Meiotic telomere clustering requires actin for its formation and cohesin for its resolution

In diploid organisms, meiosis reduces the chromosome number by half during the formation of haploid gametes. During meiotic prophase, telomeres transiently cluster at a limited sector of the nuclear envelope (bouquet stage) near the spindle pole body (SPB). Cohesin is a multisubunit complex that contributes to chromosome segregation in meiosis I and II divisions. In yeast meiosis, deficiency for Rec8 cohesin subunit induces telomere clustering to persist, whereas telomere cluster–SPB colocalization is defective. These defects are rescued by expressing the mitotic cohesin Scc1 in rec8Δ meiosis, whereas bouquet-stage exit is independent of Cdc5 pololike kinase. An analysis of living Saccharomyces cerevisiae meiocytes revealed highly mobile telomeres from leptotene up to pachytene, with telomeres experiencing an actin- but not microtubule-dependent constraint of mobility during the bouquet stage. Our results suggest that cohesin is required for exit from actin polymerization–dependent telomere clustering and for linking the SPB to the telomere cluster in synaptic meiosis

A New Thermosensitive smc-3 Allele Reveals Involvement of Cohesin in Homologous Recombination in C. elegans

The cohesin complex is required for the cohesion of sister chromatids and for correct segregation during mitosis and meiosis. Crossover recombination, together with cohesion, is essential for the disjunction of homologous chromosomes during the first meiotic division. Cohesin has been implicated in facilitating recombinational repair of DNA lesions via the sister chromatid. Here, we made use of a new temperature-sensitive mutation in the Caenorhabditis elegans SMC-3 protein to study the role of cohesin in the repair of DNA double-strand breaks (DSBs) and hence in meiotic crossing over. We report that attenuation of cohesin was associated with extensive SPO-11–dependent chromosome fragmentation, which is representative of unrepaired DSBs. We also found that attenuated cohesin likely increased the number of DSBs and eliminated the need of MRE-11 and RAD-50 for DSB formation in C. elegans, which suggests a role for the MRN complex in making cohesin-loaded chromatin susceptible to meiotic DSBs. Notably, in spite of largely intact sister chromatid cohesion, backup DSB repair via the sister chromatid was mostly impaired. We also found that weakened cohesins affected mitotic repair of DSBs by homologous recombination, whereas NHEJ repair was not affected. Our data suggest that recombinational DNA repair makes higher demands on cohesins than does chromosome segregation

Mug20, a novel protein associated with linear elements in fission yeast meiosis

In the fission yeast, Schizosaccharomyces pombe, homologous chromosomes efficiently pair and recombine during meiotic prophase without forming a canonical synaptonemal complex (SC). Instead, it features simpler filamentous structures, the so-called linear elements (LinEs), which bear some resemblance to the axial/lateral element subunits of the SC. LinEs are required for wild-type recombination frequency. Here, we recognized Mug20, the product of a meiotically upregulated gene, as a LinE-associated protein. GFP-tagged Mug20 and anti-Mug20 antibody co-localized completely with Rec10, one of the major constituents of LinEs. In the absence of Mug20, LinEs failed to elongate beyond their initial state of nuclear dots. Foci of recombination protein Rad51 and genetic recombination were reduced. Since meiotic DNA double-strand breaks (DSBs), which initiate recombination, are induced at sites of preformed LinEs, we suggest that reduced recombination is a consequence of incomplete LinE extension. Therefore, we propose that Mug20 is required to extend LinEs from their sites of origin and thereby to increase DSB proficient regions on chromosomes

Seasonal variations in the diagnosis of testicular germ cell tumors: a national cancer registry study in austria

SIMPLE SUMMARY: Seasonal variations in cancer diagnosis could already be demonstrated in prostate and breast cancer. The reasons for this observed seasonal pattern are still unclear. The health care system or other determinants such as the protective function of vitamin D3 in carcinogenesis could be assumed as one explanation. Testicular germ cell tumors are the most common developed malignancy among young men. The aim of our study was to investigate, for the first time, the seasonal variations in the clinical diagnosis of testicular germ cell tumors. We have been able to confirm that the frequency of monthly newly diagnosed cases of testicular cell tumors in Austria has a strong seasonality, with a significant reduction in the tumor incidence during the summer months and an increase during the winter months. ABSTRACT: We conducted a retrospective National Cancer Registry study in Austria to assess a possible seasonal variation in the clinical diagnosis of testicular germ cell tumors (TGCT). In total, 3615 testicular cancer diagnoses were identified during an 11-year period from 2008 to 2018. Rate ratios for the monthly number of TGCT diagnoses, as well as of seasons and half-years, were assessed using a quasi-Poisson model. We identified, for the first time, a statistically significant seasonal trend (p < 0.001) in the frequency of monthly newly diagnosed cases of TGCT. In detail, clear seasonal variations with a reduction in the tumor incidence during the summer months (Apr–Sep) and an increase during the winter months (Oct–Mar) were observed (p < 0.001). Focusing on seasonality, the incidence during the months of Oct–Dec (p = 0.008) and Jan–Mar (p < 0.001) was significantly higher compared to the months of Jul–Sep, respectively. Regarding histopathological features, there is a predominating incidence in the winter months compared to summer months, mainly concerning pure seminomas (p < 0.001), but not the non-seminoma or mixed TGCT groups. In conclusion, the incidence of TGCT diagnoses in Austria has a strong seasonal pattern, with the highest rate during the winter months. These findings may be explained by a delay of self-referral during the summer months. However, the hypothetical influence of vitamin D3 in testicular carcinogenesis underlying seasonal changes in TGCT diagnosis should be the focus of further research

