Seasonal temperatures in West Antarctica during the Holocene.

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.

Early development of the feeding larva of the sea urchin Heliocidaris tuberculata: role of the small micromeres.

The two modes of development in sea urchins are direct development, in which the adult develops directly from the gastrula to the adult and does not feed, and indirect development, in which the adult develops indirectly through a feeding larva. In this account of the indirect, feeding larva of Heliocidaris tuberculata, the question raised is whether an evolutionary difference of unequal cell divisions contributes to the development of feeding structures in the indirect larva. In indirect development, the cell divisions at the fourth and fifth cell cycles of the zygote are unequal, with four small micromeres formed at the vegetal pole at the fifth cell division. In direct development, these cell divisions are not unequal. From their position at the head of the archenteron, the small micromeres are strategically located to contribute to the feeding tissues of the larva and the adult of H. tuberculata.

Expression of genes and proteins of the pax-six-eya-dach network in the metamorphic sea urchin: Insights into development of the enigmatic echinoderm body plan and sensory structures.

BACKGROUND: Photoreception-associated genes of the Pax-Six-Eya-Dach network (PSEDN) are deployed for many roles in addition to photoreception development. In this first study of PSEDN genes during development of the pentameral body in sea urchins, we investigated their spatial expression in Heliocidaris erythrogramma. RESULTS: Expression of PSEDN genes in the hydrocoele of early (Dach, Eya, Six1/2) and/or late (Pax6, Six3/6) larvae, and the five hydrocoele lobes, the first morphological expression of pentamery, supports a role in body plan development. Pax6, Six1/2, and Six3/6 were localized to the primary and/or secondary podia and putative sensory/neuronal cells. Six1/2 and Six3/6 were expressed in the neuropil region in the terminal disc of the podia. Dach was localized to spines. Sequential up-regulation of gene expression as new podia and spines formed was evident. Rhabdomeric opsin and pax6 protein were localized to cells in the primary podia and spines. CONCLUSIONS: Our results support roles for PSEDN genes in development of the pentameral body plan, contributing to our understanding of how the most unusual body plan in the Bilateria may have evolved. Development of sensory cells within the Pax-Six expression field is consistent with the role of these genes in sensory cell development in diverse species. Developmental Dynamics 247:239-249, 2018. © 2017 Wiley Periodicals, Inc.

Anomaly Detection in Paleoclimate Records Using Permutation Entropy.

Permutation entropy techniques can be useful for identifying anomalies in paleoclimate data records, including noise, outliers, and post-processing issues. We demonstrate this using weighted and unweighted permutation entropy with water-isotope records containing data from a deep polar ice core. In one region of these isotope records, our previous calculations (See Garland et al. 2018) revealed an abrupt change in the complexity of the traces: specifically, in the amount of new information that appeared at every time step. We conjectured that this effect was due to noise introduced by an older laboratory instrument. In this paper, we validate that conjecture by reanalyzing a section of the ice core using a more advanced version of the laboratory instrument. The anomalous noise levels are absent from the permutation entropy traces of the new data. In other sections of the core, we show that permutation entropy techniques can be used to identify anomalies in the data that are not associated with climatic or glaciological processes, but rather effects occurring during field work, laboratory analysis, or data post-processing. These examples make it clear that permutation entropy is a useful forensic tool for identifying sections of data that require targeted reanalysis-and can even be useful for guiding that analysis.

Nodal and BMP expression during the transition to pentamery in the sea urchin Heliocidaris erythrogramma: insights into patterning the enigmatic echinoderm body plan.

