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The Dark Energy Spectroscopic Instrument (DESI) completed its 5 month Survey Validation in 2021 May. Spectra of stellar and extragalactic targets from Survey Validation constitute the first major data sample from the DESI survey. This paper describes the public release of those spectra, the catalogs of derived properties, and the intermediate data products. In total, the public release includes good-quality spectral information from 466,447 objects targeted as part of the Milky Way Survey, 428,758 as part of the Bright Galaxy Survey, 227,318 as part of the Luminous Red Galaxy sample, 437,664 as part of the Emission Line Galaxy sample, and 76,079 as part of the Quasar sample. In addition, the release includes spectral information from 137,148 objects that expand the scope beyond the primary samples as part of a series of secondary programs. Here, we describe the spectral data, data quality, data products, Large-Scale Structure science catalogs, access to the data, and references that provide relevant background to using these spectra.

The Dark Energy Spectroscopic Instrument (DESI) was designed to conduct a survey covering 14,000 deg2 over 5 yr to constrain the cosmic expansion history through precise measurements of baryon acoustic oscillations (BAO). The scientific program for DESI was evaluated during a 5 month survey validation (SV) campaign before beginning full operations. This program produced deep spectra of tens of thousands of objects from each of the stellar Milky Way Survey (MWS), Bright Galaxy Survey (BGS), luminous red galaxy (LRG), emission line galaxy (ELG), and quasar target classes. These SV spectra were used to optimize redshift distributions, characterize exposure times, determine calibration procedures, and assess observational overheads for the 5 yr program. In this paper, we present the final target selection algorithms, redshift distributions, and projected cosmology constraints resulting from those studies. We also present a One-Percent Survey conducted at the conclusion of SV covering 140 deg2 using the final target selection algorithms with exposures of a depth typical of the main survey. The SV indicates that DESI will be able to complete the full 14,000 deg2 program with spectroscopically confirmed targets from the MWS, BGS, LRG, ELG, and quasar programs with total sample sizes of 7.2, 13.8, 7.46, 15.7, and 2.87 million, respectively. These samples will allow exploration of the Milky Way halo, clustering on all scales, and BAO measurements with a statistical precision of 0.28% over the redshift interval z < 1.1, 0.39% over the redshift interval 1.1 < z < 1.9, and 0.46% over the redshift interval 1.9 < z < 3.5.

Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+ , as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research.

Audience: This is an in-person escape room and procedure simulation activity based on complications of human immunodeficiency virus (HIV) in India, which was created by using local HIV management guidelines. Emergency Medicine (EM) trainees of all post-graduate levels are the target audience. This may also be used by trainees in other specialties, such as infectious disease or internal medicine, who require an understanding of HIV and its complications. This escape room can be completed in teams of varying sizes and is designed to be adaptable to local resource availability.Background: Patients with HIV present to the Emergency Department (ED) for a variety of reasons such as initial viral syndrome, medication side effects, and opportunistic infections. While the widespread use of antiretroviral therapy (ART) has significantly increased the life expectancy of patients living with HIV and decreased the incidence of classical opportunistic infections, EM providers should still be vigilant and competent in diagnosing and managing these pathologies. This is particularly critical in India, where the prevalence of HIV was most recently estimated at 0.22% (2.2 million people older than 15 years) in 2020.1 This patient population, primarily infected through unprotected heterosexual contact, is at high risk for interruptions in ART and development of opportunistic infections for a variety of reasons including migration for work, low social status of women, and significant social stigma against HIV.2 Simulation is an educational opportunity to review these high-acuity low-occurrence presentations to prepare EM trainees for independent practice.Educational Objectives: By the end of the escape room, learners should be able to: 1) describe the mechanism of action of antiretroviral therapies available in India, 2) prescribe initial antiretroviral therapy to a patient presenting to the emergency department with a new diagnosis of HIV, 3) develop a differential diagnosis for a patient with HIV presenting to the ED with chest pain, 4) identify common dermatologic manifestations of opportunistic infections in patients with HIV, 5) identify computerized tomography scan and lumbar puncture features for central nervous system infections seen in patients with Acquired Immunodeficiency Syndrome (AIDS), 6) identify red flag features and appropriate workup for a patient with HIV presenting with a headache to the ED, 7) interpret images obtained during a Rapid Ultrasound for Shock and Hemorrhage (RUSH) exam, 8) identify cardiac tamponade and perform a pericardiocentesis, and 9) communicate and collaborate as a team to manage a complex, unstable patient with HIV in the ED.Educational Methods: We sought to create and implement an educational tool that could meet the complex education needs of EM trainees while being low cost, easily adapted to local resources, and engaging for trainees. Hospitals participating in the Masters in Emergency Medicine (MEM) program, a global partnership between the Ronald Reagan Institute for Emergency Medicine at the George Washington University and 18 hospitals in India, have resource variability for traditional simulation. The escape room created combines simulation, content review specific to the contextual practice of EM in India focused on HIV and its complications, and critical procedure teaching on pericardiocentesis. This innovation framework is based on Kolb’s experiential learning cycle and incorporates the gamification principles of a sense of autonomy, perception of competitiveness, and learner-relatedness.3-4 Escape rooms have been shown to engage learners, and low-fidelity procedure models could further maximize the experience for learners in resource variable settings.5 A pericardiocentesis model was adapted from Lord et al.’s low-fidelity model, ensuring it could be assembled with materials readily available in-country.6Research Methods: We adapted the escape room format to combine simulation, content review, and procedural training in a cost-effective, contextually relevant, and scalable way. The escape room was trialed using a case of chest pain and altered mental status caused by a pericardial effusion due to tuberculosis in a patient with HIV. Local practice patterns and guidelines were used to develop puzzles and clinical clues. A pericardiocentesis model was constructed using materials readily available in India. Pre- and post-surveys were developed to assess baseline trainee experience with escape rooms, self-reported knowledge of the differential diagnosis and management for altered mental status, and ways to incorporate escape room content into daily practice.Results: A total of 47 trainees participated; 41 of 47 participants completed both pre- and post-surveys (87% response rate). Participants represented all program trainee levels: 49% (n = 20) PGY-1, 27% (n = 11) PGY-2, and 24% (n = 10) PGY-3. Based on a score greater than seven on a 1-10 Likert scale, the escape room was rated as “highly effective” by 93.5% of respondents in reviewing medical knowledge. The trainees were allotted 60 minutes to escape the room; the median time for escape room completion was 57 minutes. The escape room and pericardiocentesis model cost under $100 USD, were repeated up to six times in one day, and could be recycled for future use.Discussion: Utilizing simulation in the escape room format that can be adaptable to variable resource settings is a valuable educational tool. The integrated escape room and procedure training proved to be an effective educational tool that was scalable and maintained efficacy across variable hospital resource levels. The next step includes adapting this format for other disease pathologies. This is a useful way to meet the education needs of MEM program trainees, regardless of hospital resource availability, that could be replicable in other EM training programs.

