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During the Miocene, Hyaenidae was a highly diverse family of Carnivora that has since been severely reduced to four species: the bone-cracking spotted, striped, and brown hyenas, and the specialized insectivorous aardwolf. Previous studies investigated the evolutionary histories of the spotted and brown hyenas, but little is known about the remaining two species. Moreover, the genomic underpinnings of scavenging and insectivory, defining traits of the extant species, remain elusive. Here, we generated an aardwolf genome and analyzed it together with the remaining three species to reveal their evolutionary relationships, genomic underpinnings of their scavenging and insectivorous lifestyles, and their respective genetic diversities and demographic histories. High levels of phylogenetic discordance suggest gene flow between the aardwolf lineage and the ancestral brown/striped hyena lineage. Genes related to immunity and digestion in the bone-cracking hyenas and craniofacial development in the aardwolf showed the strongest signals of selection, suggesting putative key adaptations to carrion and termite feeding, respectively. A family-wide expansion in olfactory receptor genes suggests that an acute sense of smell was a key early adaptation. Finally, we report very low levels of genetic diversity within the brown and striped hyenas despite no signs of inbreeding, putatively linked to their similarly slow decline in effective population size over the last ∼2 million years. High levels of genetic diversity and more stable population sizes through time are seen in the spotted hyena and aardwolf. Taken together, our findings highlight how ecological specialization can impact the evolutionary history, demographics, and adaptive genetic changes of an evolutionary lineage.

The Indiana University School of Medicine: A History tells the story of the school and its faculty and students in fascinating detail. Founded in the early 20th century, the Indiana University School of Medicine went on to become a leading medical facility, preparing students for careers in medicine and providing healthcare across Indiana. Historian William Schneider draws on a treasure trove of historical images and documents, to recount how the school began life as the Medical Department in 1903, and later became the Indiana University School of Medicine, which was established as a full four-year school after merging with two private schools in 1908. Thanks to state support and local philanthropy, it quickly added new hospitals, which by the 1920s made it the core of a medical center for the city of Indianapolis and the only medical school in the state. From modest beginnings, and the challenges of the Great Depression and the Second World War, the medical school has grown to meet the demands of every generation, becoming the leading resource for not only the education of physicians and for the conducting of medical research but also for the care and treatment of patients at the multi-hospital medical center. Today, the school boasts an annual income of over $1.5 billion, with over 2,000 full-time faculty teaching 1,350 MD students, and over $250 million in external research funding.

Forest cover change directly affects biodiversity, the global carbon budget, and ecosystem function. Within Latin American and the Caribbean region (LAC), many studies have documented extensive deforestation, but there are also many local studies reporting forest recovery. These contrasting dynamics have been largely attributed to demographic and socio-economic change. For example, local population change due to migration can stimulate forest recovery, while the increasing global demand for food can drive agriculture expansion. However, as no analysis has simultaneously evaluated deforestation and reforestation from the municipal to continental scale, we lack a comprehensive assessment of the spatial distribution of these processes. We overcame this limitation by producing wall-to-wall, annual maps of change in woody vegetation and other land-cover classes between 2001 and 2010 for each of the 16,050 municipalities in LAC, and we used nonparametric Random Forest regression analyses to determine which environmental or population variables best explained the variation in woody vegetation change. Woody vegetation change was dominated by deforestation (—541,835 km 2 ), particularly in the moist forest, dry forest, and savannas/shrublands biomes in South America. Extensive areas also recovered woody vegetation (+362,430 km 2 ), particularly in regions too dry or too steep for modern agriculture. Deforestation in moist forests tended to occur in lowland areas with low population density, but woody cover change was not related to municipality-scale population change. These results emphasize the importance of quantitating deforestation and reforestation at multiple spatial scales and linking these changes with global drivers such as the global demand for food.

Forest transitions (FT) have been observed in many developed countries and more recently in the developing world. However, our knowledge of FT from tropical regions is mostly derived from case studies from within a particular country, making it difficult to generalize findings across larger regions. Here we overcome these difficulties by conducting a recent (2001-2010) satellite-based analysis of trends in forest cover across Central America, stratified by biomes, which we related to socioeconomic variables associated with human development. Results show a net decrease of woody vegetation resulting from 12,201 km² of deforestation of moist forests and 6,825 km² of regrowth of conifer and dry forests. The Human Development Index was the socioeconomic variable best associated with forest cover change. The least-developed countries, Nicaragua and Guatemala, experienced both rapid deforestation of moist forests and significant recovery of conifer and dry forests. In contrast, the most developed countries, Panama and Costa Rica, had net woody vegetation gain and a more stable forest cover configuration. These results imply a good agreement with FT predictions of forest change in relation to socioeconomic development, but strong asymmetry in rates and directions of change largely dependent upon the biome where change is occurring. The FT model should be refined by incorporating ecological and socioeconomic heterogeneity, particularly in multicountry and regional studies. These asymmetric patterns of forest change should be evaluated when developing strategies for conserving biodiversity and environmental services.