BACKGROUND: The molecular mechanisms underlying the development of the unusual echinoderm pentameral body plan and their likeness to mechanisms underlying the development of the bilateral plans of other deuterostomes are of interest in tracing body plan evolution. In this first study of the spatial expression of genes associated with Nodal and BMP2/4 signalling during the transition to pentamery in sea urchins, we investigate Heliocidaris erythrogramma, a species that provides access to the developing adult rudiment within days of fertilization. RESULTS: BMP2/4, and the putative downstream genes, Six1/2, Eya, Tbx2/3 and Msx were expressed in the earliest morphological manifestation of pentamery during development, the five hydrocoele lobes. The formation of the vestibular ectoderm, the specialized region overlying the left coelom that forms adult ectoderm, involved the expression of putative Nodal target genes Chordin, Gsc and BMP2/4 and putative BMP2/4 target genes Dlx, Msx and Tbx. The expression of Nodal, Lefty and Pitx2 in the right ectoderm, and Pitx2 in the right coelom, was as previously observed in other sea urchins. CONCLUSION: That genes associated with Nodal and BMP2/4 signalling are expressed in the hydrocoele lobes, indicates that they have a role in the developmental transition to pentamery, contributing to our understanding of how the most unusual body plan in the Bilateria may have evolved. We suggest that the Nodal and BMP2/4 signalling cascades might have been duplicated or split during the evolution to pentamery.

Evolution of a pentameral body plan was not linked to translocation of anterior Hox genes: the echinoderm HOX cluster revisited.

Echinodermata is a large phylum of marine invertebrates characterized by an adult, pentameral body plan. This morphology is clearly derived as all members of Deuterostomia (the superphylum to which they belong) have a bilateral body plan. The origin of the pentameral plan has been the subject of intense debate. It is clear that the ancestor of Echinodermata had a bilateral plan but how this ancestor transformed its body "architecture" in such a drastic manner is not clear. Data from the fossil record and ontogeny are sparse and, so far, not very informative. The sequencing of the sea urchin genome a decade ago opened the possibility that the pentameral body plan was a consequence of a broken Hox cluster and a series of papers dwelt on the putative relationship between Hox gene arrangements in the chromosomes and the origin of pentamery. This relationship, sound as it was, is challenged by the revelation that the sea star HOX cluster is, in fact, intact, thus falsifying the hypothesis of a direct relationship between HOX cluster arrangement and the origin of the pentameral body plan. Here, we explore the relationship between Hox gene arrangements and echinoderm body "architecture," the expression of Hox genes in development and alternative scenarios for the origin of pentamery, with putative roles for signaling centers in generating multiple axes.

miR-155 expression and correlation with clinical outcome in pediatric AML: A report from Children's Oncology Group.

BACKGROUND: Aberrant expression of microRNA-155 (miR-155) has been implicated in acute myeloid leukemia (AML) and associated with clinical outcome. PROCEDURE: We evaluated miR-155 expression in 198 children with normal karyotype AML (NK-AML) enrolled in Children's Oncology Group (COG) AML trial AAML0531 and correlated miR-155 expression levels with disease characteristics and clinical outcome. Patients were divided into quartiles (Q1-Q4) based on miR-155 expression level, and disease characteristics were then evaluated and correlated with miR-155 expression. RESULTS: MiR-155 expression varied over 4-log10-fold range relative to its expression in normal marrow with a median expression level of 0.825 (range 0.043-25.630) for the entire study cohort. Increasing miR-155 expression was highly associated with the presence of FLT3/ITD mutations (P < 0.001) and high-risk disease (P < 0.001) and inversely associated with standard-risk (P = 0.008) and low-risk disease (P = 0.041). Patients with highest miR-155 expression had a complete remission (CR) rate of 46% compared with 82% in low expressers (P < 0.001) with a correspondingly lower event-free (EFS) and overall survival (OS) (P < 0.001 and P = 0.002, respectively). In a multivariate model that included molecular risk factors, high miR-155 expression remained a significant independent predictor of OS (P = 0.022) and EFS (0.019). CONCLUSIONS: High miR-155 expression is an adverse prognostic factor in pediatric NK-AML patients. Specifically, high miR-155 expression not only correlates with FLT3/ITD mutation status and high-risk disease but it is also an independent predictor of worse EFS and OS.

Clarification of the risk of chronic obstructive pulmonary disease in α1-antitrypsin deficiency PiMZ heterozygotes.

