Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer.

We report a comprehensive proteogenomics analysis, including whole-genome sequencing, RNA sequencing, and proteomics and phosphoproteomics profiling, of 218 tumors across 7 histological types of childhood brain cancer: low-grade glioma (n = 93), ependymoma (32), high-grade glioma (25), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16), and atypical teratoid rhabdoid tumor (12). Proteomics data identify common biological themes that span histological boundaries, suggesting that treatments used for one histological type may be applied effectively to other tumors sharing similar proteomics features. Immune landscape characterization reveals diverse tumor microenvironments across and within diagnoses. Proteomics data further reveal functional effects of somatic mutations and copy number variations (CNVs) not evident in transcriptomics data. Kinase-substrate association and co-expression network analysis identify important biological mechanisms of tumorigenesis. This is the first large-scale proteogenomics analysis across traditional histological boundaries to uncover foundational pediatric brain tumor biology and inform rational treatment selection.

Prenatal and Early Life Exposure to Ambient Air Pollutants Is Associated with the Fecal Metabolome in the First Two Years of Life.

Prenatal and early life air pollution exposure has been linked with several adverse health outcomes. However, the mechanisms underlying these relationships are not yet fully understood. Therefore, this study utilizes fecal metabolomics to determine if pre- and postnatal exposure to ambient air pollutants (i.e., PM10, PM2.5, and NO2) is associated with the fecal metabolome in the first 2 years of life in a Latino cohort from Southern California. The aims of this analysis were to estimate associations between (1) prenatal air pollution exposure with fecal metabolic features at 1-month of age, (2) prior month postnatal air pollution exposure with fecal metabolites from 1-month to 2 years of age, and (3) how postnatal air pollution exposure impacts the change over time of fecal metabolites in the first 2 years of life. Prenatal exposure to air pollutants was associated with several Level-1 metabolites, including those involved in vitamin B6 and tyrosine metabolism. Prior month air pollution exposure in the postnatal period was associated with Level-1 metabolites involved in histidine metabolism. Lastly, we found that pre- and postnatal ambient air pollution exposure was associated with changes in metabolic features involved in metabolic pathways including amino acid metabolism, histidine metabolism, and fatty acid metabolism.

AMPK governs lineage specification through Tfeb-dependent regulation of lysosomes.

Faithful execution of developmental programs relies on the acquisition of unique cell identities from pluripotent progenitors, a process governed by combinatorial inputs from numerous signaling cascades that ultimately dictate lineage-specific transcriptional outputs. Despite growing evidence that metabolism is integrated with many molecular networks, how pathways that control energy homeostasis may affect cell fate decisions is largely unknown. Here, we show that AMP-activated protein kinase (AMPK), a central metabolic regulator, plays critical roles in lineage specification. Although AMPK-deficient embryonic stem cells (ESCs) were normal in the pluripotent state, these cells displayed profound defects upon differentiation, failing to generate chimeric embryos and preferentially adopting an ectodermal fate at the expense of the endoderm during embryoid body (EB) formation. AMPK(-/-) EBs exhibited reduced levels of Tfeb, a master transcriptional regulator of lysosomes, leading to diminished endolysosomal function. Remarkably, genetic loss of Tfeb also yielded endodermal defects, while AMPK-null ESCs overexpressing this transcription factor normalized their differential potential, revealing an intimate connection between Tfeb/lysosomes and germ layer specification. The compromised endolysosomal system resulting from AMPK or Tfeb inactivation blunted Wnt signaling, while up-regulating this pathway restored expression of endodermal markers. Collectively, these results uncover the AMPK pathway as a novel regulator of cell fate determination during differentiation.

First clinical evaluation of the safety and efficacy of tarumase for the debridement of venous leg ulcers.

