Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

A positively selected FBN1 missense variant reduces height in Peruvian individuals.

On average, Peruvian individuals are among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.

Adherence to the Atrial fibrillation Better Care pathway and the risk of adverse health outcomes in older care home residents with atrial fibrillation: a retrospective data linkage study 2003-18.

BACKGROUND: The Atrial fibrillation Better Care (ABC) pathway is the gold-standard approach to atrial fibrillation (AF) management, but the effect of implementation on health outcomes in care home residents is unknown. OBJECTIVE: To examine associations between ABC pathway adherence and stroke, transient ischaemic attack, cardiovascular hospitalisation, major bleeding, mortality and a composite of all these outcomes in care home residents. METHODS: A retrospective cohort study of older care home residents (≥65 years) in Wales with AF was conducted between 1 January 2003 and 31 December 2018 using the Secure Anonymised Information Linkage Databank. Adherence to the ABC pathway was assessed at care home entry using pre-specified definitions. Cox proportional hazard and competing risk models were used to estimate the risk of health outcomes according to ABC adherence. RESULTS: From 14,493 residents (median [interquartile range] age 87.0 [82.6-91.2] years, 35.2% male) with AF, 5,531 (38.2%) were ABC pathway adherent. Pathway adherence was not significantly associated with risk of the composite outcome (adjusted hazard ratio, 95% confidence interval [CI]: 1.01 [0.97-1.05]). There was a significant independent association observed between ABC pathway adherence and a reduced risk of myocardial infarction (0.70 [0.50-0.98]), but a higher risk of haemorrhagic stroke (1.59 [1.06-2.39]). ABC pathway adherence was not significantly associated with any other individual health outcomes examined. CONCLUSION: An ABC adherent approach in care home residents was not consistently associated with improved health outcomes. Findings should be interpreted with caution owing to difficulties in defining pathway adherence using routinely collected data and an individualised approach is recommended.

Altered mechanisms of adaptation in social anxiety: differences in adapting to positive versus negative emotional faces.

Social anxiety is characterised by fear of negative evaluation and negative perceptual biases; however, the cognitive mechanisms underlying these negative biases are not well understood. We investigated a possible mechanism which could maintain negative biases: altered adaptation to emotional faces. Heightened sensitivity to negative emotions could result from weakened adaptation to negative emotions, strengthened adaptation to positive emotions, or both mechanisms. We measured adaptation from repeated exposure to either positive or negative emotional faces, in individuals high versus low in social anxiety. We quantified adaptation strength by calculating the point of subjective equality (PSE) before and after adaptation for each participant. We hypothesised: (1) weaker adaptation to angry vs happy faces in individuals high in social anxiety, (2) no difference in adaptation to angry vs happy faces in individuals low in social anxiety, and (3) no difference in adaptation to sad vs happy faces in individuals high in social anxiety. Our results revealed a weaker adaptation to angry compared to happy faces in individuals high in social anxiety (Experiment 1), with no such difference in individuals low in social anxiety (Experiment 1), and no difference in adaptation strength to sad vs happy faces in individuals high in social anxiety (Experiment 2).

Variation and Correlation of Potential Unintended Consequences of Antipsychotic Reduction in Ontario Nursing Homes Over Time.