Land use change is a key component of regional environmental change. In mountain regions, where conditions for agriculture and human life are often difficult, land use trends are dominated by changes in the population's distribution across rural and urban areas and shifts in the main human activities. In the Argentinian puna—a high-elevation subtropical plateau of about 95,000 km2 situated above 3200 masl—land is chiefly used for grazing, mining, and tourism. In this article, we analyze trends in these land uses over the last 57 years in the context of climatic changes toward drier and warmer conditions. Since 1960, the human population grew from 80,000 to 130,000; but this increase largely occurred in the scattered urban centers, while the rural population decreased. The main livestock— sheep—showed a net decrease of around 100,000 animals (–18.5%), with numbers increasing between 1960 and 1980 and then dropping markedly. The number of mining operations declined during the 1970s and 1980s and then rose sharply, reaching a 30% increase since the 1990s. Simultaneously, structural wild vicuña populations increased from a few thousand to around 130,000. These results show that environmental changes over the past half century involved a major wildlife recovery associated with a change from widespread extensive grazing to intensive but spatially limited impacts around mining operations and growing urban centers. Tourism emerged as a new activity over the last decades, but the environmental impacts have been poorly studied. To promote local development and regional conservation, research priorities should include (1) empirical assessments of the ecological consequences of land use changes, such as grazing regimes shifting from domestic to wild herbivores, as well as the impacts of mining, tourism, and urbanization on wetlands and hydrological regimes; (2) modeling of future scenarios of mining and tourism expansion and resulting conflicts with environmental conservation; and (3) coproduction of knowledge about interactions among land uses, climate change, and the different decision-making agents.

A global analysis shows that for most tree species the largest trees are the fastest-growing trees, a finding that resolves conflicting assumptions about tree growth and that has implications for understanding forest carbon dynamics, resource allocation trade-offs within trees and plant senescence. The importance of old trees Old forests and their leaves fix less carbon than do new forests, but does this apply at the individual tree level? This study uses a global analysis of more that 400 tree species to show that it does not. Rather, larger and older trees accumulate carbon more rapidly than do younger, smaller ones. This can be reconciled with the effects at other levels by taking into account increases in leaf number and reductions in forest density with age. The rapid growth of large trees means that, relative to their numbers, they could have a disproportionately important role in forest feedbacks to the terrestrial carbon cycle and global climate system. Forests are major components of the global carbon cycle, providing substantial feedback to atmospheric greenhouse gas concentrations 1 . Our ability to understand and predict changes in the forest carbon cycle—particularly net primary productivity and carbon storage—increasingly relies on models that represent biological processes across several scales of biological organization, from tree leaves to forest stands 2 , 3 . Yet, despite advances in our understanding of productivity at the scales of leaves and stands, no consensus exists about the nature of productivity at the scale of the individual tree 4 , 5 , 6 , 7 , in part because we lack a broad empirical assessment of whether rates of absolute tree mass growth (and thus carbon accumulation) decrease, remain constant, or increase as trees increase in size and age. Here we present a global analysis of 403 tropical and temperate tree species, showing that for most species mass growth rate increases continuously with tree size. Thus, large, old trees do not act simply as senescent carbon reservoirs but actively fix large amounts of carbon compared to smaller trees; at the extreme, a single big tree can add the same amount of carbon to the forest within a year as is contained in an entire mid-sized tree. The apparent paradoxes of individual tree growth increasing with tree size despite declining leaf-level 8 , 9 , 10 and stand-level 10 productivity can be explained, respectively, by increases in a tree’s total leaf area that outpace declines in productivity per unit of leaf area and, among other factors, age-related reductions in population density. Our results resolve conflicting assumptions about the nature of tree growth, inform efforts to undertand and model forest carbon dynamics, and have additional implications for theories of resource allocation 11 and plant senescence 12 .

Polar molecules are desirable systems for quantum simulations and cold chemistry. Molecular ions are easily trapped, but a bias electric field applied to polarize them tends to accelerate them out of the trap. We present a general solution to this issue by rotating the bias field slowly enough for the molecular polarization axis to follow but rapidly enough for the ions to stay trapped. We demonstrate Ramsey spectroscopy between Stark-Zeeman subleveis in ¹⁸⁰Hf¹⁹F⁺ with a coherence time of 100 milliseconds. Frequency shifts arising from well-controlled topological (Berry) phases are used to determine magnetic g factors. The rotating-bias-field technique may enable using trapped polar molecules for precision measurement and quantum information science, including the search for an electron electric dipole moment.

Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy. In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2 per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01345682. Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6·7 months (IQR 3·1–9·0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2·6 months [95% CI 2·0–2·7] for the afatinib group vs 1·7 months [1·5–2·4] for the methotrexate group; hazard ratio [HR] 0·80 [95% CI 0·65–0·98], p=0·030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 [10%] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 [9%] vs three [2%]), stomatitis (20 [6%] vs 13 [8%]), fatigue (18 [6%] vs five [3%]), and neutropenia (1 [<1%] vs 11 [7%]); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients. Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC. Boehringer Ingelheim.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

Land use is central to addressing sustainability issues, including biodiversity conservation, climate change, food security, poverty alleviation, and sustainable energy. In this paper, we synthesize knowledge accumulated in land system science, the integrated study of terrestrial social-ecological systems, into 10 hard truths that have strong, general, empirical support. These facts help to explain the challenges of achieving sustainability in land use and thus also point toward solutions. The 10 facts are as follows: 1) Meanings and values of land are socially constructed and contested; 2) land systems exhibit complex behaviors with abrupt, hard-to-predict changes; 3) irreversible changes and path dependence are common features of land systems; 4) some land uses have a small footprint but very large impacts; 5) drivers and impacts of land-use change are globally interconnected and spill over to distant locations; 6) humanity lives on a used planet where all land provides benefits to societies; 7) land-use change usually entails trade-offs between different benefits—“win–wins” are thus rare; 8) land tenure and land-use claims are often unclear, overlapping, and contested; 9) the benefits and burdens from land are unequally distributed; and 10) land users have multiple, sometimes conflicting, ideas of what social and environmental justice entails. The facts have implications for governance, but do not provide fixed answers. Instead they constitute a set of core principles which can guide scientists, policy makers, and practitioners toward meeting sustainability challenges in land use.