The Recombinases Rad51 and Dmc1 Play Distinct Roles in DNA Break Repair and Recombination Partner Choice in the Meiosis of Tetrahymena

Repair of programmed DNA double-strand breaks (DSBs) by meiotic recombination relies on the generation of flanking 3′ single-stranded DNA overhangs and their interaction with a homologous double-stranded DNA template. In various common model organisms, the ubiquitous strand exchange protein Rad51 and its meiosis-specific homologue Dmc1 have been implicated in the joint promotion of DNA–strand exchange at meiotic recombination sites. However, the division of labor between these two recombinases is still a puzzle. Using RNAi and gene-disruption experiments, we have studied their roles in meiotic recombination and chromosome pairing in the ciliated protist Tetrahymena as an evolutionarily distant meiotic model. Cytological and electrophoresis-based assays for DSBs revealed that, without Rad51p, DSBs were not repaired. However, in the absence of Dmc1p, efficient Rad51p-dependent repair took place, but crossing over was suppressed. Immunostaining and protein tagging demonstrated that only Dmc1p formed strong DSB–dependent foci on meiotic chromatin, whereas the distribution of Rad51p was diffuse within nuclei. This suggests that meiotic nucleoprotein filaments consist primarily of Dmc1p. Moreover, a proximity ligation assay confirmed that little if any Rad51p forms mixed nucleoprotein filaments with Dmc1p. Dmc1p focus formation was independent of the presence of Rad51p. The absence of Dmc1p did not result in compensatory assembly of Rad51p repair foci, and even artificial DNA damage by UV failed to induce Rad51p foci in meiotic nuclei, while it did so in somatic nuclei within one and the same cell. The observed interhomologue repair deficit in dmc1Δ meiosis is consistent with a requirement for Dmc1p in promoting the homologue as the preferred recombination partner. We propose that relatively short and/or transient Rad51p nucleoprotein filaments are sufficient for intrachromosomal recombination, whereas long nucleoprotein filaments consisting primarily of Dmc1p are required for interhomolog recombination

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Pluralism about global distributive justice