Since establishing its first campus in 1868, the University of California (UC), California’s land-grant university, developed into the nation’s first multi-campus system in the United States, and is today widely recognized as the world’s premier network of public research universities. This short essay provides an historical brief on the role that shared governance, and specifically the role of the Academic Senate, played in creating an academic culture of excellence and high achievement in pursuing its tripartite mission of teaching and learning, research and knowledge production, and public service. A key component in understanding the critical role of the Senate in UC’s evolution from a single campus in Berkeley to now a ten-campus system is the university’s unusual designation as a public trust in the state constitution that, beginning in 1879, protected the university at critical times from external political pressures and allowed the university to develop an internal academic culture guided by the Academic Senate. By the 1920s, the emergence of California’s unique and innovative public system of higher education, with UC as the sole public provider of doctoral degrees and state funded research, also helps explain the ability of the UC system to maintain its mission and formulate what is termed a One University model. The Academic Senate has created coherency and shared values within UC, and a culture and expectation for faculty performance that is unique among universities around the world. This essay also offers a brief reflection on the Academic Senate’s past influence, its current status, and prospective role. The overall intent is to provide context for the current academic community and higher education scholars regarding the past and future role of faculty in university governance and management, and what distinguishes UC in the pantheon of major research universities.

Hypothalamic gliosis associated with high-fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain. However, the body-weight-independent contribution of microglia to glucose regulation has not been determined. Here, we show that reducing microglial nuclear factor κB (NF-κB) signaling via cell-specific IKKβ deletion exacerbates HFD-induced glucose intolerance despite reducing body weight and adiposity. Conversely, two genetic approaches to increase microglial pro-inflammatory signaling (deletion of an NF-κB pathway inhibitor and chemogenetic activation through a modified Gq-coupled muscarinic receptor) improved glucose tolerance independently of diet in both lean and obese rodents. Microglial regulation of glucose homeostasis involves a tumor necrosis factor alpha (TNF-α)-dependent mechanism that increases activation of pro-opiomelanocortin (POMC) and other hypothalamic glucose-sensing neurons, ultimately leading to a marked amplification of first-phase insulin secretion via a parasympathetic pathway. Overall, these data indicate that microglia regulate glucose homeostasis in a body-weight-independent manner, an unexpected mechanism that limits the deterioration of glucose tolerance associated with obesity.

We describe the target selection and characteristics of the DESI Peculiar Velocity Survey, the largest survey of peculiar velocities (PVs) using both the fundamental plane (FP) and the Tully-Fisher (TF) relationship planned to date. We detail how we identify suitable early-type galaxies (ETGs) for the FP and suitable late-type galaxies (LTGs) for the TF relation using the photometric data provided by the DESI Legacy Imaging Survey DR9. Subsequently, we provide targets for 373 533 ETGs and 118 637 LTGs within the Dark Energy Spectroscopic Instrument (DESI) 5-yr footprint. We validate these photometric selections using existing morphological classifications. Furthermore, we demonstrate using survey validation data that DESI is able to measure the spectroscopic properties to sufficient precision to obtain PVs for our targets. Based on realistic DESI fibre assignment simulations and spectroscopic success rates, we predict the final DESI PV Survey will obtain ∼133 000 FP-based and ∼53 000 TF-based PV measurements over an area of 14 000 deg2. We forecast the ability of using these data to measure the clustering of galaxy positions and PVs from the combined DESI PV and Bright Galaxy Surveys (BGS), which allows for cancellation of cosmic variance at low redshifts. With these forecasts, we anticipate a 4 per cent statistical measurement on the growth rate of structure at z < 0.15. This is over two times better than achievable with redshifts from the BGS alone. The combined DESI PV and BGS will enable the most precise tests to date of the time and scale dependence of large-scale structure growth at z < 0.15.

The organic carbon (Corg) stored in seagrass meadows is globally significant and could be relevant in strategies to mitigate increasing CO2 concentration in the atmosphere. Most of that stored Corg is in the soils that underlie the seagrasses. We explored how seagrass and soil characteristics vary among seagrass meadows across the geographic range of turtlegrass (Thalassia testudinum) with a goal of illuminating the processes controlling soil organic carbon (Corg) storage spanning 23° of latitude. Seagrass abundance (percent cover, biomass, and canopy height) varied by over an order of magnitude across sites, and we found high variability in soil characteristics, with Corg ranging from 0.08 to 12.59% dry weight. Seagrass abundance was a good predictor of the Corg stocks in surficial soils, and the relative importance of seagrass-derived soil Corg increased as abundance increased. These relationships suggest that first-order estimates of surficial soil Corg stocks can be made by measuring seagrass abundance and applying a linear transfer function. The relative availability of the nutrients N and P to support plant growth was also correlated with soil Corg stocks. Stocks were lower at N-limited sites than at P-limited ones, but the importance of seagrass-derived organic matter to soil Corg stocks was not a function of nutrient limitation status. This finding seemed at odds with our observation that labile standard substrates decomposed more slowly at N-limited than at P-limited sites, since even though decomposition rates were 55% lower at N-limited sites, less Corg was accumulating in the soils. The dependence of Corg stocks and decomposition rates on nutrient availability suggests that eutrophication is likely to exert a strong influence on carbon storage in seagrass meadows.

Racial disparities in cardiovascular disease are unjust, systematic, and preventable. Social determinants are a primary cause of health disparities, and these include factors such as structural and overt racism. Despite a number of efforts implemented over the past several decades, disparities in cardiovascular disease care and outcomes persist, pervading more the outpatient rather than the inpatient setting, thus putting racial and ethnic minority groups at risk for hospital readmissions. In this article, we discuss differences in care and outcomes of racial and ethnic minority groups in both of these settings through a review of registries. Furthermore, we explore potential factors that connote a revolving door phenomenon for those whose adverse outpatient environment puts them at risk for hospital readmissions. Additionally, we review promising strategies, as well as actionable items at the policy, clinical, and educational levels aimed at locking this revolving door.