BACKGROUND: Potentially inappropriate antipsychotic use has declined in nursing homes over the past decade; however, increases in the documentation of relevant clinical indications (eg, delusions) and the use of other psychotropic medications have raised concerns about diagnosis upcoding and medication substitution. Few studies have examined how these trends over time vary across and within nursing homes, information that may help to support antipsychotic reduction efforts. OBJECTIVE: To jointly model facility-level time trends in potentially inappropriate antipsychotic use, antidepressant use, and the indications used to define appropriate antipsychotic use. RESEARCH DESIGN: We conducted a repeated cross-sectional study of all nursing homes in Ontario, Canada between April 1, 2010 and December 31, 2019 using linked health administrative data (N=649). Each nursing home's quarterly prevalence of potentially inappropriate antipsychotic use, antidepressant use, and relevant indications were measured as outcome variables. With time as the independent variable, multivariate random effects models jointly estimated time trends for each outcome across nursing homes and the correlations between time trends within nursing homes. RESULTS: We observed notable variations in the time trends for each outcome across nursing homes, especially for the relevant indications. Within facilities, we found no correlation between time trends for potentially inappropriate antipsychotic and antidepressant use ( r =-0.0160), but a strong negative correlation between time trends for potentially inappropriate antipsychotic use and relevant indications ( r =-0.5036). CONCLUSIONS: Nursing homes with greater reductions in potentially inappropriate antipsychotics tended to show greater increases in the indications used to define appropriate antipsychotic use-possibly leading to unmonitored use of antipsychotics.

Changes in the Initiation of Antipsychotics and Trazodone Over Time: A Cohort Study of New Admissions to Nursing Homes in Ontario, Canada.

OBJECTIVES: To investigate whether trazodone is being initiated in lieu of antipsychotics following antipsychotic reduction efforts, this study described changes in medication initiation over time. METHODS: We conducted a retrospective cohort study of new admissions to nursing homes in Ontario, Canada between April 2010 and December 2019 using health administrative data (N = 61,068). The initiation of antipsychotic and trazodone use was compared by year of admission using discrete time survival analysis and stratified by history of dementia. RESULTS: Relative to residents admitted in 2014, antipsychotic initiation significantly decreased in later years (e.g., 2017 admission year hazard odds ratio [HOR2017]=0.72 [95% confidence interval (95%CI)=0.62-0.82]) while trazodone initiation modestly increased (e.g., HOR2017=1.09 [95%CI=0.98-1.21]). The relative increase in trazodone initiation was larger among residents with dementia (e.g., HOR2017Dem =1.22 [95%CI=1.07-1.39]). CONCLUSIONS: Differences in which medications were started following nursing home admission were observed and suggest trazodone may be initiated in lieu of antipsychotics.

Evolutionary history of modern Samoans.

Archaeological studies estimate the initial settlement of Samoa at 2,750 to 2,880 y ago and identify only limited settlement and human modification to the landscape until about 1,000 to 1,500 y ago. At this point, a complex history of migration is thought to have begun with the arrival of people sharing ancestry with Near Oceanic groups (i.e., Austronesian-speaking and Papuan-speaking groups), and was then followed by the arrival of non-Oceanic groups during European colonialism. However, the specifics of this peopling are not entirely clear from the archaeological and anthropological records, and is therefore a focus of continued debate. To shed additional light on the Samoan population history that this peopling reflects, we employ a population genetic approach to analyze 1,197 Samoan high-coverage whole genomes. We identify population splits between the major Samoan islands and detect asymmetrical gene flow to the capital city. We also find an extreme bottleneck until about 1,000 y ago, which is followed by distinct expansions across the islands and subsequent bottlenecks consistent with European colonization. These results provide for an increased understanding of Samoan population history and the dynamics that inform it, and also demonstrate how rapid demographic processes can shape modern genomes.

Incidence of neurological and psychiatric comorbidity over time: a population-based cohort study in Ontario, Canada.

