally lethal cancer with a median survival time of approximately 15 months. Despite substantial efforts to define druggable targets, there are no therapeutic options that notably extend the lifespan of patients with glioblastoma. While previous work has largely focused on in vitro cellular models, here we demonstrate a more physiologically relevant approach to target discovery in glioblastoma. We adapted pooled RNA interference (RNAi) screening technology for use in orthotopic patient-derived xenograft models, creating a high-throughput negative-selection screening platform in a functional in vivo tumour microenvironment. Using this approach, we performed parallel in vivo and in vitro screens and discovered that the chromatin and transcriptional regulators needed for cell survival in vivo are non-overlapping with those required in vitro. We identified transcription pause-release and elongation factors as one set of in vivo-specific cancer dependencies, and determined that these factors are necessary for enhancer-mediated transcriptional adaptations that enable cells to survive the tumour microenvironment. Our lead hit, JMJD6, mediates the upregulation of in vivo stress and stimulus response pathways through enhancer-mediated transcriptional pause-release, promoting cell survival specifically in vivo. Targeting JMJD6 or other identified elongation factors extends survival in orthotopic xenograft mouse models, suggesting that targeting transcription elongation machinery may be an effective therapeutic strategy for glioblastoma. More broadly, this study demonstrates the power of in vivo phenotypic screening to identify new classes of 'cancer dependencies' not identified by previous in vitro approaches, and could supply new opportunities for therapeutic intervention.

Transfusion support for patients with sickle cell disease.

Red blood cell (RBC) transfusion is an essential treatment for many patients with sickle cell disease (SCD), whose RBCs express hemoglobin S (HbS), a mutated form of hemoglobin A (HbA). Transfusion goals include increasing blood oxygen carrying capacity and decreasing the relative amount of HbS to HbA to mitigate vaso-occlusion in small blood vessels. In situations where correction of severe anemia and reduction in HbS may be achieved without removal of RBCs, simple transfusion may be utilized. Partial manual RBC exchange, which removes blood containing HbS by phlebotomy and replaces with donor blood transfusion sequentially allows for larger changes in the ratio of HbS to HbA when compared to simple transfusion. Automated RBC exchange by apheresis is useful in situations where a rapid and drastic HbS reduction is indicated. Vascular access is an important consideration for transfusion. Although peripheral access may be sufficient, central venous catheters and implantable venous access devices may be necessary for adequate access over time. Blood bank considerations include adequate RBC antigen matching to mitigate the risk of RBC alloimmunization, of which patients with SCD are at risk of developing. Transfusion may be utilized in efforts to intervene in the evolution of potentially life-threatening complications of SCD such as acute stroke, severe acute anemia and acute chest syndrome. Transfusion is also useful in several non-acute settings, such as stroke prevention, pregnancy, pre-surgery, and transfusion support for curative therapies. Individualized treatment plans are an essential component of patient care. Continuous evaluation of clinical indications and evolution of guidelines will continue to optimize care for patients with SCD.

Molecular phylogeny and ancestral biogeographic reconstruction of Platanthera subgenus Limnorchis (Orchidaceae) using target capture methods.

Platanthera is one of the largest genera of temperate orchids in the Holarctic and exemplifies a lineage that has adaptively radiated into diverse habitats within North America, Asia, Europe, North Africa, Borneo, and Sarawak. Major centers of diversity in this genus are North America and eastern Asia. Despite its diversity, a thorough phylogenetic hypothesis for the genus is lacking because no studies have yet sampled taxa exhaustively or developed a robust molecular toolkit. While there is strong evidence that suggests monophyly of subgenus Limnorchis, most taxa in this group have not been included in a phylogenetic analysis. In this study, we developed a new toolkit for Platanthera consisting of genomic information from 617 low-copy nuclear loci. Using a targeted enrichment approach, we collected high-throughput sequence data in 23 accessions of nine of the 12 diploid species of subgenus Limnorchis and outgroup species across Platanthera. A maximum likelihood analysis resolved a strongly supported monophyletic clade for subgenus Limnorchis. Ancestral biogeographic reconstruction indicated that subgenus Limnorchis originated in western North America ca. 3-4.5 Mya from an ancestor that was widespread in western North America and eastern Asia and subsequently diversified in western North America, followed by dispersal of some species to eastern North America. Our results indicate complex biogeographic connections between Asia and North America, and therefore it suggests that Platanthera is a suitable system to test biogeographic hypotheses over time and space in the Holarctic. Our results are also expected to facilitate further study of diversification and biogeographic spread across Platanthera and lay the groundwork for understanding independent origins, biogeography, and morphological diversification of polyploid species within subgenus Limnorchis.

