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It has been claimed that language learners are better at acquiring phonetically motivated phonological patterns compared to unmotivated patterns; this hypothesis is known as substantively biased phonological learning. We test this hypothesis by exposing French-speaking participants (n=120) to either a vowel harmony pattern (phonetically motivated) or a vowel disharmony pattern (comparable formal complexity but phonetically unmotivated) in an artificial language. Participants were trained with noun roots and a single suffix, but at test were required to add multiple suffixes to roots, including a novel suffix with a vowel unobserved during training. Although participants performed equally well when adding a single suffix, only those in the harmony condition generalized when adding two suffixes (including the held-out suffix). This work expands on previous research by showing feature-based generalization of harmony, but not disharmony, to novel affixes held out from training. It provides strong evidence for the substantively biased phonological learning account.

The recovery of long-term climate proxy records with seasonal resolution is rare because of natural smoothing processes, discontinuities and limitations in measurement resolution. Yet insolation forcing, a primary driver of multimillennial-scale climate change, acts through seasonal variations with direct impacts on seasonal climate1. Whether the sensitivity of seasonal climate to insolation matches theoretical predictions has not been assessed over long timescales. Here, we analyse a continuous record of water-isotope ratios from the West Antarctic Ice Sheet Divide ice core to reveal summer and winter temperature changes through the last 11,000 years. Summer temperatures in West Antarctica increased through the early-to-mid-Holocene, reached a peak 4,100 years ago and then decreased to the present. Climate model simulations show that these variations primarily reflect changes in maximum summer insolation, confirming the general connection between seasonal insolation and warming and demonstrating the importance of insolation intensity rather than seasonally integrated insolation or season duration2,3. Winter temperatures varied less overall, consistent with predictions from insolation forcing, but also fluctuated in the early Holocene, probably owing to changes in meridional heat transport. The magnitudes of summer and winter temperature changes constrain the lowering of the West Antarctic Ice Sheet surface since the early Holocene to less than 162 m and probably less than 58 m, consistent with geological constraints elsewhere in West Antarctica4-7.

The phylum Actinobacteria includes important human pathogens like Mycobacterium tuberculosis and Corynebacterium diphtheriae and renowned producers of secondary metabolites of commercial interest, yet only a small part of its diversity is represented by sequenced genomes. Here, we present 824 actinobacterial isolate genomes in the context of a phylum-wide analysis of 6,700 genomes including public isolates and metagenome-assembled genomes (MAGs). We estimate that only 30%-50% of projected actinobacterial phylogenetic diversity possesses genomic representation via isolates and MAGs. A comparison of gene functions reveals novel determinants of host-microbe interaction as well as environment-specific adaptations such as potential antimicrobial peptides. We identify plasmids and prophages across isolates and uncover extensive prophage diversity structured mainly by host taxonomy. Analysis of >80,000 biosynthetic gene clusters reveals that horizontal gene transfer and gene loss shape secondary metabolite repertoire across taxa. Our observations illustrate the essential role of and need for high-quality isolate genome sequences.

BackgroundGuidelines recommend measuring blood pressure (BP) in both arms, adopting the higher arm readings for diagnosis and management. Data to support this recommendation are lacking. We evaluated associations of higher and lower arm systolic BPs with diagnostic and treatment thresholds, and prognosis in hypertension, using data from the Inter-arm Blood Pressure Difference-Individual Participant Data Collaboration.MethodsOne-stage multivariable Cox regression models, stratified by study, were used to examine associations of higher or lower reading arm BPs with cardiovascular mortality, all-cause mortality, and cardiovascular events, in individual participant data meta-analyses pooled from 23 cohorts. Cardiovascular events were modelled for Framingham and atherosclerotic cardiovascular disease risk scores. Model fit was compared throughout using Akaike information criteria. Proportions reclassified across guideline recommended intervention thresholds were also compared.ResultsWe analyzed 53 172 participants: mean age 60 years; 48% female. Higher arm BP, compared with lower arm, reclassified 12% of participants at either 130 or 140 mm Hg systolic BP thresholds (both P

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, "gero-centric" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets.

Phonemes have variant pronunciations depending on context. For instance, in American English, the [t] in pat [pæt] and the [d] in pad [pæd] are both realized with a tap [ɾ] when the -ing suffix is attached, [pæɾɪŋ]. We show that despite greater distributional and acoustic support for the [t]-tap alternation, 12-month-olds successfully relate taps to stems with a perceptually-similar final [d], not the dissimilar final-[t]. Thus, distributional learning of phonological alternations is constrained by infants' preference for the alternation of perceptually-similar segments. Further, the ability to relate variant surface forms emerges between 8- and 12-months. Our findings of biased learning provide further empirical support for a role for perceptual similarity in the acquisition of linguistically-relevant categories. We discuss the implications of our findings for phonological theory, language acquisition and models of the mental lexicon.