We report the first clinical evaluation of a new enzymatic wound debridement product containing tarumase in venous leg ulcer patients. As a first-in-human study, this was a prospective, open-label, multi-centre, dose escalation study across five dose cohorts and involving a total of 43 patients treated three times weekly for up to 4 weeks (12 applications). The primary and secondary endpoints of the study were to assess the systemic safety, local tolerability, and early proof of concept both for wound debridement and healing. Results indicated that the tarumase enzyme was well tolerated when applied topically to wounds, with no indications of systemic absorption, no evidence of antibody generation, and no systemic effects on coagulation pathways. Locally, there was no evidence of pain on application, no local itching, no increases in erythema, oedema, exudate or bleeding and only a few treatment emergent adverse events were reported. As the concentration of tarumase was escalated, trends towards faster and improved effectiveness of wound debridement were observed, especially in patients with significant slough at baseline. Trends towards faster rates of healing were also noted based on observations of increased granulation tissue, increased linear healing and reduction in surface area over the 4-week treatment period.

A comparative approach for characterizing the relationship among morphology, range-of-motion and locomotor behaviour in the primate shoulder.

Shoulder shape directly impacts forelimb function by contributing to glenohumeral (GH) range-of-motion (ROM). However, identifying traits that contribute most to ROM and visualizing how they do so remains challenging, ultimately limiting our ability to reconstruct function and behaviour in fossil species. To address these limitations, we developed an in silico proximity-driven model to simulate and visualize three-dimensional (3D) GH rotations in living primate species with diverse locomotor profiles, identify those shapes that are most predictive of ROM using geometric morphometrics, and apply subsequent insights to interpret function and behaviour in the fossil hominin Australopithecus sediba. We found that ROM metrics that incorporated 3D rotations best discriminated locomotor groups, and the magnitude of ROM (mobility) was decoupled from the anatomical location of ROM (e.g. high abduction versus low abduction). Morphological traits that enhanced mobility were decoupled from those that enabled overhead positions, and all non-human apes possessed the latter but not necessarily the former. Model simulation in A. sediba predicted high mobility and a ROM centred at lower abduction levels than in living apes but higher than in modern humans. Together these results identify novel form-to-function relationships in the shoulder and enhance visualization tools to reconstruct past function and behaviour.

Bioenergetic consequences of repeated catch-and-release fisheries interactions on adult steelhead across a range of ecologically relevant water temperatures.

The biological consequences of catch-and-release angling have been studied for decades, yet little is known about the compounding effects of repeated recreational fisheries recaptures on the physiology and behaviour of angled fish. Using heart rate biologgers and behavioural assays, this study investigated the physiological and behavioural consequences of multiple simulated angling events (i.e., repeated stressors) on female steelhead (Oncorhynchus mykiss), under current (6 °C) and future (11 °C) water temperature scenarios. While steelhead in the warmer water temperature scenario demonstrated alterations in cardiac function (e.g., increases in maximum heart rate and scope of heart rate) and evidence of behavioural impairments (e.g., decreases in chase activity and landing time) over the course of two simulated angling events, cold water treated fish had negligible change. Fish subjected to two simulated angling events under warm water temperature conditions tended to demonstrate an increase in recovery time and scope for heart rate, and a decrease in resting heart rate. A second experiment was conducted to test for sex-specific differences in the heart rate response of steelhead subjected to an increase in water temperature. Females demonstrated a higher scope for heart rate when compared to males during the event and during recovery. More work is needed to better understand the interaction between multiple angling events and recovery from these events at various water temperatures, and the biological basis for sex-specific differences in cardiac function and response to challenges. This study contributes to a growing body of evidence on the effects of repeated stressors on wild fish.

Closing the knowledge-action gap in conservation with open science.

The knowledge-action gap in conservation science and practice occurs when research outputs do not result in actions to protect or restore biodiversity. Among the diverse and complex reasons for this gap, three barriers are fundamental: knowledge is often unavailable to practitioners and challenging to interpret or difficult to use or both. Problems of availability, interpretability, and useability are solvable with open science practices. We considered the benefits and challenges of three open science practices for use by conservation scientists and practitioners. First, open access publishing makes the scientific literature available to all. Second, open materials (detailed methods, data, code, and software) increase the transparency and use of research findings. Third, open education resources allow conservation scientists and practitioners to acquire the skills needed to use research outputs. The long-term adoption of open science practices would help researchers and practitioners achieve conservation goals more quickly and efficiently and reduce inequities in information sharing. However, short-term costs for individual researchers (insufficient institutional incentives to engage in open science and knowledge mobilization) remain a challenge. We caution against a passive approach to sharing that simply involves making information available. We advocate a proactive stance toward transparency, communication, collaboration, and capacity building that involves seeking out and engaging with potential users to maximize the environmental and societal impact of conservation science.