Using fans alone or in coordination with HVAC systems to cool people offers several significant enhancements compared to conventional HVAC systems, including improved thermal comfort, indoor air quality, air distribution, energy savings, and initial cost savings.Despite the numerous benefits of fans and fan-integrated systems, comprehensive resources are unavailable to guide engineers and architects in designing and implementing such systems. The purpose of this guideline is to address this gap and provide practitioners with valuable materials and answers to common questions.What are the available fan options?Various fan types are available in the market, such as ceiling fans, desk fans, and pedestal fans. This guideline provides a comprehensive overview of the criteria for fan type selection. These criteria cover blade characteristics, fan size, airflow patterns, fan performance metrics, motors and drives, power and efficiency, and control strategies. Ceiling fans are generally preferred for their higher efficiency, control and effectiveness, but cost, flickering and fixed location are limitations. This guideline can assist users in selecting suitable fan types based on individual building characteristics and specific application needs.How to integrate fans with my existing AC system?Adequate fan choice mainly depends on design intents, space characteristics, and HVAC operation strategies. This guidebook discusses which HVAC systems can be integrated with fans. With well-defined design intent, the guidebook provides a step-by-step process for determining the number and size of fans and their layout, ensuring proper fan installation, and integrating the fans with the control of the HVAC system.How do we implement and operate fans-integrated systems?Designing a successful fans-integrated system involves more than adding fans to a building. This guidebook assists building designers and operators by helping them adjust appropriate settings in chillers, air handling units, environmental conditions, and operation strategies. This optimization maximizes energy savings while ensuring occupants' comfort within the building. Additionally, the guidelines explore HVAC systems design that can enhance air distribution effectiveness and minimize construction costs. Most importantly, the guidelines outline a transformation strategy for transitioning from conventional air conditioning to a fan-integrated system with minimal disruption to occupants. This comprehensive approach ensures a smooth and efficient integration of fans into the existing air-conditioning infrastructure.Which design tools and case studies are available?This guidebook recommends using the and the CBE Thermal Comfort Tool CBE Ceiling Fan Design Tool. These tools enable users to define the comfort zone with elevated air speed and determine the optimal arrangement of ceiling fans based on room conditions specified by the users. In addition, the guidebook highlights relevant codes and standards related to environmental conditions, fan testing procedures, fire safety, and seismic requirements (subject to variations in different countries' regulations). Furthermore, we presented several case studies of buildings successfully implementing the fan-integrated HVAC system.We released two versions of our guidebook online: the Practitioner Summary and the Full Guide. These resources support selecting, designing, constructing, operating, and implementing fans and fans integrated HVAC systems. The Practitioner Summary offers a concise overview (~15 pages) of key considerations for building practitioners, providing brief descriptions of the fan-integrated system. In contrast, the Full Guidebook provides a more comprehensive exploration (~70 pages) of the fan and fan integrated system, including real building references, catering to users from diverse backgrounds. So we expect that many readers, after studying the Practitioner Summary, will move to sections of the Full Guidebook that are relevant to their work. Fans and fans-integrated HVAC systems will result in more sustainable and healthy buildings.

Background: Indo-US Masters in Emergency Medicine (MEM) certification courses are rigorous three-year emergency medicine (EM) training courses that operate as a partnership between affiliate hospitals or universities in the United States with established EM training programs and local partner sites in India. Throughout their 15 years of operation, these global training partnerships have contributed to the EM workforce in India. Our objective in this study was to describe Indo-US MEM program graduates, their work environments, and their contribution to the growth of academic EM and to the coronavirus disease 2019 (COVID-19) response.Methods: An electronic survey was created by US and Indian MEM course stakeholders and distributed to 714 US-affiliated MEM program graduates. The survey questions investigated where graduates were working, their work environments and involvement in teaching and research, and their involvement in the COVID-19 response. We consolidated the results into three domains: work environment and clinical contribution; academic contribution; and contribution to the COVID-19 response.Results: The survey response rate was 46.9% (335 responses). Most graduates reported working within India (210, 62.7%) and in an emergency department (ED) setting (304, 91.0%). The most common reason for practicing outside of India was difficulty with formal MEM certificate recognition within India (97, 79.5%). Over half of graduates reported dedicating over 25% of their work hours to teaching others about EM (223, 66.6%), about half reported presenting research projects at conferences on the regional, national, or international level (168, 50.5%), and almost all graduates were engaged in treating COVID-19 patients during the pandemic (333, 99.4%). Most graduates agreed or strongly agreed that they were satisfied with their overall MEM training (296, 88.4%) and confident in their ability to practice EM(306, 91.6%).Conclusion: Indo-US MEM graduates have made a notable contribution to EM in India through clinical service delivery, teaching, and research, even more essential in the context of the COVID-19 pandemic. The roles of these graduates should be acknowledged and can contribute further to expand EM specialty and systems development across India.

BackgroundPsilocybin is a serotonin type 2A (5-HT2A) receptor agonist and naturally occurring psychedelic. 5-HT2A receptor density is known to be associated with body mass index (BMI), however, the impact of this on psilocybin therapy has not been explored. While body weight-adjusted dosing is widely used, this imposes a practical and financial strain on the scalability of psychedelic therapy. This gap between evidence and practice is caused by the absence of studies clarifying the relationship between BMI, the acute psychedelic experience and long-term psychological outcomes.MethodData were pooled across three studies using a fixed 25 mg dose of psilocybin delivered in a therapeutic context to assess whether BMI predicts characteristics of the acute experience and changes in well-being 2 weeks later. Supplementing frequentist analysis with Bayes Factors has enabled for conclusions to be drawn regarding the null hypothesis.ResultsResults support the null hypothesis that BMI does not predict overall intensity of the altered state, mystical experiences, perceptual changes or emotional breakthroughs during the acute experience. There was weak evidence for greater 'dread of ego dissolution' in participants with lower BMI, however, further analysis suggested BMI did not meaningfully add to the combination of the other covariates (age, sex and study). While mystical-type experiences and emotional breakthroughs were strong predictors of improvements in well-being, BMI was not.ConclusionsThese findings have important implications for our understanding of pharmacological and extra-pharmacological contributors to psychedelic-assisted therapy and for the standardization of a fixed therapeutic dose in psychedelic-assisted therapy.

The Dark Energy Spectroscopic Instrument (DESI) Survey has obtained a set of spectroscopic measurements of galaxies to validate the final survey design and target selections. To assist in these tasks, we visually inspect DESI spectra of approximately 2500 bright galaxies, 3500 luminous red galaxies (LRGs), and 10,000 emission-line galaxies (ELGs) to obtain robust redshift identifications. We then utilize the visually inspected redshift information to characterize the performance of the DESI operation. Based on the visual inspection (VI) catalogs, our results show that the final survey design yields samples of bright galaxies, LRGs, and ELGs with purity greater than 99%. Moreover, we demonstrate that the precision of the redshift measurements is approximately 10 km s−1 for bright galaxies and ELGs and approximately 40 km s−1 for LRGs. The average redshift accuracy is within 10 km s−1 for the three types of galaxies. The VI process also helps improve the quality of the DESI data by identifying spurious spectral features introduced by the pipeline. Finally, we show examples of unexpected real astronomical objects, such as Lyα emitters and strong lensing candidates, identified by VI. These results demonstrate the importance and utility of visually inspecting data from incoming and upcoming surveys, especially during their early operation phases.