RATIONALE: Severe α1-antitrypsin deficiency (typically PiZZ homozygosity) is associated with a significantly increased risk of airflow obstruction and emphysema but the risk of chronic obstructive pulmonary disease (COPD) in PiMZ heterozygotes remains uncertain. OBJECTIVES: This was a family-based study to determine the risk of COPD in PiMZ individuals. METHODS: We compared 99 PiMM and 89 PiMZ nonindex subjects recruited from 51 index probands who were confirmed PiMZ heterozygotes and also had a diagnosis of COPD Global Initiative for Chronic Obstructive Lung Disease stage II-IV. The primary outcome measures of interest were quantitative variables of pre- and post-bronchodilator FEV1/FVC ratio, FEV1 (liters), FEV1 (% predicted), forced expiratory flow midexpiratory phase (FEF25-75; liters per second), FEF25-75 (% predicted), and a categorical outcome of COPD. MEASUREMENTS AND MAIN RESULTS: PiMZ heterozygotes compared with PiMM individuals had a reduced median (interquartile range) post-bronchodilator FEV1 (% predicted) (92.0 [75.6-105.4] vs. 98.6 [85.5-109.7]; P = 0.04), FEV1/FVC ratio (0.75 [0.66-0.79] vs. 0.78 [0.73-0.83]; P = 0.004), and FEF25-75 (% predicted) (63.84 [38.45-84.35] vs. 72.8 [55.5-97.7]; P = 0.0013) compared with PiMM individuals. This effect was abrogated in never-smoking and accentuated in ever-smoking PiMZ individuals. PiMZ heterozygosity was associated with an adjusted odds ratio for COPD of 5.18 (95% confidence interval, 1.27-21.15; P = 0.02) and this was higher (odds ratio, 10.65; 95% confidence interval, 2.17-52.29; P = 0.004) in ever-smoking individuals. CONCLUSIONS: These results indicate that PiMZ heterozygotes have significantly more airflow obstruction and COPD than PiMM individuals and cigarette smoke exposure exerts a significant modifier effect.

Oral-aboral identity displayed in the expression of HpHox3 and HpHox11/13 in the adult rudiment of the sea urchin Holopneustes purpurescens.

Hox genes are noted for their roles in specifying axial identity in bilateral forms. In the radial echinoderms, the axis whose identity Hox genes might specify remains unclear. From the expression of Hox genes in the development of the sea urchin Holopneustes purpurescens reported here and that reported previously, we clarify the axis that might be specified by Hox genes in echinoderms. The expression of HpHox11/13 here is described at three developmental stages. The expression is around the rim of the blastopore in gastrulae, in the archenteron wall and adjacent mesoderm in early vestibula larvae, and in a patch of mesoderm close to the archenteron wall in later vestibula larvae. The retained expression of HpHox11/13 in the patch of mesoderm in the later vestibula larvae is, we suggest, indicative of a posterior or an aboral growth zone. The expression of HpHox3 at the echinoid-rudiment stage, in contrast, is in oral mesoderm beneath the epineural folds, concentrated in sites where the first three adult spines form. With the expression of HpHox5 and HpHox11/13 reported previously, the expressions here support the role of Hox genes in specifying oral-aboral identity in echinoderms. How such specification and a posterior growth zone add support to a concept of the structural homology between echinoderms and chordates is discussed.

Ets-1 is required for the activation of VEGFR3 during latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells.

