Tailless patterning functions are conserved in the honeybee even in the absence of Torso signaling

AbstractIn Drosophila, the maternal Torso terminal signaling pathway activates expression of the gene tailless (tll), which is required for the patterning of anterior and posterior termini. We cloned the honeybee orthologue of tll (Am-tll) and found that embryonic expression of Am-tll resembles that of Drosophila, with expression in triangular anterior dorsal–lateral domains and a posterior cap. Functional studies revealed that Am-tll has an essential role in patterning the posterior terminal segments and the brain, similar to the activity of tll in other insects. As the honeybee genome lacks many of the components of the Torso pathway required for terminal patterning, we investigated the regulation of honeybee tailless (Am-tll). Am-tll is expressed maternally and, in the honeybee ovary, Am-tll mRNA becomes localized to the dorsal side of the oocyte, a process requiring the actin cytoskeleton. This RNA becomes redistributed in early embryos to a posterior domain. We also show that the activation of the anterior domain of Am-tll is dependent on honeybee orthodenticle-1. Together these findings indicate major differences in post-transcriptional regulation of tailless in the honeybee compared to other insects but that this regulation leads to a conserved expression pattern. These results provide an example of an early event in development evolving and yet still producing a conserved output for the rest of development to build upon

Evolution of the insect Sox genes

<p>Abstract</p> <p>Background</p> <p>The <it>Sox </it>gene family of transcriptional regulators have essential roles during development and have been extensively studied in vertebrates. The mouse, human and <it>fugu </it>genomes contain at least 20 <it>Sox </it>genes, which are subdivided into groups based on sequence similarity of the highly conserved HMG domain. In the well-studied insect <it>Drosophila melanogaster</it>, eight <it>Sox </it>genes have been identified and are involved in processes such as neurogenesis, dorsal-ventral patterning and segmentation.</p> <p>Results</p> <p>We examined the available genome sequences of <it>Apis mellifera, Nasonia vitripennis, Tribolium castaneum</it>, <it>Anopheles gambiae </it>and identified <it>Sox </it>family members which were classified by phylogenetics using the HMG domains. Using <it>in situ </it>hybridisation we determined the expression patterns of eight honeybee <it>Sox </it>genes in honeybee embryo, adult brain and queen ovary. <it>AmSoxB </it>group genes were expressed in the nervous system, brain and Malphigian tubules. The restricted localization of <it>AmSox21b </it>and <it>AmSoxB1 </it>mRNAs within the oocyte, suggested a role in, or that they are regulated by, dorsal-ventral patterning. <it>AmSoxC, D </it>and <it>F </it>were expressed ubiquitously in late embryos and in the follicle cells of the queen ovary. Expression of <it>AmSoxF </it>and two <it>AmSoxE </it>genes was detected in the drone testis.</p> <p>Conclusion</p> <p>Insect genomes contain between eight and nine <it>Sox </it>genes, with at least four members belonging to <it>Sox </it>group B and other <it>Sox </it>subgroups each being represented by a single <it>Sox </it>gene. Hymenopteran insects have an additional <it>SoxE </it>gene, which may have arisen by gene duplication. Expression analyses of honeybee <it>SoxB </it>genes implies that this group of genes may be able to rapidly evolve new functions and expression domains, while the combined expression pattern of all the <it>SoxB </it>genes is maintained.</p

De novo draft assembly of the Botrylloides leachii genome provides further insight into tunicate evolution

Tunicates are marine invertebrates that compose the closest phylogenetic group to the vertebrates. These chordates present a particularly diverse range of regenerative abilities and life-history strategies. Consequently, tunicates provide an extraordinary perspective into the emergence and diversity of these traits. Here we describe the genome sequencing, annotation and analysis of the Stolidobranchian Botrylloides leachii. We have produced a high-quality 159 Mb assembly, 82% of the predicted 194  Mb genome. Analysing genome size, gene number, repetitive elements, orthologs clustering and gene ontology terms show that B. leachii has a genomic architecture similar to that of most solitary tunicates, while other recently sequenced colonial ascidians have undergone genome expansion. In addition, ortholog clustering has identified groups of candidate genes for the study of colonialism and whole-body regeneration. By analysing the structure and composition of conserved gene linkages, we observed examples of cluster breaks and gene dispersions, suggesting that several lineage-specific genome rearrangements occurred during tunicate evolution. We also found lineage-specific gene gain and loss within conserved cell-signalling pathways. Such examples of genetic changes within conserved cell-signalling pathways commonly associated with regeneration and development that may underlie some of the diverse regenerative abilities observed in tunicates. Overall, these results provide a novel resource for the study of tunicates and of colonial ascidians

Postmortem tissue distribution of morphine and its metabolites in a series of heroin related deaths