Adaptive governance good practice: Show me the evidence!

Adaptive governance has emerged in the last decade as an intriguing avenue of theory and practice for the holistic management of complex environmental problems. Research on adaptive governance has flourished since the field's inception, probing the process and mechanisms underpinning the new approach while offering various justifications and prescriptions for empirical use. Nevertheless, recent reviews of adaptive governance reveal some important conceptual and practical gaps in the field, particularly concerning challenges in its application to real-world cases. In this paper, we respond directly to the empirical challenge of adaptive governance, specifically asking: which methods contribute to the implementation of successful adaptive governance process and outcomes in practice and across cases and contexts? We adopt a systematic literature review methodology which considers the current body of empirical literature on adaptive governance of social-ecological systems in order to assess and analyse the methods affecting successful adaptive governance practice across the range of existing cases. We find that methods contributing to adaptive governance in practice resemble the design recommendations outlined in previous adaptive governance scholarship, including meaningful collaboration across actors and scales; effective coordination between stakeholders and levels; building social capital; community empowerment and engagement; capacity development; linking knowledge and decision-making through data collection and monitoring; promoting leadership capacity; and exploiting or creating governance opportunities. However, we critically contextualise these methods by analysing and summarising their patterns-in-use, drawing examples from the cases to explore the specific ways they were successfully or unsuccessfully applied to governance issues on-the-ground. Our results indicate some important underlying shared patterns, trajectories, and lessons learned for evidence-based adaptive governance good practice within and across diverse sectors, issues, and contexts.

Phylogeography and genetic structure of endemic Acmispon argophyllus and A. dendroideus (Fabaceae) across the California Channel Islands.

PREMISE OF THE STUDY: Taxa inhabiting the California Channel Islands exhibit variation in their degree of isolation, but few studies have considered patterns across the entire archipelago. We studied phylogeography of insular Acmispon argophyllus and A. dendroideus to determine whether infraspecific taxa are genetically divergent and to elucidate patterns of diversification across these islands. METHODS: DNA sequences were collected from nuclear (ADH) and plastid genomes (rpL16, ndhA, psbD-trnT) from >450 samples on the Channel Islands and California. We estimated population genetic diversity and structure, phylogenetic patterns among populations, and migration rates, and tested for population growth. KEY RESULTS: Populations of northern island A. argophyllus var. niveus are genetically distinct from conspecific populations on southern islands. On the southern islands, A. argophyllus var. argenteus populations on Santa Catalina are phylogenetically distinct from populations of var. argenteus and var. adsurgens on the other southern islands. For A. dendroideus, we found the varieties to be monophyletic. Populations of A. dendroideus var. traskiae on San Clemente are genetically differentiated from other conspecific populations, whereas populations on the northern islands and Santa Catalina show varying degrees of gene flow. Evidence of population growth was found in both species. CONCLUSIONS: Oceanic barriers between islands have had a strong influence on population genetic structure in both Acmispon species, although the species have differing phylogeographic patterns. This study provides a contrasting pattern of dispersal on a near island system that does not follow a strict stepping-stone model, commonly found on isolated island systems.

Addressing the Cost, Value, And Student Debt in Nursing Education.