The Dark Energy Spectroscopic Instrument (DESI) embarked on an ambitious 5 yr survey in 2021 May to explore the nature of dark energy with spectroscopic measurements of 40 million galaxies and quasars. DESI will determine precise redshifts and employ the baryon acoustic oscillation method to measure distances from the nearby universe to beyond redshift z > 3.5, and employ redshift space distortions to measure the growth of structure and probe potential modifications to general relativity. We describe the significant instrumentation we developed to conduct the DESI survey. This includes: a wide-field, 3.°2 diameter prime-focus corrector; a focal plane system with 5020 fiber positioners on the 0.812 m diameter, aspheric focal surface; 10 continuous, high-efficiency fiber cable bundles that connect the focal plane to the spectrographs; and 10 identical spectrographs. Each spectrograph employs a pair of dichroics to split the light into three channels that together record the light from 360-980 nm with a spectral resolution that ranges from 2000-5000. We describe the science requirements, their connection to the technical requirements, the management of the project, and interfaces between subsystems. DESI was installed at the 4 m Mayall Telescope at Kitt Peak National Observatory and has achieved all of its performance goals. Some performance highlights include an rms positioner accuracy of better than 0.″1 and a median signal-to-noise ratio of 7 of the [O ii] doublet at 8 × 10-17 erg s-1 cm-2 in 1000 s for galaxies at z = 1.4-1.6. We conclude with additional highlights from the on-sky validation and commissioning, key successes, and lessons learned.

The Dark Energy Spectroscopic Instrument (DESI) has embarked on an ambitiousfive-year survey to explore the nature of dark energy with spectroscopy of 40million galaxies and quasars. DESI will determine precise redshifts and employthe Baryon Acoustic Oscillation method to measure distances from the nearbyuniverse to z > 3.5, as well as measure the growth of structure and probepotential modifications to general relativity. In this paper we describe thesignificant instrumentation we developed for the DESI survey. The newinstrumentation includes a wide-field, 3.2-deg diameter prime-focus correctorthat focuses the light onto 5020 robotic fiber positioners on the 0.812 mdiameter, aspheric focal surface. The positioners and their fibers are dividedamong ten wedge-shaped petals. Each petal is connected to one of tenspectrographs via a contiguous, high-efficiency, nearly 50 m fiber cablebundle. The ten spectrographs each use a pair of dichroics to split the lightinto three channels that together record the light from 360 - 980 nm with aresolution of 2000 to 5000. We describe the science requirements, technicalrequirements on the instrumentation, and management of the project. DESI wasinstalled at the 4-m Mayall telescope at Kitt Peak, and we also describe thefacility upgrades to prepare for DESI and the installation and functionalverification process. DESI has achieved all of its performance goals, and theDESI survey began in May 2021. Some performance highlights include RMSpositioner accuracy better than 0.1", SNR per \sqrt{\AA} > 0.5 for a z > 2quasar with flux 0.28e-17 erg/s/cm^2/A at 380 nm in 4000s, and median SNR = 7of the [OII] doublet at 8e-17 erg/s/cm^2 in a 1000s exposure for emission linegalaxies at z = 1.4 - 1.6. We conclude with highlights from the on-skyvalidation and commissioning of the instrument, key successes, and lessonslearned. (abridged)

The Energy Sciences Network (ESnet) is the high-performance network user facility for the US Department of Energy (DOE) Office of Science (SC) and delivers highly reliable data transport capabilities optimized for the requirements of data-intensive science. In essence, ESnet is the circulatory system that enables the DOE science mission by connecting all of its laboratories and facilities in the US and abroad. ESnet is funded and stewarded by the Advanced Scientific Computing Research (ASCR) program and managed and operated by the Scientific Networking Division at Lawrence Berkeley National Laboratory (LBNL). ESnet is widely regarded as a global leader in the research and education networking community.Throughout 2021, ESnet and the Office of Fusion Energy Sciences (FES) of the DOE SC organized an ESnet requirements review of FES-supported activities. Preparation for these events included identification of key stakeholders: program and facility management, research groups, and technology providers. Each stakeholder group was asked to prepare formal case study documents about their relationship to the FES program to build a complete understanding of the current, near-term, and long-term status, expectations, and processes that will support the science going forward.

The Alliance of Genome Resources (the Alliance) is a combined effort of 7 knowledgebase projects: Saccharomyces Genome Database, WormBase, FlyBase, Mouse Genome Database, the Zebrafish Information Network, Rat Genome Database, and the Gene Ontology Resource. The Alliance seeks to provide several benefits: better service to the various communities served by these projects; a harmonized view of data for all biomedical researchers, bioinformaticians, clinicians, and students; and a more sustainable infrastructure. The Alliance has harmonized cross-organism data to provide useful comparative views of gene function, gene expression, and human disease relevance. The basis of the comparative views is shared calls of orthology relationships and the use of common ontologies. The key types of data are alleles and variants, gene function based on gene ontology annotations, phenotypes, association to human disease, gene expression, protein-protein and genetic interactions, and participation in pathways. The information is presented on uniform gene pages that allow facile summarization of information about each gene in each of the 7 organisms covered (budding yeast, roundworm Caenorhabditis elegans, fruit fly, house mouse, zebrafish, brown rat, and human). The harmonized knowledge is freely available on the alliancegenome.org portal, as downloadable files, and by APIs. We expect other existing and emerging knowledge bases to join in the effort to provide the union of useful data and features that each knowledge base currently provides.

In assessing the current and future role of universities in the nation-states in which they are chartered and funded, it is useful to ask, When are universities societal leaders as societal and constructive change agents, and when are they followers, reinforcing the existing political order? As discussed in the book, Neo-Nationalism and Universities: Populists, Autocrats and the Future of Higher Education, the national political history and contemporary context is the dominant factor for shaping the leadership or follower role of universities – what I call a political determinist interpretation.  We often think of contemporary universities, and their students and faculty, as catalysts for societal progress -- the Free Speech and Civil Rights movements, Vietnam War protests, the anti-Apartheid movement, Tiananmen Square, and more recently the pro-democracy demonstrations in Hong Kong. Universities can be, and have been, the locus for not only educating enlightened future leaders, but also for opposing oppression and dictatorships. But universities have also proved over their history to be tools for serving the privileged, and reinforcing the social class divisions of a society; they also have been factories for errant theories that reinforce the worst of nationalist tendencies. Universities are both unique environments for educating and mentoring free thinkers, entrepreneurs, and citizens with, for example, a devotion to social change, or for creating conformists -- or all of the above. How might we assess whether universities are followers or leaders in their societies? This essay considers this question, offering a framework for evaluating the follower or leader role, and with particular attention to the emergence or, in some cases, re-emergence of neo-nationalist leaders and autocratic governments.