INTRODUCTION: Comprehensive, population-based investigations of the extent and temporality of associations between common neurological and psychiatric disorders are scarce. METHODS: This retrospective cohort study used linked health administrative data for Ontarians aged 40-85 years on 1 April 2002, to estimate the adjusted rate of incident dementia, Parkinson's disease (PD), stroke or mood/anxiety disorder (over 14 years) according to the presence and time since diagnosis of a prior disorder. Sex differences in the cumulative incidence of a later disorder were also examined. RESULTS: The cohort included 5,283,546 Ontarians (mean age 56.2 ± 12.1 years, 52% female). The rate of dementia was significantly higher for those with prior PD (adjusted hazard ratio [adjHR] 4.05, 95% confidence interval [CI] 3.99-4.11); stroke (adjHR 2.49, CI 2.47-2.52) and psychiatric disorder (adjHR 1.79, CI 1.78-1.80). The rate of PD was significantly higher for those with prior dementia (adjHR 2.23, CI 2.17-2.30) and psychiatric disorder (adjHR 1.77, CI 1.74-1.81). The rate of stroke was significantly higher among those with prior dementia (adjHR 1.56, CI 1.53-1.58). Prior dementia (adjHR 2.36, CI 2.33-2.39), PD (adjHR 1.80, CI 1.75-1.85) and stroke (adjHR 1.47, CI 1.45-1.49) were associated with a higher rate of an incident psychiatric disorder. Generally, associations were strongest in the 6 months following a prior diagnosis and demonstrated a J-shape relationship over time. Significant sex differences were evident in the absolute risks for several disorders. CONCLUSIONS: The observed nature of bidirectional associations between these neurological and psychiatric disorders indicates opportunities for earlier diagnosis and interventions to improve patient care.

Prevalence and outcomes of atrial fibrillation in older people living in care homes in Wales: a routine data linkage study 2003-2018.

OBJECTIVE: To determine atrial fibrillation (AF) prevalence and temporal trends, and examine associations between AF and risk of adverse health outcomes in older care home residents. METHODS: Retrospective cohort study using anonymised linked data from the Secure Anonymised Information Linkage Databank on CARE home residents in Wales with AF (SAIL CARE-AF) between 2003 and 2018. Fine-Gray competing risk models were used to estimate the risk of health outcomes with mortality as a competing risk. Cox regression analyses were used to estimate the risk of mortality. RESULTS: There were 86,602 older care home residents (median age 86.0 years [interquartile range 80.8-90.6]) who entered a care home between 2003 and 2018. When the pre-care home entry data extraction was standardised, the overall prevalence of AF was 17.4% (95% confidence interval 17.1-17.8) between 2010 and 2018. There was no significant change in the age- and sex-standardised prevalence of AF from 16.8% (15.9-17.9) in 2010 to 17.0% (16.1-18.0) in 2018. Residents with AF had a significantly higher risk of cardiovascular mortality (adjusted hazard ratio [HR] 1.27 [1.17-1.37], P < 0.001), all-cause mortality (adjusted HR 1.14 [1.11-1.17], P < 0.001), ischaemic stroke (adjusted sub-distribution HR 1.55 [1.36-1.76], P < 0.001) and cardiovascular hospitalisation (adjusted sub-distribution HR 1.28 [1.22-1.34], P < 0.001). CONCLUSIONS: Older care home residents with AF have an increased risk of adverse health outcomes, even when higher mortality rates and other confounders are accounted for. This re-iterates the need for appropriate oral anticoagulant prescription and optimal management of cardiovascular co-morbidities, irrespective of frailty status and predicted life expectancy.

Optimal Timing of Surveillance Ultrasounds in Small Aortic Aneurysms.

