Antibodies to acetylcholine receptor in parous women with myasthenia: evidence for immunization by fetal antigen

The weakness in myasthenia gravis (MG) is mediated by autoantibodies against adult muscle acetylcholine receptors (AChR) at the neuromuscular junction; most of these antibodies also bind to fetal AChR, which is present in the thymus. In rare cases, babies of mothers with MG, or even of asymptomatic mothers, develop a severe developmental condition, arthrogryposis multiplex congenita, caused by antibodies that inhibit the ion channel function of the fetal AChR while not affecting the adult AChR. Here we show that these fetal AChR inhibitory antibodies are significantly more common in females sampled after pregnancy than in those who present before pregnancy, suggesting that they may be induced by the fetus. Moreover, we were able to clone high-affinity combinatorial Fab antibodies from thymic cells of two mothers with MG who had babies with arthrogryposis multiplex congenita. These Fabs were highly specific for fetal AChR and did not bind the main immunogenic region that is common to fetal and adult AChR. The Fabs show strong biases to VH3 heavy chains and to a single Vk1 light chain in one mother. Nevertheless, they each show extensive intraclonal diversification from a highly mutated consensus sequence, consistent with antigen-driven selection in successive steps. Collectively, our results suggest that, in some cases of MG, initial immunization against fetal AChR is followed by diversification and expansion of B cells in the thymus; maternal autoimmunity will result if the immune response spreads to the main immunogenic region and other epitopes common to fetal and adult AChR

Role of Programmed Proteolysis During Meiosis

Meiosis is the process which forms gametes and spores for reproduction in eukaryotic cells. During the pachytene phase of meiosis I, a protein structure, called the Synaptonemal Complex (SC), forms between homologous chromosomes and creates a scaffold for genetic recombination. In yeast, the Zip1 protein is a major structural component of the SC. At restrictive temperature for meiosis, ZIP1 is required for completion of meiotic divisions. At permissive temperature ZIP1 is required for proper chromosome segregation. We observed that chemical inhibition of the proteasome, with MG132, results in arrest at prophase of meiosis I. Based on these results, we questioned whether there is a regulatory relationship between the SC and the proteasome. Our findings demonstrate the localization of the proteasome along the SC, consistent with proteolysis of SC proteins by the proteasome. Furthermore, lack of double-strand breaks, lack of SC and lack of recombination proteins, result in failed proteasome recruitment to chromosomes during meiosis I. This implies that the proteasome plays not only a role in proper meiotic division, but also double-strand break repair and chromosomal recombination. Fluorescent microscopy techniques were applied to determine the chromosomal localization of the proteasome. Epitope tagged recombination proteins (ZIP1, ZIP3 and MSH4) were utilized along with tagged proteasome components to determine the pattern of proteasome localization to meiotic chromosomes. This is significant as a clearer, fundamental understanding of the proteasome’s role in meiosis may serve to illuminate the causation of many birth-defects, miscarriages and stillbirths.https://engagedscholarship.csuohio.edu/u_poster_2013/1023/thumbnail.jp

Youth Justice in Europe: Experience of Germany, the Netherlands, and Croatia in Providing Developmentally Appropriate Responses to Emerging Adults in the Criminal Justice System

There is a growing awareness, in the United States and Europe that emerging adults – those ages 18–25 – are a developmentally distinct group worth special treatment at the hands of the justice system. Four US states have proposed raising the age of their juvenile courts’ jurisdiction beyond age 18 within the last year, while four out of five European countries have special laws affecting emerging adults. Three European nations – Croatia, Germany, and the Netherlands – allow youth over age 18 to be sanctioned in the same manner as younger youth in the juvenile justice system, including the possibility of being housed in juvenile facilities. In March 2018, the Columbia University Justice Lab sponsored an educational delegation of 20 elected and appointed officials, legal system stakeholders, service providers, and advocates to Germany to learn more about the German approach to emerging adults. In advance of that delegation, the authors in this article examined the law and practice regarding court-involved emerging adults in Croatia, Germany, and the Netherlands to glean potential lessons for US policy-makers considering a developmentally distinct approach to emerging adults in their justice systems

Preglacial and Interglacial Environments of Banks Island: Pollen and Macrofossils from Duck Hawk Bluffs and Related Sites