The abuse of heroin (diamorphine) and heroin deaths are growing around the world. The interpretation of the toxicological results from suspected heroin deaths is notoriously difficult especially in cases where there may be limited samples. In order to help forensic practitioners with heroin interpretation we determined the concentration of morphine (M), morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) in blood (femoral and cardiac), brain (thalamus), liver (deep right lobe), bone marrow (sternum), skeletal muscle (psoas) and vitreous humor in 44 heroin related deaths. The presence of 6‐monoacetylmorphine (6‐MAM) in any of the postmortem samples was used as confirmation of heroin use. Quantitation was carried out using a validated LC‐MS/MS method with solid phase extraction. We also determined the presence of papaverine, noscapine and codeine in the samples, substances often found in illicit heroin and that may help determine illicit heroin use. The results of this study show that vitreous is the best sample to detect 6‐MAM (100% of cases), and thus heroin use. The results of the M, M3G and M6G quantitation in this study allow a degree of interpretation when samples are limited. However in some cases it may not be possible to determine heroin/morphine use as in 4 cases in muscle (3 cases in bone marrow) no morphine, morphine‐3‐glucuronide or morphine‐6‐glucuronide was detected, even though they were detected in other case samples. As always postmortem cases of suspected morphine/heroin intoxication should be interpreted with care and with as much case knowledge as possible

Linking Signatures of Accretion with Magnetic Field Measurements - Line Profiles are not Significantly Different in Magnetic and Non-Magnetic Herbig Ae/Be Stars

Herbig Ae/Be stars are young, pre-main-sequence stars that sample the transition in structure and evolution between low- and high-mass stars, providing a key test of accretion processes in higher-mass stars. Few Herbig Ae/Be stars have detected magnetic fields, calling into question whether the magnetospheric accretion paradigm developed for low-mass stars can be scaled to higher masses. We present He I 10830 \AA\ line profiles for 64 Herbig Ae/Be stars with a magnetic field measurement in order to test magnetospheric accretion in the physical regime where its efficacy remains uncertain. Of the 5 stars with a magnetic field detection, 1 shows redshifted absorption, indicative of infall, and 2 show blueshifted absorption, tracing mass outflow. The fraction of redshifted and blueshifted absorption profiles in the non-magnetic Herbig Ae/Be stars is remarkably similar, suggesting that the stellar magnetic field does not affect gas kinematics traced by He I 10830 \AA. Line profile morphology does not correlate with the luminosity, rotation rate, mass accretion rate, or disk inclination. Only the detection of a magnetic field and a nearly face-on disk inclination show a correlation (albeit for few sources). This provides further evidence for weaker dipoles and more complex field topologies as stars develop a radiative envelope. The small number of magnetic Herbig Ae/Be stars has already called into question whether magnetospheric accretion can be scaled to higher masses; accretion signatures are not substantially different in magnetic Herbig Ae/Be stars, casting further doubt that they accrete in the same manner as classical T Tauri stars.Comment: accepted to ApJ; 17 pages, 4 figures, 3 table

KEAP1 Cancer Mutants: A Large-Scale Molecular Dynamics Study of Protein Stability.

We have performed 280 μs of unbiased molecular dynamics (MD) simulations to investigate the effects of 12 different cancer mutations on Kelch-like ECH-associated protein 1 (KEAP1) (G333C, G350S, G364C, G379D, R413L, R415G, A427V, G430C, R470C, R470H, R470S and G476R), one of the frequently mutated proteins in lung cancer. The aim was to provide structural insight into the effects of these mutants, including a new class of ANCHOR (additionally NRF2-complexed hypomorph) mutant variants. Our work provides additional insight into the structural dynamics of mutants that could not be analyzed experimentally, painting a more complete picture of their mutagenic effects. Notably, blade-wise analysis of the Kelch domain points to stability as a possible target of cancer in KEAP1. Interestingly, structural analysis of the R470C ANCHOR mutant, the most prevalent missense mutation in KEAP1, revealed no significant change in structural stability or NRF2 binding site dynamics, possibly indicating an covalent modification as this mutant\u27s mode of action

Evolutionary origin and genomic organisation of runt-domain containing genes in arthropods