Kaposi's sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi's sarcoma (KS), is present in the predominant tumor cells of KS, the spindle cells. Spindle cells express markers of lymphatic endothelium and, interestingly, KSHV infection of blood endothelial cells reprograms them to a lymphatic endothelial cell phenotype. KSHV-induced reprogramming requires the activation of STAT3 and phosphatidylinositol 3 (PI3)/AKT through the activation of cellular receptor gp130. Importantly, KSHV-induced reprogramming is specific to endothelial cells, indicating that there are additional host genes that are differentially regulated during KSHV infection of endothelial cells that contribute to lymphatic reprogramming. We found that the transcription factor Ets-1 is highly expressed in KS spindle cells and is upregulated during KSHV infection of endothelial cells in culture. The KSHV latent vFLIP gene is sufficient to induce Ets-1 expression in an NF-κB-dependent fashion. Ets-1 is required for KSHV-induced expression of VEGFR3, a lymphatic endothelial-cell-specific receptor important for lymphangiogenesis, and Ets-1 activates the promoter of VEGFR3. Ets-1 knockdown does not alter the expression of another lymphatic-specific gene, the podoplanin gene, but does inhibit the expression of VEGFR3 in uninfected lymphatic endothelium, indicating that Ets-1 is a novel cellular regulator of VEGFR3 expression. Knockdown of Ets-1 affects the ability of KSHV-infected cells to display angiogenic phenotypes, indicating that Ets-1 plays a role in KSHV activation of endothelial cells during latent KSHV infection. Thus, Ets-1 is a novel regulator of VEGFR3 and is involved in the induction of angiogenic phenotypes by KSHV.

Early development of coelomic structures in an echinoderm larva and a similarity with coelomic structures in a chordate embryo.

Early coelomic development in the abbreviated development of the sea urchin Holopneustes purpurescens is described and then used in a comparison with coelomic development in chordate embryos to support homology between a single arm of the five-armed radial body plan of an echinoderm and the single bilateral axis of a chordate. The homology depends on a positional similarity between the origin of the hydrocoele in echinoderm development and the origin of the notochord in chordate development, and a positional similarity between the respective origins of the coelomic mesoderm and chordate mesoderm in echinoderm and chordate development. The hydrocoele is homologous with the notochord and the secondary podia are homologous with the somites. The homology between a single echinoderm arm and the chordate axis becomes clear when the aboral to oral growth from the archenteron in the echinoderm larva is turned anteriorly, more in line with the anterior-posterior axis of the early zygote. A dorsoventral axis inversion in chordates is not required in the proposed homology.

Coelomogenesis during the abbreviated development of the echinoid Heliocidaris erythrogramma and the developmental origin of the echinoderm pentameral body plan.

The development of the coeloms is described in an echinoid with an abbreviated larval development and shows the early morphogenesis of the coeloms of the adult stage. The development is described from images obtained by laser scanning confocal microscopy. The development in Heliocidaris erythrogramma is asymmetric with a larger left coelom forming on the larval-left side and a smaller right coelom forming on the larval-right side. The right coelom forms after the development of the left coelom is well advanced. The hydrocoele forms from the anterior part of the left coelom. The five lobes of the hydrocoele from which the pentamery of the adult derives take shape on the outer, distal wall of the anterior part of the left coelom. The hydrocoele separates from the more posterior part of the left coelom, which becomes the left posterior coelom. The lobes of the hydrocoele are named, based on the site of the connexion of the stone canal to the hydrocoele. The mouth is assumed to form by penetration through only the outer, distal wall of the hydrocoele and the ectoderm. Both larval and adult polarities are evident in this larva. A comparison with coelomogenesis in the asteroid Parvulastra exigua, which also has an abbreviated development, leads to predictions of homology between the echinoderm and chordate phyla that do not require the hypothesis of a dorsoventral inversion event in chordates.

The prevalence of alpha-1 antitrypsin deficiency in Ireland.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) results from mutations in the SERPINA1 gene and classically presents with early-onset emphysema and liver disease. The most common mutation presenting with clinical evidence is the Z mutation, while the S mutation is associated with a milder plasma deficiency. AATD is an under-diagnosed condition and the World Health Organisation recommends targeted detection programmes for AATD in patients with chronic obstructive pulmonary disease (COPD), non-responsive asthma, cryptogenic liver disease and first degree relatives of known AATD patients. METHODS: We present data from the first 3,000 individuals screened following ATS/ERS guidelines as part of the Irish National Targeted Detection Programme (INTDP). We also investigated a DNA collection of 1,100 individuals randomly sampled from the general population. Serum and DNA was collected from both groups and mutations in the SERPINA1 gene detected by phenotyping or genotyping. RESULTS: The Irish National Targeted Detection Programme identified 42 ZZ, 44 SZ, 14 SS, 430 MZ, 263 MS, 20 IX and 2 rare mutations. Analysis of 1,100 randomly selected individuals identified 113 MS, 46 MZ, 2 SS and 2 SZ genotypes. CONCLUSION: Our findings demonstrate that AATD in Ireland is more prevalent than previously estimated with Z and S allele frequencies among the highest in the world. Furthermore, our targeted detection programme enriched the population of those carrying the Z but not the S allele, suggesting the Z allele is more important in the pathogenesis of those conditions targeted by the detection programme.