Resource managers rely on large-scale flow and habitat enhancement actions to support sensitive species in the San Francisco Bay–Delta. The effects of these actions on target species and ecosystems are largely unknown. In 2018, we implemented an ecosystem-scale experiment to reduce salinity and improve access to high-quality habitat in Suisun Marsh, California, for Endangered Species Act-listed Delta Smelt Hypomesus transpacificus. The action included a release of approximately 46 million m3 of additional flow in conjunction with the operation of a novel water management facility, the Suisun Marsh Salinity Control Gates. This experimental action resulted in more low-salinity habitat in Suisun Marsh than would have been present as compared to similar historical low-flow summer conditions. We evaluated the effect of decreasing salinity on the species assemblage in Suisun Marsh using a combination of ordination analyses and circular statistics. We focused this analysis on long-term monitoring data collected within Suisun Marsh during July and August and found that the aquatic community changed significantly in small sloughs but not large-slough habitat in response to the Suisun Marsh action. The assemblage shift from July to August 2018 differed from historical trends in both slough sizes, albeit not significantly in large-slough habitat. Specifically, we observed (1) a shift in California bay shrimp Crangon franciscorum and Striped Bass Morone saxatilis abundance like that occurring in low-salinity, wet water year types; and (2) an uncharacteristic seasonal decline in Black Sea jellyfish Maeotias marginata. We posit that the observed community changes were driven by a combination of behavioral responses to lower-salinity conditions and physical displacement by directional flow resulting from the flow management action.

Systolic interarm differences in blood pressure have been associated with all-cause mortality and cardiovascular disease. We undertook individual participant data meta-analyses to (1) quantify independent associations of systolic interarm difference with mortality and cardiovascular events; (2) develop and validate prognostic models incorporating interarm difference, and (3) determine whether interarm difference remains associated with risk after adjustment for common cardiovascular risk scores. We searched for studies recording bilateral blood pressure and outcomes, established agreements with collaborating authors, and created a single international dataset: the Inter-arm Blood Pressure Difference - Individual Participant Data (INTERPRESS-IPD) Collaboration. Data were merged from 24 studies (53 827 participants). Systolic interarm difference was associated with all-cause and cardiovascular mortality: continuous hazard ratios 1.05 (95% CI, 1.02-1.08) and 1.06 (95% CI, 1.02-1.11), respectively, per 5 mm Hg systolic interarm difference. Hazard ratios for all-cause mortality increased with interarm difference magnitude from a ≥5 mm Hg threshold (hazard ratio, 1.07 [95% CI, 1.01-1.14]). Systolic interarm differences per 5 mm Hg were associated with cardiovascular events in people without preexisting disease, after adjustment for Atherosclerotic Cardiovascular Disease (hazard ratio, 1.04 [95% CI, 1.00-1.08]), Framingham (hazard ratio, 1.04 [95% CI, 1.01-1.08]), or QRISK cardiovascular disease risk algorithm version 2 (QRISK2) (hazard ratio, 1.12 [95% CI, 1.06-1.18]) cardiovascular risk scores. Our findings confirm that systolic interarm difference is associated with increased all-cause mortality, cardiovascular mortality, and cardiovascular events. Blood pressure should be measured in both arms during cardiovascular assessment. A systolic interarm difference of 10 mm Hg is proposed as the upper limit of normal. Registration: URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42015031227.