Sediments ranging in age from Tertiary to Late Quaternary are exposed at Duck Hawk Bluffs near Sachs Harbour on Banks Island (NWT). Fossil pollen and macrofossils of plants and arthropods from various nonglacial sediments at Duck Hawk Bluffs and related sites on Banks and Victoria islands make it possible to infer some of the climatic/biotic changes during that time span. At the time of deposition of the Miocene-Pliocene Beaufort Formation, southern Banks Island supported a rich coniferous forest, containing several species of conifers and various hardwoods. An upper member of the Beaufort Fm. is characterized by a more depauperate coniferous forest assemblage, yet still contains plants now foreign to the entire NWT. The late Tertiary/early Quaternary Worth Point Formation was deposited when larch-dominated forest-tundra characterized southern Banks Island. Larch may have grown on the island during the following Morgan Bluffs Interglaciation (>730 ka), but in other respects the flora and fauna of that time seem to have been low Arctic in character. Similar conditions existed during the Cape Collinson Interglaciation ( = Sangamon), though by that time, coniferous trees had definitely disappeared from the island.Les falaises Duck Hawk, près de Sachs Harbour, présentent des sédiments dont l'âge varie du Tertiaire jusqu'au Quaternaire supérieur. Le pollen et les macrorestes de végétaux et d'animaux fossiles, prélevés dans divers sédiments non glaciaires dans les falaises Duck Hawk et d'autres sites associés dans les îles de Banks et Victoria, enregistrent des variations climatiques et biotiques au cours de cette période. Au moment de la mise en place des dépôts miocènes-pliocènes de la Formation de Beaufort, une forêt coniférienne, composée de plusieurs espèces de conifères et de divers feuillus, existait au sud de l'île de Banks. Un membre supérieur de la Formation de Beaufort est caractérisé par une forêt coniférienne appauvrie bien que plusieurs plantes, maintenant disparues de l'ensemble des T.N.-O., ont été identifées. La Formation de Worth Point, datant de la fin du Tertiaire et du Quaternaire inférieur, a été mise en place lorsqu'une toundra forestière, dominée par le mélèze, caractérisait l'île de Banks méridionale. Le mélèze croissait peut-être dans l'île lors de l'interglaciaire subséquent de Morgan Bluffs (>730 ka BP), mais les autres indicateurs permettent de croire que la faune et la flore étaient caractéristiques de celle du bas Arctique. Des conditions semblables ont existé lors de l'interglaciaire de Cape Collinson ( = Sangamon), bien qu'à ce moment les conifères avaient définitivement disparu de l'île.An den Steilkùsten von Duck Hawk in der Nâhe von Sachs Harbour auf der Insel Banks (Nord-West-Territorien) befinden sich Sedimente, deren Datierung vom Tertiar bis zum spâten Quaternàr reicht. Fossiler Pollen und Makrofossile von Pflanzen und GliederfùBern von verschiedenen nichtglazialen Sedimenten der Steilkùsten von Duck Hawk und verwandten Standorten auf den Insein Banks und Victoria erlauben, auf einige klimatische/ biotische Verânderungen wâhrend dieser Zeitspanne zu schliBen. Wâhrend der AbIagerung der Miozàn-Pliozân-Formation von Beaufort bedeckte ein reicher Nadelwald die sùdliche Insel Banks, bestehend aus verschiedenen Arten von Nadelbàumen und verschiedenen Laubbâumen. Ein hôherer Teil der Beaufort-Formation ist durch eine ârmere Nadelbaumbewaldung gekennzeichnet, enthàlt jedoch immer noch Pflanzen, die heute in den gesamten Nord-West-Gebieten unbekannt sind. AIs im spâten Tertiâr und frùhen Quaternàr die Worth Point-Formation abgelagert wurde, war der sùdliche Teil der Insel Banks durch eine von Làrchen beherrschte Baum-Tundra gekennzeichnet. Làrchen wuchsen wohl auf der Insel wâhrend der folgenden Interglazialzeit von Morgan Bluffs (>730 ka), jedoch weisen andere Indizien darauf hin, dafi die Flora und Fauna dieser Zeit in ihrem Charakter derniedrigen Arktis entsprach. Àhnliche Bedingungen bestanden wâhrend der Interglazialzeit von Cape Collinson ( = Sangamon), obwohl zu diesem Zeitpunkt Nadelbàume endgùltig von der Insel verschwunden waren

The role of tropical-extratropical interaction and synoptic variability in maintaining the South Pacific Convergence Zone in CMIP5 models

The South Pacific Convergence Zone (SPCZ) is simulated as too zonal a feature in current generation climate models, including those in Phase 5 of the Coupled Model Intercomparison Project (CMIP5). This zonal bias induces errors in tropical convective heating, with subsequent effects on global circulation. The SPCZ structure, particularly in the subtropics, is governed by the tropical-extratropical interaction between transient synoptic systems and the mean background state. However, the fidelity of synoptic-scale interactions as simulated by CMIP5 models has not yet been evaluated. In this study, analysis of synoptic variability in the simulated subtropical SPCZ reveals that the basic mechanism of tropical-extratropical interaction is generally well simulated, with storms approaching the SPCZ along comparable trajectories to observations. However, there is a broad spread in mean precipitation and its variability across the CMIP5 ensemble. Inter-model spread appears to relate to a biased background state in which the synoptic waves propagate. In particular, the region of mean negative zonal stretching deformation or "storm graveyard" in the upper troposphere?a feature previously determined to play a key role in SPCZ-storm interactions?is typically displaced in CMIP5 models to the northeast of its position in reanalysis data, albeit with individual model graveyards displaying a pronounced (25 degree) longitudinal spread. From these findings, we suggest that SPCZs simulated by CMIP5 models are not simply too zonal; rather, in models the subtropical SPCZ manifests a diagonal tilt similar to observations while SST biases force an overly zonal tropical SPCZ, resulting in a more disjointed SPCZ than observed