Healthful behaviours such as maintaining a balanced diet, being physically active and refraining from smoking have major impacts on the risk of developing cancer, diabetes, cardiovascular diseases and other serious conditions. The burden of the so-called 'lifestyle diseases'-in personal suffering, premature mortality and public health costs-is considerable. Consequently, interventions designed to promote healthy behaviours are increasingly being studied, e.g., using psychobiological models of behavioural regulation and change. In this article, we explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health. Psilocybin has a low toxicity, is non-addictive and has been shown to predict favourable changes in patients with depression, anxiety and other conditions marked by rigid behavioural patterns, including substance (mis)use. While it is still early days for modern psychedelic science, research is advancing fast and results are promising. Here we describe psychedelics' proposed mechanisms of action and research findings pertinent to health behaviour change science, hoping to generate discussion and new research hypotheses linking the two areas. Therapeutic models including psychedelic experiences and common behaviour change methods (e.g., Cognitive Behaviour Therapy, Motivational Interviewing) are already being tested for addiction and eating disorders. We believe this research may soon be extended to help promote improved diet, exercise, nature exposure and also mindfulness or stress reduction practices, all of which can contribute to physical and psychological health and well-being.

Controlled air movement is an effective strategy for maintaining occupant comfort while reducing energy consumption, since comfort at moderately warmer temperatures requires less space cooling. Modern ceiling fans provide a 2–4 °C cooling effect at power consumption comparable to LED lightbulbs (2–30 W) with gentle air speeds (0.5–1 m/s). However, very limited design guidance and performance data are available for using ceiling fans and air conditioning together, especially in commercial buildings. We present results from a 29-month field study of 99 automated ceiling fans and 12 thermostats installed in ten air-conditioned buildings in a hot/dry climate in California. Staging ceiling fans to automatically cool before, and then operate together with air conditioning enabled raising air conditioning cooling temperature setpoints in most zones, with overall positive occupant interview and survey responses. Overall measured cooling season (April– October) compressor energy savings were 36%, normalized by floor area served (41% during summer peak billing hours). Weather-normalized changes in zone energy use varied from 24% increase to 73% decrease across 13 compressors, reflecting variation in occupant schedules and other uncontrolled factors in occupied buildings. Median weather-normalized energy savings per compressor were 21%. Staging ceiling fans and air conditioning provided comfort across a wider temperature range, using less energy, than air conditioning alone.

ObjectivesActive learning techniques help with motivation, involvement, and retention during didactics. There are few studies comparing different active learning methods, and these have yielded mixed results. The objective of this study was to compare the effect of two active learning methods-small-group discussion and audience response system (ARS)-on immediate- and long-term knowledge gain.MethodsThis was a prospective experimental study of emergency medicine (EM) subinterns and residents. Participants were randomized into two groups, and baseline knowledge was assessed with a multiple-choice pretest. Didactic sessions on salicylate toxicity and ocular trauma were given to both groups utilizing either small-group discussion or ARS. A crossover design was utilized to ensure that both groups received instruction by each method. A multiple-choice posttest was administered following the didactics and again 2 months later. Pre- and posttests were identical. All test items were written by an academic faculty member with advanced training in medical education and item writing and were based on the goals and objectives of the session. Test items were piloted with a reference group of learners. Didactic instructors were blinded to test items. Data were analyzed using a linear mixed-effects model.ResultsThirty-eight subinterns and residents participated in the study. Both instructional methods showed immediate- and long-term knowledge gain. The linear mixed-effects model did not demonstrate any significant difference between instructional methods on immediate knowledge gain (mean difference = 0.18, p = 0.62, 95% confidence interval [CI] = -0.52 to 0.88) or long-term knowledge gain (mean difference = -0.42, p = 0.36, 95% CI = -1.32 to 0.47).ConclusionIn this small study, there was no significant difference between instructional methods on immediate- and long-term knowledge gain in EM subinterns and residents.

Study objectiveAntibiotic resistance is a global health threat. India has one of the highest rates of antibiotic use in the world. The objective of this study was to evaluate the prevalence of self-prescribed antibiotic use of patients presenting with febrile and infectious disease-related complaints to Indian emergency departments.MethodsThis was a prospective observational study conducted at 6 Indian emergency departments (EDs) between January 1, 2019 and December 31, 2019. Adult patients who presented with a chief complaint of febrile illness or infectious disease complaints were included. Our principal outcomes of interest were self-prescribed use of antibiotics within the prior 6 months or for the presenting complaint. We queried respondents about source of antibiotics as well as about demographic characteristics that influenced use.ResultsA total of 1421 patients were enrolled. Sixty percent (n = 856) of respondents reported using antibiotics in the prior 6 months or for their current complaint. Those who reported self-prescribing antibiotics either in the past or currently had at least some college education (P

Undergraduate students participating in the UCLA Undergraduate Research Consortium for Functional Genomics (URCFG) have conducted a two-phased screen using RNA interference (RNAi) in combination with fluorescent reporter proteins to identify genes important for hematopoiesis in Drosophila. This screen disrupted the function of approximately 3500 genes and identified 137 candidate genes for which loss of function leads to observable changes in the hematopoietic development. Targeting RNAi to maturing, progenitor, and regulatory cell types identified key subsets that either limit or promote blood cell maturation. Bioinformatic analysis reveals gene enrichment in several previously uncharacterized areas, including RNA processing and export and vesicular trafficking. Lastly, the participation of students in this course-based undergraduate research experience (CURE) correlated with increased learning gains across several areas, as well as increased STEM retention, indicating that authentic, student-driven research in the form of a CURE represents an impactful and enriching pedagogical approach.

The Gene Ontology Consortium (GOC) provides the most comprehensive resource currently available for computable knowledge regarding the functions of genes and gene products. Here, we report the advances of the consortium over the past two years. The new GO-CAM annotation framework was notably improved, and we formalized the model with a computational schema to check and validate the rapidly increasing repository of 2838 GO-CAMs. In addition, we describe the impacts of several collaborations to refine GO and report a 10% increase in the number of GO annotations, a 25% increase in annotated gene products, and over 9,400 new scientific articles annotated. As the project matures, we continue our efforts to review older annotations in light of newer findings, and, to maintain consistency with other ontologies. As a result, 20 000 annotations derived from experimental data were reviewed, corresponding to 2.5% of experimental GO annotations. The website (http://geneontology.org) was redesigned for quick access to documentation, downloads and tools. To maintain an accurate resource and support traceability and reproducibility, we have made available a historical archive covering the past 15 years of GO data with a consistent format and file structure for both the ontology and annotations.