Sudden cardiac death in 14- to 35-year olds in Ireland from 2005 to 2007: a retrospective registry.

INTRODUCTION: Sudden cardiac death (SCD) in young people is a rare but devastating event for families and communities. Ireland has previously had no measure of the incidence of SCD in young people. We report the incidence and causes of SCD in persons <35 years of age. METHODS AND RESULTS: We undertook a retrospective study of SCD between 2005 and 2007 in persons aged 15-35 years in the Republic of Ireland. We identified potential cases of out of hospital SCD through the Central Statistics Office (CSO) death certificate records. Autopsy, toxicology, and inquest reports were then obtained and analysed by an expert panel who adjudicated on the cause of death. A total of 342 potential SCD cases were identified through the CSO. Fifty were younger than 15 years of age, and 86 had either incomplete or unavailable post-mortem reports. Of 206 full reports obtained, 116 were adjudicated as cases of SCD. Cases were predominantly male (75%), with a mean age of 25.8 years (standard deviation 6.3). The incidence of SCD in this age range was 2.85 per 100,000 person-years (4.36 for males and 1.30 for females) and the incidence of sudden arrhythmic death syndrome (SADS) was 0.76 per 100,000 person-years. The commonest causes were SADS, 26.7% (31 of 116), followed by coronary artery disease, 20.7% (24 of 116), hypertrophic cardiomyopathy (HCM), 14.7% (17 of 116), and idiopathic left ventricular hypertrophy not fulfilling criteria for HCM, 10.3% (12 of 116). CONCLUSIONS: The incidence of SCD in the young in Ireland was 4.96 (95% CI 3.06, 6.4) for males and 1.3 (95% CI 0.62, 2.56) for females per 100 000 person-years. Sudden arrhythmic death syndrome was the commonest cause of SCD in the young, and the incidence of SADS was more than five times that in official reports of the Irish CSO.

On the sites of secondary podia formation in a juvenile echinoid: growth of the body types in echinoderms.

The growth of the adult echinoderm body is addressed here in the echinoid Holopneustes purpurescens in a study of the early development of the secondary podia along the five radial canals of the adult rudiment. At a stage when the first four secondary podia have formed along each radius oral to the primary podium, two podia are on one side of the radius and two are on the other side, all at a different distance from the primary podium. The pattern of the connexions of these secondary podia to the radial canals changes in successive radii in a manner similar to Lovén's law for skeletal plates and matches the reported sequence in the times at which the first ambulacral skeletal plates form in the adult echinoid rudiment. A similar pattern is described for the reported origins of the secondary podia in apodid holothurians. A common plan for the growth of the body types is described for echinoids, asteroids, holothurians and concentricycloids. The five metameric series of secondary podia formed in echinoderms have a coelomic developmental origin like the single metameric series of somites formed in the axial structures of chordates.

Activation of Akt through gp130 receptor signaling is required for Kaposi's sarcoma-associated herpesvirus-induced lymphatic reprogramming of endothelial cells.