Background The need to engage boys in gender-transformative relationships and sexuality education (RSE) to reduce adolescent pregnancy is endorsed by the World Health Organization and the United Nations Educational, Scientific and Cultural Organization. Objectives To evaluate the effects of If I Were Jack on the avoidance of unprotected sex and other sexual health outcomes. Design A cluster randomised trial, incorporating health economics and process evaluations. Setting Sixty-six schools across the four nations of the UK. Participants Students aged 13–14 years. Intervention A school-based, teacher-delivered, gender-transformative RSE intervention (If I Were Jack) versus standard RSE. Main outcome measures Self-reported avoidance of unprotected sex (sexual abstinence or reliable contraceptive use at last sex) after 12–14 months. Secondary outcomes included knowledge, attitudes, skills, intentions and sexual behaviours. Results The analysis population comprised 6556 students: 86.6% of students in the intervention group avoided unprotected sex, compared with 86.4% in the control group {adjusted odds ratio 0.85 [95% confidence interval (CI) 0.58 to 1.26], p = 0.42}. An exploratory post hoc analysis showed no difference for sexual abstinence [78.30% intervention group vs. 78.25% control group; adjusted odds ratio 0.85 (95% CI 0.58 to 1.24), p = 0.39], but more intervention group students than control group students used reliable contraception at last sex [39.62% vs. 26.36%; adjusted odds ratio 0.52 (95% CI 0.29 to 0.920), p = 0.025]. Students in schools allocated to receive the intervention had significantly higher scores on knowledge [adjusted mean difference 0.18 (95% CI 0.024 to 0.34), p = 0.02], gender-equitable attitudes and intentions to avoid unintended pregnancy [adjusted mean difference 0.61 (95% CI 0.16 to 1.07), p = 0.01] than students in schools allocated to receive the control. There were positive but non-significant differences in sexual self-efficacy and communication skills. The total mean incremental cost of the intervention compared with standard RSE was £2.83 (95% CI –£2.64 to £8.29) per student. Over a 20-year time horizon, the intervention is likely to be cost-effective owing to its impact on unprotected sex because it would result in 379 (95% CI 231 to 477) fewer unintended pregnancies, 680 (95% CI 189 to 1467) fewer sexually transmitted infections and a gain of 10 (95% CI 5 to 16) quality-adjusted life-years per 100,000 students for a cost saving of £9.89 (95% CI –£15.60 to –£3.83). Limitations The trial is underpowered to detect some effects because four schools withdrew and the intraclass correlation coefficient (0.12) was larger than that in sample size calculation (0.01). Conclusions We present, to our knowledge, the first evidence from a randomised trial that a school-based, male engagement gender-transformative RSE intervention, although not effective in increasing avoidance of unprotected sex (defined as sexual abstinence or use of reliable contraception at last sex) among all students, did increase the use of reliable contraception at last sex among students who were, or became, sexually active by 12–14 months after the intervention. The trial demonstrated that engaging all adolescents early through RSE is important so that, as they become sexually active, rates of unprotected sex are reduced, and that doing so is likely to be cost-effective. Future work Future studies should consider the longer-term effects of gender-transformative RSE as students become sexually active. Gender-transformative RSE could be adapted to address broader sexual health and other settings. Trial registration This trial is registered as ISRCTN10751359. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (PHR 15/181/01) and will be published in full in Public Health Research; Vol. 11, No. 8. See the NIHR Journals Library website for further project information. Plain language summary Adolescent pregnancy is often thought to be an issue for young women alone, but it is important to engage young men to tackle the problem and find solutions. The If I Were Jack intervention was especially designed to engage with boys as well as girls aged 14 years and to promote positive masculinity and gender equality to prevent adolescent pregnancy and promote positive sexual health. It uses tailored interactive films and resources, made with the help of students and teachers, to make it relevant to each of the four UK nations. This relationship and sexuality education intervention encourages adolescents to avoid unprotected sex by delaying sexual activity until they feel ready and to use reliable contraception once sexually active. It also promotes knowledge, attitudes (such as beliefs about gender and masculinities), skills and intentions for safe and pleasurable relationships. In this trial, we compared students in 33 schools randomly allocated to deliver the intervention with students in 33 schools that continued with their usual relationship and sexuality education practices. Four schools withdrew, two because of COVID-19 school closures. This left a total of 6556 students who completed questionnaires at the start of the study and 12–14 months later. Responses from all these students showed that If I Were Jack had a positive impact on knowledge, attitudes and intentions required for safe and pleasurable relationships, but did not have a significant effect on overall avoidance of unprotected sex. This was because the intervention had no effect on delaying sexual activity. However, we found that the intervention was effective in increasing the use of reliable contraception as students became sexually active, as well as for those who already were sexually active prior to receiving the intervention. We also found that If I Were Jack was likely to provide value for money by reducing unintended pregnancies and improving sexual health. Scientific summary Background The need for relationship and sexuality education (RSE) to especially engage with young men and boys to promote positive sexual health for all, and to be gender transformative to challenge the gender inequalities that underlie young women’s generally poorer sexual health outcomes (especially in relation to sexual violence, adolescent pregnancy and sexually transmitted infections), is widely endorsed by the World Health Organization and the United Nations Educational, Scientific and Cultural Organization, among others. Objectives The JACK trial evaluated the effectiveness and cost-effectiveness of the If I Were Jack intervention, a schools-based RSE intervention, which is designed to especially engage young men as well as young women and promote joint responsibility in preventing adolescent pregnancy by avoiding unprotected sex and in promoting positive sexual health and relationships. We assessed whether there would be higher rates of self-reported avoidance of unprotected sex (either by remaining sexually abstinent or by using a reliable form of contraception) among students in schools allocated to use If I Were Jack than among those in schools that continued with their usual RSE. Design We undertook a multicentre, parallel-group cluster randomised trial of the If I Were Jack intervention with schools as the unit of randomisation. We incorporated a health economic cost–consequences analysis and process evaluation. Setting The trial was conducted in secondary-level schools across the four nations of the UK. Recruitment We sampled schools from Department of Education-listed secondary schools in each nation of the UK (Northern Ireland, Wales, Scotland and England), with consideration of the socioeconomic status of schools [based on the proportion of students eligible for free school meals (FSM) as indicated by the School Meal Census]. In each nation, eligible schools were stratified into two levels according to FSM eligibility rates (schools above and below the median national percentage of FSM for all eligible schools). Independent private, special, and Irish/Welsh-medium and Scottish Gaelic schools and schools with