Background: Anorexia nervosa (AN) is a serious and life-threatening psychiatric condition. With a paucity of approved treatments, there is a desperate need for novel treatment avenues to be explored. Here, we present (1) an overview of the ways through which Public Patient Involvement (PPI) has informed a trial of psilocybin-assisted therapy for AN and (2) a protocol for a pilot study of psilocybin-assisted therapy in AN currently underway at Imperial College London. The study aims to assess the feasibility, brain mechanisms and preliminary outcomes of treating anorexia nervosa with psilocybin. Methods: (1) PPI: Across two online focus groups, eleven individuals with lived experience of AN were presented with an overview of the protocol. Their feedback not only identified solutions to possible barriers for future participants, but also helped the research team to better understand the concept of "recovery" from the perspective of those with lived experience. (2) Protocol: Twenty female participants [21-65 years old, body mass index (BMI) 15 kg/m2 or above] will receive three oral doses of psilocybin (up to 25 mg) over a 6-week period delivered in a therapeutic environment and enveloped by psychological preparation and integration. We will work with participant support networks (care teams and an identified support person) throughout and there will be an extended remote follow-up period of 12 months. Our two-fold primary outcomes are (1) psychopathology (Eating Disorder Examination) across the 6-month follow-up and (2) readiness and motivation to engage in recovery (Readiness and Motivation Questionnaire) across the 6-week trial period. Neurophysiological outcome measures will be: (1) functional magnetic resonance imaging (fMRI) brain changes from baseline to 6-week endpoint and (2) post-acute changes in electroencephalography (EEG) activity, including an electrophysiological marker of neuronal plasticity. Discussion: The results of this pilot study will not only shed light on the acceptability, brain mechanisms, and impression of the potential efficacy of psilocybin as an adjunct treatment for AN but will be essential in shaping a subsequent Randomised Control Trial (RCT) that would test this treatment against a suitable control condition. Clinical Trial Registration: identifier: NCT04505189.

ObjectiveThis study aimed to describe two cases of acute respiratory distress syndrome (ARDS) secondary to novel coronavirus disease 2019 (COVID-19) in pregnant women requiring extracorporeal membrane oxygenation (ECMO), and resulting in premature delivery.Study designThe clinical course of two women hospitalized with ARDS due to COVID-19 care in our intensive care (ICU) is summarized; both participants provided consent to be included in this case series.ResultsBoth women recovered with no clinical sequelae. Neonatal outcomes were within the realm of expected for prematurity with the exception of coagulopathy. There was no vertical transmission to the neonates.ConclusionThis case series highlights that ECMO is a feasible treatment in the pregnant woman with severe COVID-19 and that delivery can be performed safely on ECMO with no additional risk to the fetus. While ECMO carries its natural risks, it should be considered a viable option during pregnancy and the postpartum period.Key points· COVID-19 may present with a more severe course in pregnancy.. · ECMO may be used in pregnant woman with severe COVID-19.. · Delivery can be performed on ECMO without added fetal risk..

Biological invasions offer model systems of contemporary evolution. We examined trait differences and evolution across geographic clines among continents of the intertidal grass Spartina alterniflora within its invasive and native ranges. We sampled vegetative and reproductive traits in the field at 20 sites over 20° latitude in China (invasive range) and 28 sites over 17° in the US (native range). We grew both Chinese and US plants in a glasshouse common garden for 3 yr. Chinese plants were c. 15% taller, c. 10% denser, and set up to four times more seed than US plants in both the field and common garden. The common garden experiments showed a striking genetic cline of seven-fold greater seed set at higher latitudes in the introduced but not the native range. By contrast, there was a slight genetic cline in some vegetative traits in the native but not the introduced range. Our results are consistent with others showing that introduced plants can evolve rapidly in the new range. S. alterniflora has evolved different trait clines in the native and introduced ranges, showing the importance of phenotypic plasticity and genetic control of change during the invasion process.

This guide enables architects, designers, and engineers to maximize the many benefits of integrating ceiling fans into building systems. It introduces the advantages of using ceiling fans, describes how ceiling fans work, provides guidance and resources for designing spaces with ceiling fans and specifying ceiling fan products.

Introduction: Bull-related injuries are commonly observed in rural areas of India as result of the animal’s use in sporting events as well as for agricultural purposes. These patients need early resuscitation due to complications from severe injuries. Previous work examining the epidemiology of bull-related injuries is limited, with most studies focusing on injuries in Spain and Latin America.  There is scant literature examining the prevalence of such injuries in India. The objective of this study was to evaluate the demographic and clinical characteristics of bull-related injuries at a hospital in Tamil Nadu, India.Methods: This was a prospective, observational study of patients who presented to an emergency department (ED) in Madurai, India, with a reported history of bull-related injuries between June 2017 and March 2019. We recorded information about patient demographics, location of injury, disposition, initial Injury Severity Score (ISS), and transport time.Results: Our sample included a total of 42 patients. Almost a third of patients who presented were between the ages of 20-30 years (31%, n = 13), and most were male (86%, n = 36). Approximately 59% of patients (n = 25) had provoked injuries, occurring as a result of active participation during sporting activities. Injuries to the trunk were most common (55%, n = 23), followed by injuries to the perineum (19%, n = 19). The majority of patients (59.5%) had penetrating injuries (n = 25), The mean ISS was 10.1 (standard deviation 6.3).  Five (12%) patients had a complication after injury including intra-abdominal abscess formation, peritonitis, and sepsis. Two patients died as a result of septicemia from peritonitis.Conclusion: Bull-related injuries may result in significant morbidity and mortality. Education of the population about the dangers of bull injuries from sporting events and the need for early transportation to the ED have the potential for significant reduction in morbidity and mortality.

BackgroundOntologies are invaluable in the life sciences, but building and maintaining ontologies often requires a challenging number of distinct tasks such as running automated reasoners and quality control checks, extracting dependencies and application-specific subsets, generating standard reports, and generating release files in multiple formats. Similar to more general software development, automation is the key to executing and managing these tasks effectively and to releasing more robust products in standard forms. For ontologies using the Web Ontology Language (OWL), the OWL API Java library is the foundation for a range of software tools, including the Protégé ontology editor. In the Open Biological and Biomedical Ontologies (OBO) community, we recognized the need to package a wide range of low-level OWL API functionality into a library of common higher-level operations and to make those operations available as a command-line tool.ResultsROBOT (a recursive acronym for "ROBOT is an OBO Tool") is an open source library and command-line tool for automating ontology development tasks. The library can be called from any programming language that runs on the Java Virtual Machine (JVM). Most usage is through the command-line tool, which runs on macOS, Linux, and Windows. ROBOT provides ontology processing commands for a variety of tasks, including commands for converting formats, running a reasoner, creating import modules, running reports, and various other tasks. These commands can be combined into larger workflows using a separate task execution system such as GNU Make, and workflows can be automatically executed within continuous integration systems.ConclusionsROBOT supports automation of a wide range of ontology development tasks, focusing on OBO conventions. It packages common high-level ontology development functionality into a convenient library, and makes it easy to configure, combine, and execute individual tasks in comprehensive, automated workflows. This helps ontology developers to efficiently create, maintain, and release high-quality ontologies, so that they can spend more time focusing on development tasks. It also helps guarantee that released ontologies are free of certain types of logical errors and conform to standard quality control checks, increasing the overall robustness and efficiency of the ontology development lifecycle.