BACKGROUND: Small abdominal aortic aneurysms (AAA) surveillance intervals remain controversial and difficult to standardize. Current Society for Vascular Surgery guidelines lack quality evidence. The objective of this study is to examine patients followed in a high volume non-invasive vascular laboratory, determine if the current guidelines are fitting in clinical practice, and attempt to further identify risk factors for accelerated aneurysm growth. METHODS: A retrospective analysis of patients who underwent at least two ultrasounds for AAA in the vascular laboratory during 2008 -2018 with baseline diameter less than 5.0 cm was conducted. Patient demographics were collected. Groups were then created for comparison using the size criteria according to SVS guidelines. In addition, we compared overall growth rates specifically evaluating rapid growth (rate of at least 1.0 cm/year and size change of at least 0.5 cm from previous imaging), expected growth (any growth below 1.0 cm/year and of at least 0.5 cm from baseline) and no growth. RESULTS: A total of 1581 patients (1232 male and 349 female) were identified with a total of 5945 ultrasound studies. The median age was 73 years and mean follow-up was 27.8 months. Baseline AAA size was 3.0 -3.9 cm in 986 patients and 4.0 -4.9 cm in 595 patients. The average maximum growth rate was 0.18 cm/year for AAAs 3.0 -3.9 cm and 0.36 cm/year for AAAs 4.0 -4.9 cm (P <0.001). Patients with AAA 4.0 -4.9 cm at baseline were more likely to be white, male, hypertensive and have chronic kidney disease (P <0.05). 1078 patients (68.2%) demonstrated no growth over the observed time period with 342 patients (21.6%) demonstrating expected growth and 161 (10.2%) rapid growth. Male gender and baseline AAA size of 4.0 -4.9 cm were more likely to demonstrate rapid growth (P = 0.002) and eventual repair (P <0.001). Metformin use was more common in the AAA group with no growth (P <0.05). Freedom from rapid growth and repair indication at 2 years was significantly lower in those patients with baseline aneurysms 3.0 -3.9 cm (P <0.001). CONCLUSION: The overall low rate of events in small AAAs supports continued surveillance every 3 years for AAAs 3.0-3.9 cm and yearly for male patients with AAAs 4.0 -4.9 cm as recommended by the SVS Guidelines. Female gender may have less rapid growth than previously reported but likely merit more rigorous surveillance particularly as the AAAs approach 5.0 cm. Metformin use continues to demonstrate it may abrogate aneurysmal growth. Lastly, there is a subset of patients that exhibit more rapid growth of their small AAAs, and further study will be required to classify these patients.

Prevalence of prescription and non-prescription polypharmacy by frailty and sex among middle-aged and older Canadians.

Background: Estimates of polypharmacy have primarily been derived from prescription claims, and less is known about the use of non-prescription medications (alone or in combination with prescription medications) across the frailty spectrum or by sex. Our objectives were to estimate the prevalence of polypharmacy (total, prescription, non-prescription, and concurrent prescription and non-prescription) overall, and by frailty, sex and broad age group. Data: Canadian Health Measures Survey, Cycle 5, 2016 to 2017. Methods: Among Canadians aged 40 to 79 years, all prescription and non-prescription medications used in the month prior to the survey were documented. Polypharmacy was defined as using five or more medications total (prescription and non-prescription), prescription only and non-prescription only. Concurrent prescription and non-prescription use was defined as two or more and three or more of each. Frailty was defined using a 31-item frailty index (FI) and categorized as non-frail (FI ≤ 0.1) and pre-frail or frail (FI > 0.1). Survey-weighted descriptive statistics were calculated overall and age standardized. Results: We analyzed 2,039 respondents, representing 16,638,026 Canadians (mean age of 56.9 years; 51% women). Overall, 52.4% (95% confidence interval [CI] = 47.3 to 57.4) were defined as pre-frail or frail. Age-standardized estimates of total polypharmacy, prescription polypharmacy and concurrent prescription and non-prescription medication use were significantly higher among pre-frail or frail versus non-frail adults (e.g., total polypharmacy: 64.1% versus 31.8%, respectively). Polypharmacy with non-prescription medications was common overall (20.5% [95% CI = 16.1 to 25.8]) and greater among women, but did not differ significantly by frailty. Interpretation: Polypharmacy and concurrent prescription and non-prescription medication use were common among Canadian adults, especially those who were pre-frail or frail. Our findings highlight the importance of considering non-prescribed medications when measuring the exposure to medications and the potential risk for adverse outcomes.

Epilepsy, antiepileptic drugs, and the risk of major cardiovascular events.