The current initiatives to improve the academic preparation of nurses have added emphasis to the presence or prediction of thousands of dollars of debt, which may influence personal decisions about returning to school. In this study, nearly 40% of survey respondents reported less than $25,000 in college debt and 23.5% reported greater than $25,000 of prior college debt. Slightly less than a third of respondents reported no plans to return to school for more education but of those who did have an educational plan, the influence of prior college debt on their plans for academic progression was significant. Debt and the influence of debt on education planning for nurses was confirmed as a concern that will impede achievement of the baccalaureate education benchmark for nurses unless steps are taken to address prior college debt and the cost of further education. Nurse executives should take nurses' debt load into account when planning academic advancement initiatives.

Atmospheric evolution of sulfur emissions from KiÌ lauea: real-time measurements of oxidation, dilution, and neutralization within a volcanic plume.

The high atmospheric concentrations of toxic gases, particulate matter, and acids in the areas immediately surrounding volcanoes can have negative impacts on human and ecological health. To better understand the atmospheric fate of volcanogenic emissions in the near field (in the first few hours after emission), we have carried out real-time measurements of key chemical components of the volcanic plume from Ki̅lauea on the Island of Hawai'i. Measurements were made at two locations, one ∼ 3 km north-northeast of the vent and the other 31 km to the southwest, with sampling at each site spanning a range of meteorological conditions and volcanic influence. Instrumentation included a sulfur dioxide monitor and an Aerosol Chemical Speciation Monitor, allowing for a measurement of the partitioning between the two major sulfur species (gas-phase SO2 and particulate sulfate) every 5 min. During trade wind conditions, which sent the plume toward the southwest site, sulfur partitioning exhibited a clear diurnal pattern, indicating photochemical oxidation of SO2 to sulfate; this enabled the quantitative determination of plume age (5 h) and instantaneous SO2 oxidation rate (2.4 × 10(-6) s(-1) at solar noon). Under stagnant conditions near the crater, the extent of SO2 oxidation was substantially higher, suggesting faster oxidation. The particles within the plume were extremely acidic, with pH values (controlled largely by ambient relative humidity) as low as -0.8 and strong acidity (controlled largely by absolute sulfate levels) up to 2200 nmol/m(3). The high variability of sulfur partitioning and particle composition underscores the chemically dynamic nature of volcanic plumes, which may have important implications for human and ecological health.

Cultural Self-Efficacy of Second- Degree Nursing Students in Providing Care to Immigrants.

The purpose of this study was to determine the levels of perceived cultural self-efficacy of senior students in second-degree pre-licensure nursing programs in the provision of culturally appropriate care to immigrants. The study employed a quantitative, non-experimental design with survey methodology. The convenience sample consisted of 117 senior students enrolled in accelerated bachelor of sciences in nursing and entry levels master of sciences programs. The study used Bernal and Froman's Cultural Self-Efficacy Scale (CSES). The study found that the participants had low levels of transcultural self-efficacy. There was no association between the participants' demographic characteristics and their CSES scores. These findings were consistent with the findings of previous studies that surveyed traditional nursing students. The study provided important assessment data on learning needs of second-degree nursing student concerning the provision of culturally congruent care.

An evaluation and 20-year follow-up of a community forensic intellectual disability service.

BACKGROUND: Since the middle of the 20th century, there have been several heterogeneous studies of recidivism by offenders with intellectual disabilities (ID) who have been in specialist mental health services after an index offence. Although some were long term, as befits a chronically needy group, laws and services have changed in that time. It may no longer be appropriate to rely on findings from the 1960s and 1970s. AIMS: To compare mental health presentations and recidivism between male sex offenders, men convicted of other offences and female offenders from a 1986-2008 cohort of offenders referred to specialist forensic ID services in Scotland. METHOD: A 20-year follow-up of an assessment and treatment service for 309 offenders with ID (156 sex offenders, 126 non sexual male offenders and 27 women) was conducted. RESULTS: Sex offenders were more likely to be referred from the courts and had lower anger levels. Women were more likely to be diagnosed with mental illness. There was a split between groups with sex offenders committing few nonsexual offences and the other groups showing few sexual offences. During the study period, 16% of sexual offenders, 43% of male nonsexual offenders and 23% of women committed at least one further offence. Following assessment and treatment there was a 90-95% reduction in offending incidents. CONCLUSIONS: Although recidivism rates are disappointing, harm reduction data suggests that assessment and treatment for offenders with ID can be highly successful in terms of public safety.