Homologous recombination (HR) uses a homologous template to accurately repair DNA double-strand breaks and stalled replication forks to maintain genome stability. During homology search, Rad51 nucleoprotein filaments probe and interact with dsDNA, forming the synaptic complex that is stabilized on a homologous sequence. Strand intertwining leads to the formation of a displacement-loop (D-loop). In yeast, Rad54 is essential for HR in vivo and required for D-loop formation in vitro, but its exact role remains to be fully elucidated. Using electron microscopy to visualize the DNA-protein complexes, here we find that Rad54 is crucial for Rad51-mediated synaptic complex formation and homology search. The Rad54-K341R ATPase-deficient mutant protein promotes formation of synaptic complexes but not D-loops and leads to the accumulation of stable heterologous associations, suggesting that the Rad54 ATPase is involved in preventing non-productive intermediates. We propose that Rad51/Rad54 form a functional unit operating in homology search, synaptic complex and D-loop formation.

BackgroundDuring emergency medicine (EM) training, residents are exposed to a wide spectrum of patient complaints. We sought to determine how resident clinical experience changes based on training level in relation to the patient acuity levels, chief complaints, and dispositions.MethodsWe performed a retrospective chart review of patients seen at a safety-net, academic hospital in Los Angeles from July 1, 2015, to June 30, 2016. Resident postgraduate year (PGY) level and specialty, patient acuity (based on the Emergency Severity Index), chief complaint (based on one of 30 categories), and disposition were abstracted. Our primary objective was to examine the progression of EM resident experience throughout the course of training. As a secondary objective, we compared the cases seen by EM and off-service PGY-1s.ResultsA total of 49,535 visits were examined, and of these, 32,870 (66.4%) were in the adult ED (AED) and 16,665 (33.6%) were in the pediatric ED (PED). The median acuity level was 3, and 27.4% of AED patients and 7.3% of PED patients were admitted. Data from 126 residents were analyzed. This included 94 PGY-1 residents (16 EM and 78 off-service), 16 PGY-2 EM, and 16 PGY-3 EM residents. Residents of different training levels evaluated different types of patients. Senior EM residents were more likely to care for higher-acuity patients than junior EM residents. EM PGY-3s saw higher percentages of acuity level 1 and 2 patients (2.3 and 37.8%, respectively, of their total patients) than EM PGY-1s (0.3 and 18.7%, respectively). Conversely, EM PGY-1s saw higher percentages of acuity level 4 and 5 patients (27.9 and 1.6%, respectively) compared to EM PGY-3s (10.7 and 0.7%, respectively). There was a significant linear trend for increasing acuity with training year among EM residents (p

The expansion of the Universe is understood to have accelerated during twoepochs: in its very first moments during a period of Inflation and much morerecently, at $z < 1$, when Dark Energy is hypothesized to drive cosmicacceleration. The undiscovered mechanisms behind these two epochs representsome of the most important open problems in fundamental physics. The largecosmological volume at $2 < z < 5$, together with the ability to efficientlytarget high-$z$ galaxies with known techniques, enables large gains in thestudy of Inflation and Dark Energy. A future spectroscopic survey can test theGaussianity of the initial conditions up to a factor of ~50 better than ourcurrent bounds, crossing the crucial theoretical threshold of$\sigma(f_{NL}^{\rm local})$ of order unity that separates single field andmulti-field models. Simultaneously, it can measure the fraction of Dark Energyat the percent level up to $z = 5$, thus serving as an unprecedented test ofthe standard model and opening up a tremendous discovery space.

Opening up a new window of millimeter-wave observations that span frequencybands in the range of 30 to 500 GHz, survey half the sky, and are both an orderof magnitude deeper (about 0.5 uK-arcmin) and of higher-resolution (about 10arcseconds) than currently funded surveys would yield an enormous gain inunderstanding of both fundamental physics and astrophysics. In particular, sucha survey would allow for major advances in measuring the distribution of darkmatter and gas on small-scales, and yield needed insight on 1.) dark matterparticle properties, 2.) the evolution of gas and galaxies, 3.) new lightparticle species, 4.) the epoch of inflation, and 5.) the census of bodiesorbiting in the outer Solar System.

Displacement loops (D-loops) are pivotal intermediates of homologous recombination (HR), a universal DNA double strand break (DSB) repair pathway. We developed a versatile assay for the physical detection of D-loops in vivo, which enabled studying the kinetics of their formation and defining the activities controlling their metabolism. Nascent D-loops are detected within 2 h of DSB formation and extended in a delayed fashion in a genetic system designed to preclude downstream repair steps. The majority of nascent D-loops are disrupted by two pathways: one supported by the Srs2 helicase and the other by the Mph1 helicase and the Sgs1-Top3-Rmi1 helicase-topoisomerase complex. Both pathways operate without significant overlap and are delineated by the Rad54 paralog Rdh54 in an ATPase-independent fashion. This study uncovers a layer of quality control of HR relying on nascent D-loop dynamics.

Although writing is well established as a high-impact educational practice, scaling that practice is challenging. Writing is a modeof engaged learning, and teaching it requires providing careful attention informed by expertise. These conditions are labor-intensive and expensive, even as public universities are hardly awash in funds. Writing skills develop over time as a function ofencountering challenges and being coached on addressing them. What counts as “good” writing varies according to context,target readership, and purpose. Students need to build a repertory of strategies and experiences, along with the executivefunctions to know when to access what. They acquire this repertory by writing: doing it, not simply being told about it, andreceiving feedback and advice. Technologies cannot currently or foreseeably provide feedback of sufficient quality to solveproblems of scale. Writing Across the Curriculum programs can supplement first year writing courses, even replace some ofthem—but only if accompanied by sustained professional development that includes thorough knowledge of effective writingpedagogies, knowledge bolstered by existing research, theory, and best practices. New faculty models that feature full-time,benefited continuing lecturers or teaching professors exist at many universities, private and public; these models are more cost-effective than tenure-line faculty owing to enrollments. Even when they’re more expensive than adjuncts, these models’ return inquality is profound. The bottom line is that, even with cost ceilings, it’s possible to scale quality writing instruction, howeverincrementally. At least minimally, this requires faculty writing specialists who can work directly with disciplinary faculty and whocan ensure that anyone teaching writing is doing so in well-designed courses, using effective and efficient pedagogies. Writingcenters are vital in supporting these efforts. Permanent, professional writing faculties, in new kinds of faculty roles, offer thegreatest promise, albeit at greater costs.