Cierre de la Brecha entre el Conocimiento y la Acción en la Conservación con Ciencia Abierta 21-311 Resumen La brecha entre el conocimiento y la acción en las ciencias de la conservación y en su práctica ocurre cuando los resultados de las investigaciones no derivan en acciones para proteger o restaurar la biodiversidad. Entre las razones complejas y diversas de esta brecha, existen tres barreras que son fundamentales: con frecuencia el conocimiento no está disponible para los practicantes, es difícil de interpretar o difícil de usar, o ambas. Los problemas con la disponibilidad, interpretabilidad y utilidad son solucionables mediante las prácticas de ciencia abierta. Consideramos los beneficios y los obstáculos de tres prácticas de ciencia abierta para su uso por parte de los científicos y practicantes de la conservación. Primero, las publicaciones de acceso abierto hacen que la literatura científica esté disponible para todos. Segundo, los materiales abiertos (métodos detallados, datos, códigos y software) incrementan la transparencia y el uso de los hallazgos de las investigaciones. Tercero, los recursos educativos abiertos permiten que los científicos y practicantes de la conservación adquieran las habilidades necesarias para utilizar los productos de las investigaciones. La adopción a largo plazo de las prácticas de ciencia abierta ayudaría a los investigadores y a los practicantes a lograr los objetivos de conservación mucho más rápido y de manera eficiente y a reducir las desigualdades que existen en la divulgación de información. Sin embargo, los costos a corto plazo para los investigadores individuales (incentivos institucionales insuficientes para participar en la ciencia abierta y en la movilización del conocimiento) todavía son un reto. Advertimos sobre las estrategias pasivas de divulgación que simplemente hacen que la información esté disponible. Abogamos por una postura proactiva hacia la transparencia, la comunicación, la colaboración y la construcción de las capacidades que incluyen la búsqueda de y la interacción con los usuarios potenciales para maximizar el impacto ambiental y social de las ciencias de la conservación.

Natural Resource Managers Use and Value Western-Based Science, but Barriers to Access Persist.

Natural resources management (NRM) is complex and relies on decisions supported by evidence, including Western-based science (WBS) and Indigenous and local knowledge. However, it has been shown that there is a disconnect between WBS and its application, whereby managers often draw on non-empirical sources of information (i.e., intuition or advice from colleagues). This article focuses on the role of WBS in decisions made in management of rainbow trout (Oncorhynchus mykiss) in the province of British Columbia, Canada. We conducted open-ended interviews with NRM branches of Indigenous and parliamentary governments, as well as with nongovernmental stakeholder groups, to examine (a) sources of WBS consulted in decision-making and (b) barriers to accessing WBS by managers. We found that respondents involved with NRM relied on a diverse set of sources for WBS, seldom relying exclusively on one source. However, respondents relied more on internal sources (government databases) compared to external ones (peer-reviewed journal articles). We also found that respondents described WBS as valuable and generally accessible, yet barriers were identified with respect to the interface and organization of government grey data and literature, paywalls associated with peer-reviewed journals and articles, and institutional capacity, time, and support. We recommend strategies and tools to facilitate accessibility of WBS in support of bridging the knowledge-action divide, including increased publishing of open access data/articles, systematic reviews, use of knowledge brokers, specialized WBS training, and knowledge co-production. It is our hope that identification of barriers and the implementation of improved access to WBS will result in more effective NRM by giving managers access to the tools and knowledge they need for evidence-based decision-making.

The developmental-genetics of canalization.

Canalization, or robustness to genetic or environmental perturbations, is fundamental to complex organisms. While there is strong evidence for canalization as an evolved property that varies among genotypes, the developmental and genetic mechanisms that produce this phenomenon are very poorly understood. For evolutionary biology, understanding how canalization arises is important because, by modulating the phenotypic variation that arises in response to genetic differences, canalization is a determinant of evolvability. For genetics of disease in humans and for economically important traits in agriculture, this subject is important because canalization is a potentially significant cause of missing heritability that confounds genomic prediction of phenotypes. We review the major lines of thought on the developmental-genetic basis for canalization. These fall into two groups. One proposes specific evolved molecular mechanisms while the other deals with robustness or canalization as a more general feature of development. These explanations for canalization are not mutually exclusive and they overlap in several ways. General explanations for canalization are more likely to involve emergent features of development than specific molecular mechanisms. Disentangling these explanations is also complicated by differences in perspectives between genetics and developmental biology. Understanding canalization at a mechanistic level will require conceptual and methodological approaches that integrate quantitative genetics and developmental biology.