OBJECTIVE: This study was undertaken to determine whether epilepsy and antiepileptic drugs (including enzyme-inducing and non-enzyme-inducing drugs) are associated with major cardiovascular events using population-level, routinely collected data. METHODS: Using anonymized, routinely collected, health care data in Wales, UK, we performed a retrospective matched cohort study (2003-2017) of adults with epilepsy prescribed an antiepileptic drug. Controls were matched with replacement on age, gender, deprivation quintile, and year of entry into the study. Participants were followed to the end of the study for the occurrence of a major cardiovascular event, and survival models were constructed to compare the time to a major cardiovascular event (cardiac arrest, myocardial infarction, stroke, ischemic heart disease, clinically significant arrhythmia, thromboembolism, onset of heart failure, or a cardiovascular death) for individuals in the case group versus the control group. RESULTS: There were 10 241 cases (mean age = 49.6 years, 52.2% male, mean follow-up = 6.1 years) matched to 35 145 controls. A total of 3180 (31.1%) cases received enzyme-inducing antiepileptic drugs, and 7061 (68.9%) received non-enzyme-inducing antiepileptic drugs. Cases had an increased risk of experiencing a major cardiovascular event compared to controls (adjusted hazard ratio = 1.58, 95% confidence interval [CI] = 1.51-1.63, p < .001). There was no notable difference in major cardiovascular events between those treated with enzyme-inducing antiepileptic drugs and those treated with non-enzyme-inducing antiepileptic drugs (adjusted hazard ratio = .95, 95% CI = .86-1.05, p = .300). SIGNIFICANCE: Individuals with epilepsy prescribed antiepileptic drugs are at an increased risk of major cardiovascular events compared with population controls. Being prescribed an enzyme-inducing antiepileptic drug is not associated with a greater risk of a major cardiovascular event compared to treatment with other antiepileptic drugs. Our data emphasize the importance of cardiovascular risk management in the clinical care of people with epilepsy.

The feeling of "kiki": Comparing developmental changes in sound-shape correspondence for audio-visual and audio-tactile stimuli.

Sound-shape crossmodal correspondence, the naturally occurring associations between abstract visual shapes and nonsense sounds, is one aspect of multisensory processing that strengthens across early childhood. Little is known regarding whether school-aged children exhibit other variants of sound-shape correspondences such as audio-tactile (AT) associations between tactile shapes and nonsense sounds. Based on previous research in blind individuals suggesting the role of visual experience in establishing sound-shape correspondence, we hypothesized that children would show weaker AT association than adults and that children's AT association would be enhanced with visual experience of the shapes. In Experiment 1, we showed that, when asked to match shapes explored haptically via touch to nonsense words, 6- to 8-year-olds exhibited inconsistent AT associations, whereas older children and adults exhibited the expected AT associations, despite robust audio-visual (AV) associations found across all age groups in a related study. In Experiment 2, we confirmed the role of visual experience in enhancing AT association; here, 6- to 8-year-olds could exhibit the expected AT association if first exposed to the AV condition, whereas adults showed the expected AT association irrespective of whether the AV condition was tested first or second. Our finding suggests that AT sound-shape correspondence is weak early in development relative to AV sound-shape correspondence, paralleling previous findings on the development of other types of multisensory associations. The potential role of visual experience in the development of sound-shape correspondences in other senses is discussed.

Evolutionary genomic dynamics of Peruvians before, during, and after the Inca Empire.

Native Americans from the Amazon, Andes, and coastal geographic regions of South America have a rich cultural heritage but are genetically understudied, therefore leading to gaps in our knowledge of their genomic architecture and demographic history. In this study, we sequence 150 genomes to high coverage combined with an additional 130 genotype array samples from Native American and mestizo populations in Peru. The majority of our samples possess greater than 90% Native American ancestry, which makes this the most extensive Native American sequencing project to date. Demographic modeling reveals that the peopling of Peru began ∼12,000 y ago, consistent with the hypothesis of the rapid peopling of the Americas and Peruvian archeological data. We find that the Native American populations possess distinct ancestral divisions, whereas the mestizo groups were admixtures of multiple Native American communities that occurred before and during the Inca Empire and Spanish rule. In addition, the mestizo communities also show Spanish introgression largely following Peruvian Independence, nearly 300 y after Spain conquered Peru. Further, we estimate migration events between Peruvian populations from all three geographic regions with the majority of between-region migration moving from the high Andes to the low-altitude Amazon and coast. As such, we present a detailed model of the evolutionary dynamics which impacted the genomes of modern-day Peruvians and a Native American ancestry dataset that will serve as a beneficial resource to addressing the underrepresentation of Native American ancestry in sequencing studies.