Fine-scale genetic structure in rhizosphere microbial communities associated with Chamaecrista fasciculata (Fabaceae).

Soil microbiota of the rhizosphere are an important extension of the plant phenotype because they impact the health and fitness of host plants. The composition of these communities is expected to differ among host plants due to influence by host genotype. Given that many plant populations exhibit fine-scale genetic structure (SGS), associated microbial communities may also exhibit SGS. In this study, we tested this hypothesis using Chamaecrista fasciculata, a legume species that has previously been determined to have significant SGS. We collected genetic data from prokaryotic and fungal rhizosphere communities in association with 70 plants in an area of ~400 square meters to investigate the presence of SGS in microbial communities. Bacteria of Acidobacteria, Protobacteria, and Bacteroidetes and fungi of Basidiomycota, Ascomycota, and Mortierellomycota were dominant members of the rhizosphere. Although microbial alpha diversity did not differ significantly among plants hosts, we detected significant compositional differences among the microbial communities as well as isolation by distance. The strongest factor associated with microbial distance was genetic distance of the other microbial community, followed by geographic distance, but there was not a significant association with plant genetic distance for either microbial community. This study further demonstrates the strong potential for spatial structuring of soil microbial communities at the smallest spatial scales and provides further insight into the complexity of factors that influence microbial composition in soils and in association with host plants.

Variable length chloroplast markers for population genetic studies in Acmispon (Fabaceae).

PREMISE OF THE STUDY: To estimate genetic structure, chloroplast loci containing length-variable regions were developed for two legumes, Acmispon argophyllus and A. dendroideus. • METHODS AND RESULTS: Primers for 14 chloroplast loci containing repeat regions were developed from the chloroplast genome sequence of the legume Lotus japonicus and tested in Acmispon. Nine loci exhibited polymorphism in Acmispon, with up to six alleles per locus. Gene diversity ranged from 0 to 0.775 in A. argophyllus and 0.142 to 0.766 in A. dendroideus. The primers also amplified in other Acmispon species. Sequencing of the fragments revealed discordance between fragment sizes and underlying sequence for three loci containing complex repeat regions. • CONCLUSIONS: Although genotypes were easily generated and sized, sequencing may be more informative of genetic variation in loci with complex repeat regions. These loci exhibit substantial variation and should be useful for understanding genetic structure associated with seed dispersal in Acmispon.

Parental resilience and psychological distress in the neonatal intensive care unit.

OBJECTIVE: To evaluate the associations between parental resilience and psychological distress during the neonatal intensive care unit (NICU) hospitalization. STUDY DESIGN: Observational cohort study of parents of preterm infants (n = 45) admitted to a NICU between December 2017-October 2019. Data on resilience and psychological distress were collected using validated scales. Regression analysis was used to evaluate associations. RESULT: One-third of NICU parents screened positive for depression or anxiety. There were no identified sociodemographic factors or parental engagement activities associated with resilience. Parents with higher resilience had lower scores on depression and anxiety screens. However, resilience alone was not a predictor for a positive depression or anxiety screen (aOR 0.93, CI 0.86-1.00; aOR 0.95, CI 0.89-1.02, respectively). CONCLUSION: Resilience may be associated with lower scores on depression and anxiety screens but is not an independent predictor for a positive screen during the early NICU hospitalization.

The challenges of growing orchids from seeds for conservation: An assessment of asymbiotic techniques.

Lewis Knudson first successfully germinated orchid seeds asymbiotically on artificial medium in 1922. While many orchid species have since been grown asymbiotically, the tremendous variation in how species respond to artificial medium and growth conditions ex situ has also become apparent in the past century. In this study, we reviewed published journal articles on asymbiotic orchid seed germination to provide a summary of techniques used and to evaluate if these differ between terrestrial and epiphytic species, to identify areas where additional research is needed, and to evaluate whether asymbiotic germination could be used more often in ex situ conservation. We found articles reporting successful asymbiotic germination of 270 species and 20 cultivars across Orchidaceae. Researchers often used different techniques with epiphytic versus terrestrial species, but species-specific responses to growth media and conditions were common, indicating that individualized protocols will be necessary for most species. The widespread success in generating seedlings on artificial media suggests that asymbiotic techniques should be another tool for the conservation of rare orchid species. Further advances are needed in understanding how to introduce mycorrhizae to axenically grown orchids and to maximize the viability of seedlings reintroduced into natural habitats to fully utilize these methods for conservation.