"Consulted to death": Personal stress as a major barrier to environmental co-management.

Co-management is widely seen as a way of improving environmental governance and empowering communities. When successful, co-management enhances the validity and legitimacy of decision-making, while providing stakeholders with influence over processes and outcomes that directly impact them. However, our research with participants in co-management across several cases leads us to argue that many of the individuals who contribute to co-management are subject to significant personal stress arising from both the logistical and social/emotional demands of participation in these processes. We argue that the literature on co-management has touched on this only indirectly, and that personal stress is a major challenge for participants that ought to be integrated into research agendas and addressed by policy-makers. In this article, we review the contours of the personal stress issue as it has appeared in our observations of co-management events and interviews with participants. While these findings are partial and preliminary, we argue that personal stress has theoretical and practical significance to the broader literature and process design. We conclude the article with recommendations for participants, researchers and policy-makers about how to consider and respond to problems of personal stress.

Nonlinear gene expression-phenotype relationships contribute to variation and clefting in the A/WySn mouse.

BACKGROUND: Cleft lip and palate is one of the most common human birth defects, but the underlying etiology is poorly understood. The A/WySn mouse is a spontaneously occurring model of multigenic clefting in which 20% to 30% of individuals develop an orofacial cleft. Recent work has shown altered methylation at a specific retrotransposon insertion downstream of the Wnt9b locus in clefting animals, which results in decreased Wnt9b expression. RESULTS: Using a newly developed protocol that allows us to measure morphology, gene expression, and DNA methylation in the same embryo, we relate gene expression in an individual embryo directly to its three-dimensional morphology for the first time. We find that methylation at the retrotransposon relates to Wnt9b expression and morphology. IAP methylation relates to shape of the nasal process in a manner consistent with clefting. Embryos with low IAP methylation exhibit increased among-individual variance in facial shape. CONCLUSIONS: Methylation and gene expression relate nonlinearly to nasal process morphology. Individuals at one end of a continuum of phenotypic states display a clinical phenotype and increased phenotypic variation. Variable penetrance and expressivity in this model is likely determined both by among-individual variation in methylation and changes in phenotypic robustness along the underlying liability distribution for orofacial clefting.

Collaboration and engagement produce more actionable science: quantitatively analyzing uptake of fish tracking studies.

Aquatic telemetry technology generates new knowledge about the underwater world that can inform decision-making processes and thus can improve conservation and natural resource management. Still, there is lack of evidence on how telemetry-derived knowledge can or has informed management, and what factors facilitate or deter its use. We present one of the first quantitative studies related to the science-action gap and evaluate factors that influence the uptake of fish telemetry findings into policies and practices, as well as social acceptance of these findings. We globally surveyed 212 fish telemetry researchers regarding the knowledge uptake of an applied fish telemetry research project of their choice. Respondents' personal and professional attributes, as well as the attributes of their chosen projects, were analyzed using machine learning algorithms to identify important factors that influenced the uptake (i.e., use, trust, and/or acceptance) of their findings. Researchers with extensive collaborations and who spent more time engaging in public outreach experienced greater uptake of their findings. Respondents with greater telemetry experience and commitment (e.g., more telemetry publications, higher proportion of research on fish telemetry) tended to achieve more social acceptance of their findings. Projects led by researchers who were highly involved and familiar with the fisheries management processes, and those where greater effort was devoted to research dissemination, also tended to experience greater uptake. Last, the levels of complexity and controversy of the issue addressed by the research project had a positive influence on the uptake of findings. The empirical results of this study support recent messages in the science practitioner literature for greater collaboration, knowledge co-production with partners, and public engagement to enable the transfer of knowledge and the use of evidence in decision-making and policies. Scientific organizations should consider shifting reward incentives to promote engagement and collaboration with non-scientific actors, and perhaps even rethinking hiring practices to consider personal and professional characteristics or attitudes such as altruism and networking skills given the influence of these factors in our model. Last, networks composed of both research and practice potentially have a key role in brokering and facilitating knowledge exchange and actions.

