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A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01181-w

This paper assessed 300 surfboard riders, comprising 229 males and 71 females to determine the prevalence and rate of growth of exostoses in this population. A group of cold water swimmers and a control group were also examined. Significant obstruction, defined as two thirds or more occlusion of the ear canal was noted in 90 of the male surfers and 10 female surfers. This degree of occlusion was found in seven of the 32 cold water swimmers. A male surfer who has surfed regularly for 20 years or more has a one in two chance of developing significant obstruction of the external ear canal resulting from exostoses and this is a three in seven chance for females.

Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, we found that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3. These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.

A large literature shows that the self-employed underreport their income to tax authorities. In this paper, we quantify the extent to which the self-employed also systematically underreport their income in U.S. household surveys. We use the Engel curve describing the relationship between income and expenditures of wage and salary workers to infer the actual income, and thus the reporting gap, of the self-employed based on their reported expenditures. On average, the self-employed underreport their income by about 25%. We show that failing to account for such income underreporting leads to biased conclusions in a variety of settings.

Heterozygous germ-line mutations in the bone morphogenetic protein type-II receptor (BMPR-II) gene underlie heritable pulmonary arterial hypertension (HPAH). Although inflammation promotes PAH, the mechanisms by which inflammation and BMPR-II dysfunction conspire to cause disease remain unknown. Here we identify that tumour necrosis factor-α (TNFα) selectively reduces BMPR-II transcription and mediates post-translational BMPR-II cleavage via the sheddases, ADAM10 and ADAM17 in pulmonary artery smooth muscle cells (PASMCs). TNFα-mediated suppression of BMPR-II subverts BMP signalling, leading to BMP6-mediated PASMC proliferation via preferential activation of an ALK2/ACTR-IIA signalling axis. Furthermore, TNFα, via SRC family kinases, increases pro-proliferative NOTCH2 signalling in HPAH PASMCs with reduced BMPR-II expression. We confirm this signalling switch in rodent models of PAH and demonstrate that anti-TNFα immunotherapy reverses disease progression, restoring normal BMP/NOTCH signalling. Collectively, these findings identify mechanisms by which BMP and TNFα signalling contribute to disease, and suggest a tractable approach for therapeutic intervention in PAH. Reduced BMP receptor II signalling underlies pulmonary arterial hypertension (PAH). Here, Hurst et al . show that TNFα subverts BMP signalling by increasing BMP6 expression and signalling via an alternative BMP receptor, ALK2, in pulmonary artery smooth muscle cells to drive abnormal proliferation and PAH.

Bacterial protein secretion is crucial to the maintenance of viability and pathogenicity. Although many bacterial secretion systems have been identified, the underlying mechanisms regulating their expression are less well explored. Yersinia entomophaga MH96, an entomopathogenic bacterium, releases an abundance of proteins including the Yen-Tc into the growth medium when cultured in Luria Bertani broth at ≤ 25˚C. Through the development of a high-throughput exoproteome screening assay (HESA), genes involved in MH96 exoprotein production were identified. Of 4,080 screened transposon mutants, 34 mutants exhibited a decreased exoprotein release, and one mutation located in the intergenic region of the Yen-Tc operon displayed an elevated exoprotein release relative to the wild-type strain MH96. DNA sequencing revealed several transposon insertions clustered in gene regions associated with lipopolysaccharide (LPSI and LPSII), and N-acyl-homoserine lactone synthesis (quorum sensing). Twelve transposon insertions were located within transcriptional regulators or intergenic regions. The HESA will have broad applicability for identifying genes associated with exoproteome production in a range of microorganisms.

