Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter ...disease risk. At least 332 million bases (~10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth's vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.
There is considerable evidence that the increases in circulating corticosterone levels following acute stress, such as sudden storms, can trigger facultative behavioral patterns designed to maximize ...survival. During the breeding season, adrenocortical responses to aseasonal storms may trigger facultative behavioral patterns resulting in temporary disruption of nesting. A renesting cycle often follows when conditions become favorable again. However, in arctic ecosystems the brief breeding season limits the capacity of most avian populations to renest, and yet spring weather may be extreme. This led to the hypothesis that arctic birds may down-regulate their sensitivity to acute stress (such as severe storms) so that breeding can begin and be completed before the first storms of autumn (only 6–8 weeks later). To test this we have used the “stress-series protocol” that takes advantage of the fact that capture, handling and restraint constitutes a more-or-less equal stress among all vertebrate species, and that corticosterone concentrations in small blood samples collected during the first hour post-capture indicate sensitivity of the hypothalamo-adenohypophysial- adrenal axis to acute stresses in general. Comparisons of the increases in plasma levels of corticosterone following capture in several taxa of arctic birds indicated that suppression of the adrenocortical response to acute stress was not ubiquitous. Although some species did show low amplitude responses of the circulating corticosterone increase during the stress series protocol, others did not, and some (especially males) showed an increase in sensitivity to acute stress. Additional hypotheses were suggested as follows: 1) species with greater body mass have larger relative energy reserves and would be more able to resist acute stresses than smaller energy reserves and would be more able to resist acute stresses than smaller species; 2) short-lived birds with an expectancy of one or two breeding seasons should be more resistant to acute stress than long-lived birds that may have many attempts at successful breeding; 3) resistance of the adrenocortical response to stress is a function of the degree of parental care provided by the individual (also takes into account sex differences in parental investment). Correlations of the maximum corticosterone level and the ratio of maximum to minimum corticosterone levels generated during the stress series protocol with body mass and longevity were not significant. However, maximum corticosterone level was significantly lower in birds providing most parental care and almost significant for the ratio of maximum to minimum corticosterone levels. These comparative data from free-living arctic birds suggest an ecological basis for modulation of the adrenocortical responses to stress. In at least one species, up-regulation of the response appears to involve a change in sensitivity to glucocorticosteroid feedback. Further investigations will explore neuroendocrine mechanisms further in the light of these ecological bases.
The Arctic is an extremely inhospitable region for most of the year, but during the summer months it bursts with life. A major proportion of avian species nesting in the Arctic are shorebirds (order ...Charadriiformes; suborder Charadrii). They migrate thousands of kilometers from their wintering grounds to take advantage of abundant food resources each summer and display a variety of migratory strategies. In an attempt to classify this variation, not only between spring and autumn migration, but within a migration, we present four categories. These relate to the distance a species generally flies between stopovers: short distance bout, intermediate distance bout, long distance bout, and combinations. We then explore further differences between spring and autumn migration. Spring migrants experience poor weather and decreased food availability as they fly north. Many cope with huge flocks, which serve as protection from predators, but may also reduce foraging efficiency and increase aggression. In contrast, autumn migrants generally encounter favorable weather and ample food. Flock sizes are usually smaller, thus foraging efficiency is higher and aggression lower than during spring migration. Physiologically, spring migrants are preparing for breeding and reproductive hormones are secreted. In the Western Sandpiper (Calidris mauri), luteinizing hormone levels are higher for spring than autumn migrants. Late spring migrants have higher testosterone levels than either early spring migrants or autumn migrants. Corticosterone levels are also higher in spring vs. autumn migrants. Although spring and autumn migrants travel similar distances, their strategies differ behaviorally and physiologically.
BACKGROUNDInitial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. ...Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODSWe prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTSTwenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSIONPediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDINGFinancial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.
This study evaluates sources of individual variation in child pretense play as an expression of emerging mental representation. Family sociodemographic characteristics, maternal personological ...characteristics, and maternal affective and cognitive play behaviors, as well as children's gender, language competence, and play, were examined simultaneously. Naturalistic child solitary play and child collaborative play with mother were videorecorded in 141 20-month-olds. Child solitary play, child-initiated and mother-initiated collaborative play with mother, and maternal demonstrations and solicitations of play were then coded into nonsymbolic and symbolic acts. Zero-order relations obtained between child play and, respectively, child gender and language, family SES, and maternal verbal intelligence, personality, physical affection, and play demonstrations and solicitations. Structural equation modeling supported the following unique predictive relations: Child language and mothers' symbolic play positively influenced child collaborative play, and child gender and mothers' verbal intelligence predicted child solitary play. Child gender and mothers' verbal intelligence and physical affection influenced mothers' play and so influenced child collaborative play indirectly. The cognitive advantages of child play and maternal influences on child play are placed in an adaptive parenting framework.