Episodic and Chronic Migraine in Primary Care.

OBJECTIVE: To inform migraine care model development by assessing differences between patients with chronic migraine (CM) and episodic migraine (EM) in the current state of treatment, disability, patient satisfaction, and quality improvement opportunities. BACKGROUND: Efficient and focused use of scarce resources will be needed to address challenges within large populations of migraine patients. METHODS: We deployed a cross-sectional survey study of randomly selected migraine patients within a community primary care practice. RESULTS: There were 516 survey respondents (516/1804 [30%] response rate). CM patients were more likely than EM patients to report care from a neurologist (76/110 [69%] vs 229/406 [56%]; P = .0026), and higher disability according to the Migraine Disability Assessment and Headache Impact Test - 6 questionnaires (P < .0001). CM patients were less likely than EM patients to report overall satisfaction with care (16/110 [38%] vs 156/406 [66%], P = .0002), satisfaction with access to care (17/110 [33%] vs 176/406 [68%], P < .0001), and advice they needed (16/110 [31%] vs 160/406 [62%], P < .0001). Most patients with migraine had been offered triptan medications 377/516 (78%). Overall, 156/516 (31%) of individuals were currently taking any medication for migraine prevention, and 208/516 (40%) including botulinum toxin injections. CM patients were more likely to be taking preventive medication (39/110 [36%] vs 117/406 [29%], P = .0191) and report familiarity with the diagnosis of medication-overuse headache than patients with EM (80/110 [81%] vs 256/406 [69%], P = .0178). CONCLUSIONS: We observed differences between patients with chronic and EM and expected care delivery improvement opportunities for migraine patients in primary care. CM patients report higher levels of disability and less satisfaction with access to perceived needed medical advice and care. These findings support the need to further develop and study novel care models to efficiently and effectively deliver high-quality care and expertise in limited supply to a diverse migraine population.

Stress System Response and Decision Making in Heavy Episodic Users of Alcohol and Online Video Games.

Objective: Few empirical studies have addressed stress system response and subsequent decision making in problematic online video game players who also consume alcohol. Method: Participants were randomly assigned to either receive a psychosocial stressor, including evaluated public speaking and mental arithmetic, or control condition. Salivary cortisol, cardiovascular and subjective responses were collected. Following, decision making was assessed using the Iowa Gambling Task. Results: In this sample of moderate internet gamers (N = 71; 45 male, 16.9% meeting suggested DSM-5 criteria for internet gaming disorder), 53.52% met gender-specific cut-points for heavy episodic drinking. Overall, participants in the TSST condition demonstrated elevated systolic and diastolic blood pressure, self-reported anxiety, and negative affect (ps < .05). However, response to the TSST was varied, particularly in individuals reporting binge internet gaming (6 h or more consecutive use in the last 30 d) who did not display the expected decline in positive affect in response to the TSST (p = .02). Differences in greater advantageous decision making between heavy episodic internet gaming participants in the stress condition, versus those reading a travel magazine, were also noted. These differences were not significant in participants reporting an absence of heavy episodic gaming behavior. Conclusions: These findings support the continued study of individuals who engage in problematic internet gaming behavior, particularly those who engage in heavy episodic use of alcohol.

Anatomic shoulder parameters and their relationship to the presence of degenerative rotator cuff tears and glenohumeral osteoarthritis: a systematic review and meta-analysis.