Synthesis of Metastable Ternary Pd-W and Pd-Mo Transition Metal Carbide Nanomaterials.

Research and catalytic testing of platinum group transition metal carbides have been extremely limited due to a lack of reliable, simple synthetic approaches. Powder samples have been reported to phase separately above 1%, and only thin-film samples have been reported to have appreciable amounts of precious metal doping. Herein, we demonstrated, through the simple co-precipitation of Pd and W or Mo precursors and their subsequent annealing, the possibility to readily form ternary carbide powders. During the investigation of the Pd-W ternary system, we discovered a new hexagonal phase, (PdW)2C, which represents the first non-cubic Pd ternary carbide. Additionally, the solubility of Pd in the Pd-W-C and Pd-Mo-C systems was increased to 24 and 32%, respectively. As a potential application, these new materials show an enhanced activity for the methanol oxidation reaction (MOR) compared to industrial Pd/C.

Service evaluation of the bereavement care delivered in a UK intensive care unit.

BACKGROUND: Losing a loved one in the intensive care unit (ICU) can be a traumatic experience. The literature highlights that relatives of those who have died in ICU can experience symptoms of stress, anxiety, depression, post-traumatic stress disorder (PTSD) and prolonged grief. AIM: To evaluate the service delivery of the bereavement care that is provided on a 20-bed general ICU. METHODS AND ANALYSIS: A literature review informing and supporting the service evaluation and development of the questionnaire. Thematic analysis was undertaken using the six-phase framework. FINDINGS: Five main themes were found: timing; care, dignity and respect; support; information; and memory making. Bereavement care is described as after-death care. However, the participants stipulated that bereavement care should be discussed prior to the death. Participants described using a range of interventions, such as memorial services, condolence letters, follow-up meetings and diaries. CONCLUSION: Bereavement care was regarded as an important aspect of the care delivered in ICU. It was evident that participants strived to deliver an holistic approach, yet some found this difficult to achieve.

An Engineered T Cell Receptor Variant Realizes the Limits of Functional Binding Modes.

T cell receptors (TCRs) orchestrate cellular immunity by recognizing peptides presented by a range of major histocompatibility complex (MHC) proteins. Naturally occurring TCRs bind the composite peptide/MHC surface, recognizing peptides that are structurally and chemically compatible with the TCR binding site. Here we describe a molecularly evolved TCR variant that binds the human class I MHC protein HLA-A2 independent of the bound peptide, achieved by a drastic perturbation of the TCR binding geometry that places the molecule far from the peptide binding groove. This unique geometry is unsupportive of normal T cell signaling. A substantial divergence between affinity measurements in solution and in two dimensions between proximal cell membranes leads us to attribute the lack of signaling to steric hindrance that limits binding in the confines of a cell-cell interface. Our results provide an example of how receptor binding geometry can impact T cell function and provide further support for the view that germline-encoded residues in TCR binding loops evolved to drive productive TCR recognition and signaling.

The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology.