In einer globalisierten und interdependenten Welt stellen sich unausweichlich Fragen darüber, wie die Nutzen und Lasten aus unseren gemeinschaftlichen Unterfangen verteilt werden sollen. Diese Arbeit beschäftigt sich mit neueren Entwicklungen in philosophischen Theorien zu Fragen globaler Verteilungsgerechtigkeit. Im Zentrum steht dabei die Herausarbeitung, Begründung und Vervollständigung eines pluralistischen Zugangs zum Thema globale Verteilungsgerechtigkeit. Nach einem einführenden Kapitel zum gegenwärtigen Stand der Theoriebildung bezüglich dieses Themas werden in einem zweiten Kapitel die Idee, das Konzept und Vertreter der pluralistischen These in Moraltheorie und Politischer Theorie vorgestellt und deren zentralen Thesen herausgearbeitet. In Kapitel drei werden vier Gegenargumente von konkurrierenden Theorien gegen diese These konsultiert aber schlussendlich widerlegt. Die Diskussion dieser Einwände resultiert in drei thematischen Fragen, um deren Beantwortung jede Theorie globaler Verteilungsgerechtigkeit bemüht sein muss. Diese Fragen betreffen 1) die Rolle empirischer Forschung für die moralische Bewertung globaler politischer und ökonomischer Prozesse, 2) die Rechtfertigung normativer Prinzipien in diesen Prozessen und 3) die Relevanz sowohl idealer als auch nicht-idealer Theorie für die Begründung von globaler Gerechtigkeit. Während bereits in diesem Kapitel die These aufgestellt wird, dass pluralistische Ansätze diese Aufgaben geeigneter bewerkstelligen können als alternative Zugänge, wird in Kapitel vier eine detaillierte Begründung zu jeder dieser drei Fragen geliefert. Diese Arbeit argumentiert dabei für eine ausschlaggebende Rolle von empirischen Fakten für moralische Argumente in pluralistischen Theorien, für eine konstruktivistische Methode zur Begründung normativer Prinzipien und für eine limitierte Aufgabe idealer Theorie. Nach dieser systematischen Begründung des pluralistischen Ansatzes wird dieser schließlich in Kapitel fünf auf ein Fallbeispiel, den globalen Handel, angewandt. Die aus der pluralistischen Analyse folgende Begründung normativer Forderungen an megaregionale Freihandelsabkommen zeigt die Vorteile dieses Ansatzes zur globalen Verteilungsgerechtigkeit auf. Zuletzt fasst eine Conclusio die wesentlichen Ergebnisse dieser Arbeit zusammen und gibt einen Ausblick auf zukünftige Forschungsvorhaben zu diesem pluralistischen Ansatz.In a globalised and interdependent world, questions of how the benefits and burdens of our collective endeavours ought to be distributed arise inevitably. The thesis at hand follows recent developments in philosophical theorising about these questions of global distributive justice. It develops, defends and completes a pluralist framework for global distributive justice. Following an introductory chapter on contemporary theories of global distributive justice in the philosophical literature, in chapter 2 the notion, concept and advocates of pluralism in moral and political theory are discussed and its central tenets developed. In chapter 3, four arguments against the pluralist outlook from rival approaches are considered but eventually refuted. The discussion of these objections results in three thematic issues that represent crucial questions any convincing approach towards global distributive justice has to answer. These questions concern: 1) the role of factual knowledge for moral assessment, 2) the justification of normative principles for global political and economic affairs, and 3) the understanding of ideal and non-ideal theory for an account of global justice. While the outcome of the discussion in chapter 3 suggests that the pluralist approach is better suited to deal with these challenges, in chapter 4 explicit accounts of all three topics are given. This thesis defends a substantive role of empirical data for pluralistic accounts, a constructivist method of normative justification and argues for a restricted purpose of ideal theory for a pluralist framework on global justice. Having established a complete, systematic pluralist approach, in chapter 5 this framework is subsequently applied to a case study of global trade. The derived, genuine account of distributive justice in megaregional trade agreements demonstrates the desirability of the pluralist approach for questions of global distributive justice. At last, concluding remarks on the main findings of this thesis are drawn and an outlook for further research in this area of philosophical scholarship is provided

An MCM family protein promotes interhomolog recombination by preventing precocious intersister repair of meiotic DSBs.

Recombinational repair of meiotic DNA double-strand breaks (DSBs) uses the homologous chromosome as a template, although the sister chromatid offers itself as a spatially more convenient substrate. In many organisms, this choice is reinforced by the recombination protein Dmc1. In Tetrahymena, the repair of DSBs, which are formed early in prophase, is postponed to late prophase when homologous chromosomes and sister chromatids become juxtaposed owing to tight parallel packing in the thread-shaped nucleus, and thus become equally suitable for use as repair templates. The delay in DSB repair is achieved by rejection of the invading strand by the Sgs1 helicase in early meiotic prophase. In the absence of Mcmd1, a meiosis-specific minichromosome maintenance (MCM)-like protein (and its partner Pamd1), Dmc1 is prematurely lost from chromatin and DNA synthesis (as monitored by BrdU incorporation) takes place in early prophase. In mcmd1Δ and pamd1Δ mutants, only a few crossovers are formed. In a mcmd1Δ hop2Δ double mutant, normal timing of Dmc1 loss and DNA synthesis is restored. Because Tetrahymena Hop2 is believed to enable homologous strand invasion, we conclude that Dmc1 loss in the absence of Mcmd1 affects only post-invasion recombination intermediates. Therefore, we propose that the Dmc1 nucleofilament becomes dismantled immediately after forming a heteroduplex with a template strand. As a consequence, repair synthesis and D-loop extension starts in early prophase intermediates and prevents strand rejection before the completion of homologous pairing. In this case, DSB repair may primarily use the sister chromatid. We conclude that Mcmd1‒Pamd1 protects the Dmc1 nucleofilament from premature dismantling, thereby suppressing precocious repair synthesis and excessive intersister strand exchange at the cost of homologous recombination

DNA double-strand break formation and repair in Tetrahymena meiosis

Acknowledgements We wish to thank Anura Shodhan for sharing unpublished results and Peter Schlögelhofer and Anura Shodhan for critically reading the manuscript. Part of this work was supported by grant P 27313-B20 from the Austrian Science Fund to JL.Peer reviewedPublisher PD