BACKGROUND: Scapular anatomy, as measured by the acromial index (AI), critical shoulder angle (CSA), lateral acromial angle (LAA), and glenoid inclination (GI), has emerged as a possible contributor to the development of degenerative shoulder conditions such as rotator cuff tears and glenohumeral osteoarthritis. The purpose of this study was to investigate the published literature on influences of scapular morphology on the development of degenerative shoulder conditions. METHODS: A systematic review of the Embase and PubMed databases was performed to identify published studies on the potential influence of scapular bony morphology on the development of degenerative rotator cuff tears and glenohumeral osteoarthritis. The studies were reviewed by 2 authors. The findings were summarized for various anatomic parameters. A meta-analysis was completed for parameters reported in more than 5 related publications. RESULTS: A total of 660 unique titles and 55 potentially relevant abstracts were reviewed with 30 published articles identified for inclusion. The AI, CSA, LAA, and GI were the most commonly reported bony measurements. Increased CSA and AI correlated with rotator cuff tears, whereas lower CSA appeared to be related to the presence of glenohumeral osteoarthritis. Decreased LAA correlated with degenerative rotator cuff tears. Five articles reported on the GI with mixed results on shoulder pathology. DISCUSSION: Degenerative rotator cuff tears appear to be significantly associated with the AI, CSA, and LAA. There does not appear to be a significant relationship between the included shoulder parameters and the development of osteoarthritis.

Predictors of Recurrent Hospitalizations and the Importance of These Hospitalizations for Subsequent Mortality After Incident Transient Ischemic Attack.

BACKGROUND: We examined predictors of recurrent hospitalizations and the importance of these hospitalizations for subsequent mortality after incident transient ischemic attacks (TIA) that have not yet been investigated. METHODS: Adults hospitalized for TIA from 2000 through 2017 were examined for recurrent hospitalizations, days, and percentage of time spent hospitalized and long-term mortality. RESULTS: Of 266 patients hospitalized for TIA, 122 died, 212 had 826 anycondition hospitalization (59 from TIA-related conditions) corresponding to 3384 inpatient days during 1693 person-years of follow-up. Of 42 patient-level characteristics, age greater than or equal to 65 years (Incidence rate ratio [IRR] 1.75, 95% confidence interval [CI] 1.19-2.55), current smoking (IRR 2.15, 95% CI 1.39-3.33), concurrent heart failure (IRR 1.81, 95% CI 1.17-2.80) or anemia (IRR 1.90, 95% CI 1.40-2.48), and no prescription statin (IRR 1.45, 95% CI 1.04-2.03, P = .0289) emerged as significant predictors of anycondition rehospitalization. All these variables except heart failure remained significant predictors of TIA-related rehospitalizations. All-cause mortality was significantly increased after each hospitalization from anycondition (hazard ratio [HR] 1.32, 95% CI 1.26-1.39), TIA-related condition (HR 1.72; 95% CI 1.28-2.30), and per each day (HR 1.05, 95% CI 1.04-1.05) and per 1% of follow-up time spent hospitalized from anycondition (HR 1.45, 95% CI 1.34-1.58). CONCLUSIONS: Older age, current tobacco smoking, concurrent heart failure or anemia, and no prescription statin, easily measured patient-level characteristics, identifies patients with TIA at high risk for recurrent hospitalizations and the burden of these hospitalizations predicts subsequent mortality.

Five-Year Mortality After Transient Ischemic Attack: Focus on Cardiometabolic Comorbidity and Hospital Readmission.

BACKGROUND AND PURPOSE: We aimed at providing estimates of mortality associated with cardiometabolic comorbidity and incident readmission from cardiometabolic as compared with noncardiometabolic conditions after a first transient ischemic attack. METHODS: Between 2000 and 2015, patients hospitalized for a first transient ischemic attack were examined for cardiometabolic comorbidities (diabetes mellitus, coronary artery disease, heart failure, and atrial fibrillation), 5-year incident hospitalization, and time to death. RESULTS: Of 251 patients with transient ischemic attack, 134 (53%) had at least 1 and 55 (22%) had at least 2 cardiometabolic conditions. By 5 years, 491 readmissions (134 [27%] cardiometabolic and 357 [73%] noncardiometabolic) and 75 deaths (27 [36%] cardiometabolic and 47 [64%] noncardiometabolic) were observed. Mortality was increased with any concurrent cardiometabolic comorbidity (hazard ratio, 1.89; 95% confidence interval, 1.17-3.03; P=0.0089) with multiplicative mortality risk from a combination of coronary artery disease and heart failure. Each hospitalization was associated with a 1.5-fold risk of death (95% confidence interval, 1.37-1.64; P<0.0001). Risk of cardiometabolic and noncardiometabolic mortality was correlated with the corresponding category-specific readmission. CONCLUSIONS: Among patients hospitalized for first transient ischemic attack, 5-year mortality is associated with concurrent cardiometabolic comorbidity and rates of subsequent hospitalization.