Three-dimensional organoid culture unveils resistance to clinical therapies in adult and pediatric glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common primary brain tumor with a dismal prognosis. The inherent cellular diversity and interactions within tumor microenvironments represent significant challenges to effective treatment. Traditional culture methods such as adherent or sphere cultures may mask such complexities whereas three-dimensional (3D) organoid culture systems derived from patient cancer stem cells (CSCs) can preserve cellular complexity and microenvironments. The objective of this study was to determine if GBM organoids may offer a platform, complimentary to traditional sphere culture methods, to recapitulate patterns of clinical drug resistance arising from 3D growth. METHODS: Adult and pediatric surgical specimens were collected and established as organoids. We created organoid microarrays and visualized bulk and spatial differences in cell proliferation using immunohistochemistry (IHC) staining, and cell cycle analysis by flow cytometry paired with 3D regional labeling. We tested the response of CSCs grown in each culture method to temozolomide, ibrutinib, lomustine, ruxolitinib, and radiotherapy. RESULTS: GBM organoids showed diverse and spatially distinct proliferative cell niches and include heterogeneous populations of CSCs/non-CSCs (marked by SOX2) and cycling/senescent cells. Organoid cultures display a comparatively blunted response to current standard-of-care therapy (combination temozolomide and radiotherapy) that reflects what is seen in practice. Treatment of organoids with clinically relevant drugs showed general therapeutic resistance with drug- and patient-specific antiproliferative, apoptotic, and senescent effects, differing from those of matched sphere cultures. CONCLUSIONS: Therapeutic resistance in organoids appears to be driven by altered biological mechanisms rather than physical limitations of therapeutic access. GBM organoids may therefore offer a key technological approach to discover and understand resistance mechanisms of human cancer cells.

Estimating the species tree for Hawaiian Schiedea (Caryophyllaceae) from multiple loci in the presence of reticulate evolution.

Schiedea (Caryophyllaceae) is a monophyletic genus of 34 species, all endemic to the Hawaiian Islands, that arose from a single colonization, providing one of the best examples of adaptive radiation in Hawai'i. Species utilize a range of habitats and exhibit a variety of growth forms and transitions in breeding systems from hermaphroditism toward dimorphism or autogamy. Our study included the most thorough sampling to date: 2-5 individuals per species and 4 independent genetic partitions: eight plastid and three low-copy nuclear loci (9217bps), allowing a three-locus BEST species tree. Despite incomplete resolution at the tips, our results support monophyly for each extant species. Gene trees revealed several clear cases of cytonuclear incongruence, likely created by interspecific introgression. Conflict occurs at the divergence of section Alphaschiedea as well as at the tips. Ages inferred from a BEAST analysis allow an original colonization onto either Nihoa or Kauaì and inform some aspects of inter-island migrations. We suggest that several hard polytomies on the species tree are biologically realistic, signifying either nearly simultaneous speciation or historical introgressive hybridization. Based on inferred node ages that exceed expected coalescent times, we propose that undetected nuclear introgression may play a larger role than incomplete lineage sorting in sections Schiedea and Mononeura.

A Multisite Randomized Controlled Trial Comparing the Effects of Intervention Intensity and Intervention Style on Outcomes for Young Children With Autism.