<p>Abstract</p> <p>Background</p> <p>Gene clusters, such as the <it>Hox </it>gene cluster, are known to have critical roles in development. In eukaryotes gene clusters arise primarily by tandem gene duplication and divergence. Genes within a cluster are often co-regulated, providing selective pressure to maintain the genome organisation, and this co-regulation can result in temporal or spatial co-linearity of gene expression. It has been previously noted that in <it>Drosophila melanogaster</it>, three of the four runt-domain (RD) containing genes are found in a relatively tight cluster on chromosome 1, raising the possibility of a putative functional RD gene cluster in <it>D. melanogaster</it>.</p> <p>Results</p> <p>To investigate the possibility of such a gene cluster, orthologues of the <it>Drosophila melanogaste</it>r RD genes were identified in several endopterygotan insects, two exopterygotan insects and two non-insect arthropods. In all insect species four RD genes were identified and orthology was assigned to the <it>Drosophila </it>sequences by phylogenetic analyses. Although four RD genes were found in the crustacean <it>D. pulex</it>, orthology could not be assigned to the insect sequences, indicating independent gene duplications from a single ancestor following the split of the hexapod lineage from the crustacean lineage.</p> <p>In insects, two chromosomal arrangements of these genes was observed; the first a semi-dispersed cluster, such as in <it>Drosophila</it>, where <it>lozenge </it>is separated from the core cluster of three RD genes often by megabases of DNA. The second arrangement was a tight cluster of the four RD genes, such as in <it>Apis mellifera</it>.</p> <p>This genomic organisation, particularly of the three core RD genes, raises the possibility of shared regulatory elements. <it>In situ </it>hybridisation of embryonic expression of the four RD genes in <it>Drosophila melanogaster </it>and the honeybee <it>A. mellifera </it>shows no evidence for either spatial or temporal co-linearity of expression during embryogenesis.</p> <p>Conclusion</p> <p>All fully sequenced insect genomes contain four RD genes and orthology can be assigned to these genes based on similarity to the <it>D. melanogaster </it>protein sequences. Examination of the genomic organisation of these genes provides evidence for a functional RD gene cluster. RD genes from non-insect arthropods are also clustered, however the lack of orthology between these and insect RD genes suggests this cluster is likely to have resulted from a duplication event independent from that which created the insect RD gene cluster. Analysis of embryonic RD gene expression in two endopterygotan insects, <it>A. mellifera </it>and <it>D. melanogaster</it>, did not show evidence for coordinated gene expression, therefore while the functional significance of this gene cluster remains unknown its maintenance during insect evolution implies some functional significance to the cluster.</p

Andean and Tibetan Patterns of Adaptation to High Altitude

Objectives: High-altitude hypoxia, or decreased oxygen levels caused by low barometric pressure, challenges the ability of humans to live and reproduce. Despite these challenges, human populations have lived on the Andean Altiplano and the Tibetan Plateau for millennia and exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. We and others have identified natural selection candidate genes and gene regions for these adaptations using dense genome scan data. One gene previously known to be important in cellular oxygen sensing, egl nine homolog 1 (EGLN1), shows evidence of positive selection in both Tibetans and Andeans. Interestingly, the pattern of variation for this gene differs between the two populations. Continued research among Tibetan populations has identified statistical associations between hemoglobin concentration and single nucleotide polymorphism (SNP) genotype at EGLN1 and a second gene, endothelial PAS domain protein 1 (EPAS1). Methods: To measure for the effects of EGLN1 and EPAS1 altitude genotypes on hemoglobin concentration among Andean highlanders, we performed a multiple linear regression analysis of 10 candidate SNPs in or near these two genes. Results: Our analysis did not identify significant associations between EPAS1 or EGLN1 SNP genotypes and hemoglobin concentration in Andeans. Conclusions: These results contribute to our understanding of the unique set of adaptations developed in different highland groups to the hypoxia of high altitude. Overall, the results provide key insights into the patterns of genetic adaptation to high altitude in Andean and Tibetan populations

Review: Smokehouse Associates

Review of Smokehouse Associates by Eric Booker. Yale University Press, December 2022. 258 p. ill. ISBN 978-0-300-26720-4 (h/c), $55.00. https://yalebooks.yale.edu/book/9780300267204/smokehouse-associates/. Reviewed March 2023 by Kristen J. Owens, Librarian for African American and Black Diaspora Studies, New York University Libraries, Independent Curator, [email protected]

The atypical chemokine receptor Ackr2 constrains NK cell migratory activity and promotes metastasis

Chemokines have been shown to be essential players in a range of cancer contexts. In this study, we demonstrate that mice deficient in the atypical chemokine receptor Ackr2 display impaired development of metastasis in vivo in both cell line and spontaneous models. Further analysis reveals that this relates to increased expression of the chemokine receptor CCR2, specifically by KLRG1+ NK cells from the Ackr2−/− mice. This leads to increased recruitment of KLRG1+ NK cells to CCL2-expressing tumors and enhanced tumor killing. Together, these data indicate that Ackr2 limits the expression of CCR2 on NK cells and restricts their tumoricidal activity. Our data have important implications for our understanding of the roles for chemokines in the metastatic process and highlight Ackr2 and CCR2 as potentially manipulable therapeutic targets in metastasis