BackgroundDespite great progress made in methods to prevent mother-to-child transmission of HIV (MTCT), delivery and uptake of these measures remains a challenge in many countries. Although the Brazilian Ministry of Health aimed to eliminate MTCT by 2015, infection still occured in 15-24% of infants born to HIV-infected mothers. We sought to identify remaining factors that constrain MTCT elimination.MethodsWe conducted a retrospective, matched case-control study by reviewing hospital charts of infants born to HIV-infected mothers between 1997 and 2014 at three MTCT reference hospitals in the Rio de Janeiro metropolitan area. Cases were defined as HIV-exposed children with two positive HIV tests before 18 months of age; controls were defined as HIV-exposed children with two negative HIV tests before 18 months of age. We performed bivariate and MTCT cascade analyses to identify risk factors for MTCT and gaps in prevention services.ResultsWe included 435 infants and their mothers (145 cases, 290 controls). Bivariate analyses of MTCT preventative care (PMTCT) indicated that cases were less likely to complete all individual measures in the antenatal, delivery, and postnatal period (p

Despite massive cuts in state funding over the past thirty years, the University of California has managed to keep enrollment on pace with growth in population.  With California’s population projected to grow 22.5 percent (from 40 to 49 million by 2040), that will no longer be the case, unless UC is able to find a new funding model. Informed by the historical analysis in the report Approaching a Tipping Point: A History and Prospectus of Funding for the University of California, this essay revisits the options for funding UC from that report, including: reinvestment by California lawmakers and a proposed general bond measure for capital construction; increasing research funding to help subsidize teaching and public service programs; revising the indirect-cost agreement with the State of California; raising undergraduate tuition and fees for upper income students and establishing tuition pricing model tiered by student family income; explore differential fees by major; and reducing the percentage of UC undergraduate tuition income that is “returned-to-aid” in favor of increased fundraising for financial aid. All relate to two central questions: a) can UC afford to grow in its enrollment and academic programs with the state’s population and needs? and b) how to identify new sources of revenue and pursue management efficiencies to reduce operating and capital costs? Without a substantial boost in income from the state or other sources, UC may be approaching a crossroads, where it continues to grow in enrollment without adequate funding, or where it instead chooses to halt or limit growth to focus on maintaining quality and productivity, but with serious consequences for California. Any significant state reinvestment will depend on the new California governor. Governors in the past have been key players in creating and building California’s pioneering higher education system.  A new governor should have ambitions for higher education that match those of Californians.

Purpose: We have shown that the aged microenvironment increases melanoma metastasis, and decreases response to targeted therapy, and here we queried response to anti-PD1.Experimental Design: We analyzed the relationship between age, response to anti-PD1, and prior therapy in 538 patients. We used mouse models of melanoma, to analyze the intratumoral immune microenvironment in young versus aged mice and confirmed our findings in human melanoma biopsies.Results: Patients over the age of 60 responded more efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy. Placing genetically identical tumors in aged mice (52 weeks) significantly increased their response to anti-PD1 as compared with the same tumors in young mice (8 weeks). These data suggest that this increased response in aged patients occurs even in the absence of a more complex mutational landscape. Next, we found that young mice had a significantly higher population of regulatory T cells (Tregs), skewing the CD8+:Treg ratio. FOXP3 staining of human melanoma biopsies revealed similar increases in Tregs in young patients. Depletion of Tregs using anti-CD25 increased the response to anti-PD1 in young mice.Conclusions: While there are obvious limitations to our study, including our inability to conduct a meta-analysis due to a lack of available data, and our inability to control for mutational burden, there is a remarkable consistency in these data from over 500 patients across 8 different institutes worldwide. These results stress the importance of considering age as a factor for immunotherapy response. Clin Cancer Res; 24(21); 5347-56. ©2018 AACR See related commentary by Pawelec, p. 5193.

Down syndrome cell adhesion molecules (DSCAMs) are broadly expressed in nervous systems and play conserved roles in programmed cell death, neuronal migration, axon guidance, neurite branching and spacing, and synaptic targeting. However, DSCAMs appear to have distinct functions in different vertebrate animals, and little is known about their functions outside the retina. We leveraged the genetic tractability and optical accessibility of larval zebrafish to investigate the expression and function of a DSCAM family member, dscamb. Using targeted genome editing to create transgenic reporters and loss-of-function mutant alleles, we discovered that dscamb is expressed broadly throughout the brain, spinal cord, and peripheral nervous system, but is not required for overall structural organization of the brain. Despite the absence of obvious anatomical defects, homozygous dscamb mutants were deficient in their ability to ingest food and rarely survived to adulthood. Thus, we have discovered a novel function for dscamb in feeding behavior. The mutant and transgenic lines generated in these studies will provide valuable tools for identifying the molecular and cellular bases of these behaviors.

This year marks the University of California’s (UC) 150th anniversary. In part to reflect on that history, and to provide a basis to peer into the future, the following report provides a history of the University of California’s revenue sources and expenditures. The purpose is to provide the University’s academic community, state policymakers, and Californians with a greater understanding of the University’s financial history, focusing in particular on the essential role of public funding.In its first four decades, UC depended largely on income generated by federal land grants and private philanthropy, and marginally on funding from the state. The year 1911 marked a major turning point: henceforth, state funding was linked to student enrollment workload. As a result, the University grew with California’s population in enrollment, academic programs, and new campuses. This historic commitment to systematically fund UC, the state’s sole land-grant university, helped create what is now considered the world’s premier public university system.However, beginning with cutbacks in the early 1990s UC’s state funding per student steadily declined. The pattern of state disinvestment increased markedly with the onset of the Great Recession. As chronicled in this report, the University diversified its sources of income and attempted to cut costs in response to this precipitous decline, while continuing to enroll more and more Californians. Even with the remarkable improvement in California’s economy, state funding per student remains significantly below what it was only a decade ago.Peering into the future, this study also provides a historically informed prospectus on the budget options available to UC. Individual campuses, such as Berkeley and UCLA, may be able to generate other income sources to maintain their quality and reputation. But there is no clear funding model or pathway for the system to grow with the needs of the people of California. UC may be approaching a tipping point in which it will need to decide whether to continue to grow in enrollment without adequate funding, or limit enrollment and program growth to focus on quality and productivity.Funding support was provided by the Center for Studies in Higher Education of the Goldman School of Public Policy, Speaker Emeritus John A. Pérez, and UC Berkeley Deans Henry E. Brady and Bob Jacobsen. The views expressed are those of the authors.

The observed scatter in intergalactic Lyα opacity at z ≲ 6 requires large-scale fluctuations in the neutral fraction of the intergalactic medium (IGM) after the expected end of reionization. Post-reionization models that explain this scatter invoke fluctuations in either the ionizing ultraviolet background (UVB) or IGM temperature. These models make very different predictions, however, for the relationship between Lyα opacity and local density. Here, we test these models using Lyα-emitting galaxies (LAEs) to trace the density field surrounding the longest and most opaque known Lyα trough at z < 6. Using deep Subaru Hyper Suprime-Cam narrowband imaging, we find a highly significant deficit of z ≃ 5.7 LAEs within 20 of the trough. The results are consistent with a model in which the scatter in Lyα opacity near z ∼ 6 is driven by large-scale UVB fluctuations, and disfavor a scenario in which the scatter is primarily driven by variations in IGM temperature. UVB fluctuations at this epoch present a boundary condition for reionization models, and may help shed light on the nature of the ionizing sources.