OBJECTIVE: This randomized, multisite, intent-to-treat study tested the effects of 2 levels of treatment intensity (number of hours) and 2 treatment styles on the progress of young children with autism spectrum disorder (ASD). We predicted that initial severity of developmental delay or autism symptoms would moderate the effects of intensity and style on progress in 4 domains: autism symptom severity, expressive communication, receptive language, and nonverbal ability. METHOD: A total of 87 children with ASD, mean age 23.4 months, were assigned to 1 of 2 intervention styles (naturalistic developmental/behavioral or discrete trial teaching), each delivered for either 15 or 25 hours per week of 1:1 intervention for 12 months by trained research staff. All caregivers received coaching twice monthly. Children were assessed at 4 timepoints. Examiners and coders were naive to treatment assignment. RESULTS: Neither style nor intensity had main effects on the 4 outcome variables. In terms of moderating the effects of initial severity of developmental delay and of autism symptom severity, neither moderated the effects of treatment style on progress in any of the 4 domains. In terms of treatment intensity, initial severity moderated effect of treatment intensity on only 1 domain, namely, change in autism symptom severity; in a secondary analysis, this effect was found in only 1 site. CONCLUSION: Neither treatment style nor intensity had overall effects on child outcomes in the 4 domains examined. Initial severity did not predict better response to 1 intervention style than to another. We found very limited evidence that initial severity predicted better response to 25 vs 15 hours per week of intervention in the domains studied. CLINICAL TRIAL REGISTRATION INFORMATION: Intervention Effects of Intensity and Delivery Style for Toddlers With Autism: https://clinicaltrials.gov/; NCT02272192.

Altered lipid metabolism marks glioblastoma stem and non-stem cells in separate tumor niches.

Glioblastoma (GBM) displays marked cellular and metabolic heterogeneity that varies among cellular microenvironments within a tumor. Metabolic targeting has long been advocated as a therapy against many tumors including GBM, but how lipid metabolism is altered to suit different microenvironmental conditions and whether cancer stem cells (CSCs) have altered lipid metabolism are outstanding questions in the field. We interrogated gene expression in separate microenvironments of GBM organoid models that mimic the transition between nutrient-rich and nutrient-poor pseudopalisading/perinecrotic tumor zones using spatial-capture RNA-sequencing. We revealed a striking difference in lipid processing gene expression and total lipid content between diverse cell populations from the same patient, with lipid enrichment in hypoxic organoid cores and also in perinecrotic and pseudopalisading regions of primary patient tumors. This was accompanied by regionally restricted upregulation of hypoxia-inducible lipid droplet-associated (HILPDA) gene expression in organoid cores and pseudopalisading regions of clinical GBM specimens, but not lower-grade brain tumors. CSCs have low lipid droplet accumulation compared to non-CSCs in organoid models and xenograft tumors, and prospectively sorted lipid-low GBM cells are functionally enriched for stem cell activity. Targeted lipidomic analysis of multiple patient-derived models revealed a significant shift in lipid metabolism between GBM CSCs and non-CSCs, suggesting that lipid levels may not be simply a product of the microenvironment but also may be a reflection of cellular state. CSCs had decreased levels of major classes of neutral lipids compared to non-CSCs, but had significantly increased polyunsaturated fatty acid production due to high fatty acid desaturase (FADS1/2) expression which was essential to maintain CSC viability and self-renewal. Our data demonstrate spatially and hierarchically distinct lipid metabolism phenotypes occur clinically in the majority of patients, can be recapitulated in laboratory models, and may represent therapeutic targets for GBM.

Sensory auditory interval perception errors in developmental dyslexia.

Developmental dyslexia (DD) is a heritable condition associated with reading, visual and auditory deficits. Atypical processes involved in low-level sensory coding have been implicated. We tested the contribution made by auditory magnocellular function using a behavioural task which considered the temporal difference between pairs of identical sinewave tones. Adult undergraduates with an existing diagnosis of DD (n = 78) were compared with controls (n = 111) from the same population on error rates and response times at different interval durations. Error rates and response times increased in both groups with increasing task difficulty. However, on average the DD group made uniformly more errors and slower decisions than controls. Unsupervised learning of error patterns exposed a trait continuum associated with individual differences in response efficiency. Difficulty in using temporal information in DD arising from impaired sensory coding in the auditory thalamus is suggested. The results provide strong support for the idea that auditory processing difficulties in dyslexia, along with visual and sensorimotor deficits, have a common neurodevelopmental cause.