Assessing the burden of COVID-19 on the basis of medically attended case numbers is suboptimal given its reliance on testing strategy, changing case definitions, and disease presentation. Population-based serosurveys measuring anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies provide one method for estimating infection rates and monitoring the progression of the epidemic. Here, we estimate weekly seroprevalence of anti-SARS-CoV-2 antibodies in the population of Geneva, Switzerland, during the epidemic. The SEROCoV-POP study is a population-based study of former participants of the Bus Santé study and their household members. We planned a series of 12 consecutive weekly serosurveys among randomly selected participants from a previous population-representative survey, and their household members aged 5 years and older. We tested each participant for anti-SARS-CoV-2-IgG antibodies using a commercially available ELISA. We estimated seroprevalence using a Bayesian logistic regression model taking into account test performance and adjusting for the age and sex of Geneva's population. Here we present results from the first 5 weeks of the study. Between April 6 and May 9, 2020, we enrolled 2766 participants from 1339 households, with a demographic distribution similar to that of the canton of Geneva. In the first week, we estimated a seroprevalence of 4·8% (95% CI 2·4–8·0, n=341). The estimate increased to 8·5% (5·9–11·4, n=469) in the second week, to 10·9% (7·9–14·4, n=577) in the third week, 6·6% (4·3–9·4, n=604) in the fourth week, and 10·8% (8·2–13·9, n=775) in the fifth week. Individuals aged 5–9 years (relative risk [RR] 0·32 [95% CI 0·11–0·63]) and those older than 65 years (RR 0·50 [0·28–0·78]) had a significantly lower risk of being seropositive than those aged 20–49 years. After accounting for the time to seroconversion, we estimated that for every reported confirmed case, there were 11·6 infections in the community. These results suggest that most of the population of Geneva remained uninfected during this wave of the pandemic, despite the high prevalence of COVID-19 in the region (5000 reported clinical cases over <2·5 months in the population of half a million people). Assuming that the presence of IgG antibodies is associated with immunity, these results highlight that the epidemic is far from coming to an end by means of fewer susceptible people in the population. Further, a significantly lower seroprevalence was observed for children aged 5–9 years and adults older than 65 years, compared with those aged 10–64 years. These results will inform countries considering the easing of restrictions aimed at curbing transmission. Swiss Federal Office of Public Health, Swiss School of Public Health (Corona Immunitas research program), Fondation de Bienfaisance du Groupe Pictet, Fondation Ancrage, Fondation Privée des Hôpitaux Universitaires de Genève, and Center for Emerging Viral Diseases.

The eastern North Pacific is simultaneously experiencing ocean warming (OW) and ocean acidification (OA), which may negatively affect fish early life stages. Pacific cod ( Gadus macrocephalus ) is an economically and ecologically important species with demonstrated sensitivity to OW and OA, but their combined impacts are unknown. Through a ~ 9-week experiment, Pacific cod embryos and larvae were reared at one of six combinations of three temperatures (3, 6, 10 °C) and two CO 2 levels (ambient: ~ 360 μatm; high: ~ 1560 μatm) in a factorial design. Both embryonic and larval mortality were highest at the warmest temperature. Embryonic daily mortality rates were lower under elevated CO 2 and there was no effect of CO 2 level on larval daily mortality rates. Growth rates of young larvae (0 to 11 days post-hatch) were faster at warmer temperatures and at high CO 2 levels, but growth during the 11–28 days post-hatch interval increased by temperature alone. The condition of larvae decreased with age, but less markedly under high CO 2 levels. However, at 6 °C, fish incubated in ambient CO 2 remained in higher condition than fish in the high CO 2 treatment throughout the experiment. Overall, temperature had the greater influence on Pacific cod early life stages across each measurement endpoint, while CO 2 effects were more modest and inconsistent. Subtle developmental differences in larval Pacific cod could be magnified later in life and important in the context of recruitment. These results show the complexity of stage- and trait-specific responses to and value of investigating the combined effects of co-occurring climatic stressors.

Regional shocks are an important feature of the US economy. Households' ability to self-insure against these shocks depends on how they affect local interest rates. In the United States, most borrowing occurs through the mortgage market and is influenced by the presence of government-sponsored enterprises (GSE). We establish that despite large regional variation in predictable default risk, GSE mortgage rates for otherwise identical loans do not vary spatially. In contrast, the private market does set interest rates which vary with local risk. We use a spatial model of collateralized borrowing to show that the national interest rate policy substantially affects welfare by redistributing resources across regions.

Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4–RBX1–DDB1–CRBN (known as CRL4 CRBN ), resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4 CRBN . These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases. Lenalidomide, a derivative of thalidomide, is an effective drug for myelodysplastic syndrome; lenalidomide binds the CRL4 CRBN E3 ubiquitin ligase and promotes degradation of casein kinase 1a, on which the malignant cells rely for survival. Mechanism of action of lenalidomide Thalidomide was taken off the market when it was found to cause malformation in children whose mothers had taken it as a treatment for morning sickness in the late 1950s and early 1960s. Later it emerged that thalidomide and derivatives could be successfully used to treat certain haematopoietic disorders, and the thalidomide derivative lenalidomide has proved an effective therapy for myelodysplastic syndrome (MDS). Ben Ebert and colleagues now show why lenalidomide is particularly efficient in so-called del(5q) MDS — a frequent form of MDS carrying deletions in one copy of the chromosome 5q arm. They find that lenalidomide binds the CRL4 CRBN E3 ubiquitin ligase and promotes degradation of casein kinase 1α, which the malignant cells rely on for survival. In addition, a new analogue of thalidomide, CC-122, is shown to have greater potency than lenalidomide in inducing degradation of other CRBN substrates that are important in certain B cell malignancies.