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BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also ...associated with other diseases or traits. Objectives This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. Methods In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. Results We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 ( KCNJ13-GIGYF2 ), 6p21 ( C2 ), 11p15 ( MRVI1-CTR9 ), 12q13 ( LRP1 ), 12q24 ( SCARB1 ), and 16q13 ( CETP ). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10−4 with a range of other diseases/traits. Conclusions We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
Squamous cell carcinoma can invade the carotid artery. The treatment options then include irradiation, “palliative peeling” of tumor from the artery, and carotid resection with ligation or in-line ...grafting. Twelve patients with invasion of the carotid artery by cancer had en bloc resection of the artery and tumor. Reconstruction after in-line carotid artery grafting with autogenous vein was completed with a myocutaneous flap. No neurologic events occurred perioperatively or during the follow-up period of 3 to 50 months. Computed tomography and arteriography were unreliable in predicting tumor involvement of the carotid artery. Three patients died during the study—two of unrelated causes, and one of metastases. None of the patients showed evidence of local recurrence from 3 to 50 months. In two of four wound infections the carotid artery graft was exposed. This was successfully treated by a myocutaneous flap. The mean survival for the group was 18 months. Resection and in-line bypass grafting of the carotid artery invaded by cancer can safety be performed in irradiated and potentially infected fields.
Published literature reports controversial results about the association of physical activity (PA) with risk of hypertension. A meta-analysis of prospective cohort studies was performed to ...investigate the effect of PA on hypertension risk. PubMed and Embase databases were searched to identify all related prospective cohort studies. The Q test and I(2) statistic were used to examine between-study heterogeneity. Fixed or random effects models were selected based on study heterogeneity. A funnel plot and modified Egger linear regression test were used to estimate publication bias. Thirteen prospective cohort studies were identified, including 136,846 persons who were initially free of hypertension, and 15,607 persons developed hypertension during follow-up. The pooled relative risk (RR) of main results from these studies suggests that both high and moderate levels of recreational PA were associated with decreased risk of hypertension (high versus low: RR, 0.81; 95% confidence interval, 0.76-0.85 and moderate versus low: RR, 0.89; 95% confidence interval, 0.85-0.94). The association of high or moderate occupational PA with decreased hypertension risk was not significant (high versus low: RR, 0.93; 95% confidence interval, 0.81-1.08 and moderate versus low: RR, 0.96; 95% confidence interval, 0.87-1.06). No publication bias was observed. The results of this meta-analysis suggested that there was an inverse dose-response association between levels of recreational PA and risk of hypertension, whereas there was no significant association between occupational PA and hypertension.
BACKGROUND. Initial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. ...Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology. METHODS. We prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data. RESULTS. Twenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-y, IL-10, IL-6, IL-8, and TNF-a) contributed to the analysis. TNF-a and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C. CONCLUSION. Pediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19. FUNDING. Financial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.
The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a ...meta–genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes, and neurodevelopmental conditions, including attention-deficit/hyperactivity disorder (ADHD).
We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 children of European descent. Meta-analyses were performed for early-phase expressive (infancy, 15–18 months), late-phase expressive (toddlerhood, 24–38 months), and late-phase receptive (toddlerhood, 24–38 months) vocabulary. Subsequently, we estimated single nucleotide polymorphism–based heritability (SNP-h2) and genetic correlations (rg) and modeled underlying factor structures with multivariate models.
Early-life vocabulary size was modestly heritable (SNP-h2 = 0.08–0.24). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (rg = 0.07), although each measure was moderately related to toddler expressive vocabulary (rg = 0.69 and rg = 0.67, respectively), suggesting a multifactorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g., spelling: rg = 0.58 and rg = 0.79, respectively), underlining genetic similarity. However, a genetic association of early-life vocabulary with educational attainment and intelligence emerged only during toddlerhood (e.g., receptive vocabulary and intelligence: rg = 0.36). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (rg = 0.23). Multivariate genetic models in the ALSPAC (Avon Longitudinal Study of Parents and Children) cohort confirmed this finding for ADHD symptoms (e.g., at age 13; rg = 0.54) but showed that the association effect reversed for toddler receptive vocabulary (rg = −0.74), highlighting developmental heterogeneity.
The genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy, and cognition-related traits.
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