In this study, we incorporate analyses of genome-wide sequence and structural alterations with pre- and on-therapy transcriptomic and T cell repertoire features in immunotherapy-naive melanoma patients treated with immune checkpoint blockade. Although tumor mutation burden is associated with improved treatment response, the mutation frequency in expressed genes is superior in predicting outcome. Increased T cell density in baseline tumors and dynamic changes in regression or expansion of the T cell repertoire during therapy distinguish responders from non-responders. Transcriptome analyses reveal an increased abundance of B cell subsets in tumors from responders and patterns of molecular response related to expressed mutation elimination or retention that reflect clinical outcome. High-dimensional genomic, transcriptomic, and immune repertoire data were integrated into a multi-modal predictor of response. These findings identify genomic and transcriptomic characteristics of tumors and immune cells that predict response to immune checkpoint blockade and highlight the importance of pre-existing T and B cell immunity in therapeutic outcomes.

Magnesium borohydride (Mg(BH4)2, abbreviated here MBH) has received tremendous attention as a promising onboard hydrogen storage medium due to its excellent gravimetric and volumetric hydrogen storage capacities. While the polymorphs of MBH-alpha (α), beta (β), and gamma (γ)-have distinct properties, their synthetic homogeneity can be difficult to control, mainly due to their structural complexity and similar thermodynamic properties. Here, we describe an effective approach for obtaining pure polymorphic phases of MBH nanomaterials within a reduced graphene oxide support (abbreviated MBHg) under mild conditions (60-190 °C under mild vacuum, 2 Torr), starting from two distinct samples initially dried under Ar and vacuum. Specifically, we selectively synthesize the thermodynamically stable α phase and metastable β phase from the γ-phase within the temperature range of 150-180 °C. The relevant underlying phase evolution mechanism is elucidated by theoretical thermodynamics and kinetic nucleation modeling. The resulting MBHg composites exhibit structural stability, resistance to oxidation, and partially reversible formation of diverse [BH4]- species during de- and rehydrogenation processes, rendering them intriguing candidates for further optimization toward hydrogen storage applications.

There is an extensive literature establishing, validating, and quantifying a wide range of responses of fishes to fasting. Our study complements this work by comparing fed and unfed treatments of hatchery-raised Delta Smelt (Hypomesus transpacificus)-an imperiled fish that is endemic to the San Francisco Estuary and its tributaries in California, USA-across a diverse suite of endpoints over a two-month time series. The experiment was conducted at 15.9°C, and individuals were sampled at 12 time points as starvation became increasingly severe. We found that hepatosomatic index and condition factor were relatively sensitive to starvation, becoming significantly depressed at Day 4 and 7, respectively. Histological analysis of liver showed elevated cytoplasmic inclusion bodies at Day 7, followed by increased glycogen depletion, single cell necrosis, and hydropic vacuolar degeneration at Day 14, 21, and 28, respectively. Of four antioxidants measured, glutathione decreased at Day 4, superoxide dismutase increased at Day 14, catalase increased at Day 56, and glutathione peroxidase was not affected by starvation. The net result was a ~2-fold increase in lipid peroxidation (malondialdehyde) in fasted fish that was highly inconsistent through time. RNA to DNA ratio and triglycerides in muscle were relatively insensitive to starvation, only consistently decreasing with fasting after mortality began increasing in the 'No Feeding' treatment, at Day 21. Together, these results suggest that Delta Smelt mobilize hepatic energy stores far more rapidly than lipids in muscle when subjected to fasting, leading to rapid atrophy of liver and the development of cytoplasmic inclusion bodies-possibly autophagosomes-in hepatocytes.