Kaposi's sarcoma (KS) is the most common tumor of AIDS patients worldwide. KS-associated herpesvirus (KSHV) is the infectious cause of this highly vascularized skin tumor. The main cell type found within a KS lesion, the spindle cell, is latently infected with KSHV and has markers of both blood and lymphatic endothelial cells. During development, lymphatic endothelial cells differentiate from preexisting blood endothelial cells. Interestingly, KSHV infection of blood endothelial cells induces lymphatic endothelial cell differentiation. Here, we show that KSHV gene expression is necessary to maintain the expression of the lymphatic markers vascular endothelial growth factor receptor 3 (VEGFR-3) and podoplanin. KSHV infection activates many cell signaling pathways in endothelial cells and persistently activates STAT3 through the gp130 receptor, the common receptor of the interleukin 6 family of cytokines. We find that KSHV infection also activates the phosphatidylinositol 3-OH-kinase (PI3K)/Akt cell signaling pathway in latently infected endothelial cells and that gp130 receptor signaling is necessary for Akt activation. Using both pharmacological inhibitors and small interfering RNA knockdown, we show that the gp130 receptor-mediated activation of both the JAK2/STAT3 and PI3K/Akt cell signaling pathways is necessary for KSHV-induced lymphatic reprogramming of endothelial cells. The induction of the lymphatic endothelial cell-specific transcription factor Prox1 is also involved in KSHV-induced lymphatic reprogramming. The activation of gp130 receptor signaling is a novel mechanism for the differentiation of blood endothelial cells into lymphatic endothelial cells and may be relevant to the developmental or pathological differentiation of lymphatic endothelial cells as well as to KSHV pathogenesis.

Development of the five primary podia from the coeloms of a sea star larva: homology with the echinoid echinoderms and other deuterostomes.

Confocal laser scanning microscopy of larvae of the asteroid Parvulastra exigua was used to investigate the development of the five primary podia from the coeloms in the echinoderm phylum in an approach to the problem of morphological homology in the deuterostome phyla. The development is shown from an early brachiolaria larval stage to a pre-settlement late brachiolaria larval stage. In the early brachiolaria larva, a single enterocoele connected to the archenteron has formed into two lateral coeloms and an anterior coelom. The primary podia form from the coelomic regions on the left side of the brachiolaria larva, while on the right the coelomic regions connect with the exterior through the pore canal and hydropore. The anterior coelom forms the coelom of the brachia. Homology between the primary podia of the asteroid and the echinoid classes of echinoderms is described and extended to coeloms of other deuterostome phyla.

Origins of radial symmetry identified in an echinoderm during adult development and the inferred axes of ancestral bilateral symmetry.

How the radial body plan of echinoderms is related to the bilateral body plan of their deuterostome relatives, the hemichordates and the chordates, has been a long-standing problem. Now, using direct development in a sea urchin, I show that the first radially arranged structures, the five primary podia, form from a dorsal and a ventral hydrocoele at the oral end of the archenteron. There is a bilateral plane of symmetry through the podia, the mouth, the archenteron and the blastopore. This adult bilateral plane is thus homologous with the bilateral plane of bilateral metazoans and a relationship between the radial and bilateral body plans is identified. I conclude that echinoderms retain and use the bilateral patterning genes of the common deuterostome ancestor. Homologies with the early echinoderms of the Cambrian era and between the dorsal hydrocoele, the chordate notochord and the proboscis coelom of hemichordates become evident.

Analysis of coelom development in the sea urchin Holopneustes purpurescens yielding a deuterostome body plan.

An analysis of early coelom development in the echinoid Holopneustes purpurescens yields a deuterostome body plan that explains the disparity between the pentameral plan of echinoderms and the bilateral plans of chordates and hemichordates, the three major phyla of the monophyletic deuterostomes. The analysis shows an early separation into a medial hydrocoele and lateral coelomic mesoderm with an enteric channel between them before the hydrocoele forms the pentameral plan of five primary podia. The deuterostome body plan thus has a single axial or medial coelom and a pair of lateral coeloms, all surrounding an enteric channel, the gut channel. Applied to the phyla, the medial coelom is the hydrocoele in echinoderms, the notochord in chordates and the proboscis coelom in hemichordates: the lateral coeloms are the coelomic mesoderm in echinoderms, the paraxial mesoderm in chordates and the lateral coeloms in hemichordates. The plan fits frog and chick development and the echinoderm fossil record, and predicts genes involved in coelomogenesis as the source of deuterostome macroevolution.