A dynamic Shh expression pattern, regulated by SHH and BMP signaling, coordinates fusion of primordia in the amniote face.

The mechanisms of morphogenesis are not well understood, yet shaping structures during development is essential for establishing correct organismal form and function. Here, we examine mechanisms that help to shape the developing face during the crucial period of facial primordia fusion. This period of development is a time when the faces of amniote embryos exhibit the greatest degree of similarity, and it probably results from the necessity for fusion to occur to establish the primary palate. Our results show that hierarchical induction mechanisms, consisting of iterative signaling by Sonic hedgehog (SHH) followed by Bone morphogenetic proteins (BMPs), regulate a dynamic expression pattern of Shh in the ectoderm covering the frontonasal (FNP) and maxillary (MxP) processes. Furthermore, this Shh expression domain contributes to the morphogenetic processes that drive the directional growth of the globular process of the FNP toward the lateral nasal process and MxP, in part by regulating cell proliferation in the facial mesenchyme. The nature of the induction mechanism that we discovered suggests that the process of fusion of the facial primordia is intrinsically buffered against producing maladaptive morphologies, such as clefts of the primary palate, because there appears to be little opportunity for variation to occur during expansion of the Shh expression domain in the ectoderm of the facial primordia. Ultimately, these results might explain why this period of development constitutes a phylotypic stage of facial development among amniotes.

Development of high performance green c-plane III-nitride light-emitting diodes.

The effect of employing an AlGaN cap layer in the active region of green c-plane light-emitting diodes (LEDs) was studied. Each quantum well (QW) and barrier in the active region consisted of an InGaN QW and a thin Al0.30Ga0.70N cap layer grown at a relatively low temperature and a GaN barrier grown at a higher temperature. A series of experiments and simulations were carried out to explore the effects of varying the Al0.30Ga0.70N cap layer thickness and GaN barrier growth temperature on LED efficiency and electrical performance. We determined that the Al0.30Ga0.70N cap layer should be around 2 nm and the growth temperature of the GaN barrier should be approximately 75° C higher than the growth temperature of the InGaN QW to maximize the LED efficiency, minimize the forward voltage, and maintain good morphology. Optimized Al0.30Ga0.70N cap growth conditions within the active region resulted in high efficiency green LEDs with a peak external quantum efficiency (EQE) of 40.7% at 3 A/cm2. At a normal operating condition of 20 A/cm2, output power, EQE, forward voltage, and emission wavelength were 13.8 mW, 29.5%, 3.5 V, and 529.3 nm, respectively.

Neuroimaging utilization and findings in headache outpatients: Significance of red and yellow flags.

Background Neuroimaging for headache commonly exceeds published guideline recommendations and may be overutilized. Methods We conducted a retrospective cross-sectional study of all outpatient community patients at Mayo Clinic Rochester who underwent a neuroimaging study for a headache indication in 2015. We assessed the neuroimaging utilization pattern, clinical application of red flags, and concordance with neuroimaging guidelines. Results We identified 190 outpatients who underwent 304 neuroimaging studies for headache. The median age was 46.5 years (range 18-91 years), 65% were female, and most reported no prior history of headache (n = 97, 51%). A minority of patients had prior brain imaging studies (n = 44, 23%) and neurological consultations for headache (n = 29, 15%). Few studies were ordered after consultation with a neurologist (n = 14, 7%). Seventy-seven percent of patients were documented to have a "red flag" justifying the imaging study. Abnormal neuroimaging findings were found in 3.1% of patients with warning flags (5/161); carotid dissection (n = 3) and reversible cerebral vasoconstrictive syndrome (n = 2). An estimated 35% of patients were imaged against guidelines. Conclusions The prevalence of serious causes of headache in a community practice was low despite the presence of a documented red flag symptom. Inadequate understanding or application of red flags may be contributing to recommendations to image patients against current guidelines. Interventions to reduce unnecessary neuroimaging of patients with headache need to be designed and implemented.