Mobile element insertions (MEIs) represent ∼25% of all structural variants in human genomes. Moreover, when they disrupt genes, MEIs can influence human traits and diseases. Therefore, MEIs should be fully discovered along with other forms of genetic variation in whole genome sequencing (WGS) projects involving population genetics, human diseases, and clinical genomics. Here, we describe the Mobile Element Locator Tool (MELT), which was developed as part of the 1000 Genomes Project to perform MEI discovery on a population scale. Using both Illumina WGS data and simulations, we demonstrate that MELT outperforms existing MEI discovery tools in terms of speed, scalability, specificity, and sensitivity, while also detecting a broader spectrum of MEI-associated features. Several run modes were developed to perform MEI discovery on local and cloud systems. In addition to using MELT to discover MEIs in modern humans as part of the 1000 Genomes Project, we also used it to discover MEIs in chimpanzees and ancient (Neanderthal and Denisovan) hominids. We detected diverse patterns of MEI stratification across these populations that likely were caused by (1) diverse rates of MEI production from source elements, (2) diverse patterns of MEI inheritance, and (3) the introgression of ancient MEIs into modern human genomes. Overall, our study provides the most comprehensive map of MEIs to date spanning chimpanzees, ancient hominids, and modern humans and reveals new aspects of MEI biology in these lineages. We also demonstrate that MELT is a robust platform for MEI discovery and analysis in a variety of experimental settings.

Comparison of T Cell Activities Mediated by Human TCRs and CARs That Use the Same Recognition Domains.

Adoptive T cell therapies have achieved significant clinical responses, especially in hematopoietic cancers. Two types of receptor systems have been used to redirect the activity of T cells, normal heterodimeric TCRs or synthetic chimeric Ag receptors (CARs). TCRs recognize peptide-HLA complexes whereas CARs typically use an Ab-derived single-chain fragments variable that recognizes cancer-associated cell-surface Ags. Although both receptors mediate diverse effector functions, a quantitative comparison of the sensitivity and signaling capacity of TCRs and CARs has been limited due to their differences in affinities and ligands. In this study we describe their direct comparison by using TCRs that could be formatted either as conventional αß heterodimers, or as single-chain fragments variable constructs linked to CD3ζ and CD28 signaling domains or to CD3ζ alone. Two high-affinity TCRs (KD values of ∼50 and 250 nM) against MART1/HLA-A2 or WT1/HLA-A2 were used, allowing MART1 or WT1 peptide titrations to easily assess the impact of Ag density. Although CARs were expressed at higher surface levels than TCRs, they were 10-100-fold less sensitive, even in the absence of the CD8 coreceptor. Mathematical modeling demonstrated that lower CAR sensitivity could be attributed to less efficient signaling kinetics. Furthermore, reduced cytokine secretion observed at high Ag density for both TCRs and CARs suggested a role for negative regulators in both systems. Interestingly, at high Ag density, CARs also mediated greater maximal release of some cytokines, such as IL-2 and IL-6. These results have implications for the next-generation design of receptors used in adoptive T cell therapies.

Giant boulders and Last Interglacial storm intensity in the North Atlantic.

As global climate warms and sea level rises, coastal areas will be subject to more frequent extreme flooding and hurricanes. Geologic evidence for extreme coastal storms during past warm periods has the potential to provide fundamental insights into their future intensity. Recent studies argue that during the Last Interglacial (MIS 5e, ∼128-116 ka) tropical and extratropical North Atlantic cyclones may have been more intense than at present, and may have produced waves larger than those observed historically. Such strong swells are inferred to have created a number of geologic features that can be observed today along the coastlines of Bermuda and the Bahamas. In this paper, we investigate the most iconic among these features: massive boulders atop a cliff in North Eleuthera, Bahamas. We combine geologic field surveys, wave models, and boulder transport equations to test the hypothesis that such boulders must have been emplaced by storms of greater-than-historical intensity. By contrast, our results suggest that with the higher relative sea level (RSL) estimated for the Bahamas during MIS 5e, boulders of this size could have been transported by waves generated by storms of historical intensity. Thus, while the megaboulders of Eleuthera cannot be used as geologic proof for past "superstorms," they do show that with rising sea levels, cliffs and coastal barriers will be subject to significantly greater erosional energy, even without changes in storm intensity.