Long-term atmospheric CO2 mole fraction and δ13CO2 observations over North America document persistent responses to the El Niño-Southern Oscillation. We estimate these responses corresponded to 0.61 (0.45 to 0.79) PgC year-1 more North American carbon uptake during El Niño than during La Niña between 2007 and 2015, partially offsetting increases of net tropical biosphere-to-atmosphere carbon flux around El Niño. Anomalies in derived North American net ecosystem exchange (NEE) display strong but opposite correlations with surface air temperature between seasons, while their correlation with water availability was more constant throughout the year, such that water availability is the dominant control on annual NEE variability over North America. These results suggest that increased water availability and favorable temperature conditions (warmer spring and cooler summer) caused enhanced carbon uptake over North America near and during El Niño.

In this article, the capabilities of soft and hard X-ray techniques, including X-ray absorption (XAS), soft X-ray emission spectroscopy (XES), resonant inelastic soft X-ray scattering (RIXS), X-ray photoelectron spectroscopy (XPS), and X-ray diffraction (XRD), and their application to solid-state hydrogen storage materials are presented. These characterization tools are indispensable for interrogating hydrogen storage materials at the relevant length scales of fundamental interest, which range from the micron scale to nanometer dimensions. Since nanostructuring is now well established as an avenue to improve the thermodynamics and kinetics of hydrogen release and uptake, due to properties such as reduced mean free paths of transport and increased surface-to-volume ratio, it becomes of critical importance to explicitly identify structure-property relationships on the nanometer scale. X-ray diffraction and spectroscopy are effective tools for probing size-, shape-, and structure-dependent material properties at the nanoscale. This article also discusses the recent development of in-situ soft X-ray spectroscopy cells, which enable investigation of critical solid/liquid or solid/gas interfaces under more practical conditions. These unique tools are providing a window into the thermodynamics and kinetics of hydrogenation and dehydrogenation reactions and informing a quantitative understanding of the fundamental energetics of hydrogen storage processes at the microscopic level. In particular, in-situ soft X-ray spectroscopies can be utilized to probe the formation of intermediate species, byproducts, as well as the changes in morphology and effect of additives, which all can greatly affect the hydrogen storage capacity, kinetics, thermodynamics, and reversibility. A few examples using soft X-ray spectroscopies to study these materials are discussed to demonstrate how these powerful characterization tools could be helpful to further understand the hydrogen storage systems.

Solid-state metal hydrides are prime candidates to replace compressed hydrogen for fuel cell vehicles due to their high volumetric capacities. Sodium aluminum hydride has long been studied as an archetype for higher-capacity metal hydrides, with improved reversibility demonstrated through the addition of titanium catalysts; however, atomistic mechanisms for surface processes, including hydrogen desorption, are still uncertain. Here, operando and ex situ measurements from a suite of diagnostic tools probing multiple length scales are combined with ab initio simulations to provide a detailed and unbiased view of the evolution of the surface chemistry during hydrogen release. In contrast to some previously proposed mechanisms, the titanium dopant does not directly facilitate desorption at the surface. Instead, oxidized surface species, even on well-protected NaAlH4 samples, evolve during dehydrogenation to form surface hydroxides with differing levels of hydrogen saturation. Additionally, the presence of these oxidized species leads to considerably lower computed barriers for H2 formation compared to pristine hydride surfaces, suggesting that oxygen may actively participate in hydrogen release, rather than merely inhibiting diffusion as is commonly presumed. These results demonstrate how close experiment-theory feedback can elucidate mechanistic understanding of complex metal hydride chemistry and potentially impactful roles of unavoidable surface impurities.

The Integrated Microbial Genomes & Microbiomes system v.5.0 (IMG/M: https://img.jgi.doe.gov/m/) contains annotated datasets categorized into: archaea, bacteria, eukarya, plasmids, viruses, genome fragments, metagenomes, cell enrichments, single particle sorts, and metatranscriptomes. Source datasets include those generated by the DOE's Joint Genome Institute (JGI), submitted by external scientists, or collected from public sequence data archives such as NCBI. All submissions are typically processed through the IMG annotation pipeline and then loaded into the IMG data warehouse. IMG's web user interface provides a variety of analytical and visualization tools for comparative analysis of isolate genomes and metagenomes in IMG. IMG/M allows open access to all public genomes in the IMG data warehouse, while its expert review (ER) system (IMG/MER: https://img.jgi.doe.gov/mer/) allows registered users to access their private genomes and to store their private datasets in workspace for sharing and for further analysis. IMG/M data content has grown by 60% since the last report published in the 2017 NAR Database Issue. IMG/M v.5.0 has a new and more powerful genome search feature, new statistical tools, and supports metagenome binning.

[This corrects the article DOI: 10.1038/s41522-017-0040-3.].