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Two diphtheria outbreaks occurred in a Swiss asylum center from July to October 2022, one is still ongoing. Outbreaks mainly involved minors and included six symptomatic respiratory diphtheria cases requiring antitoxin. Phylogenomic analyses showed evidence of imported and local transmissions of toxigenic strains in respiratory and skin lesion samples. Given the number of cases (n = 20) and the large genetic diversity accumulating in one centre, increased awareness and changes in public health measures are required to prevent and control diphtheria outbreaks.

Funder: Biotechnology and Biological Sciences Research Council East of Scotland Bioscience Doctoral Training Partnership Ph.D. studentship, Funder: Korean Institute for Basic Science, IBS-R022-A1-2019, Cells possess an armamentarium of DNA repair pathways to counter DNA damage and prevent mutation. Here we use C. elegans whole genome sequencing to systematically quantify the contributions of these factors to mutational signatures. We analyse 2,717 genomes from wild-type and 53 DNA repair defective backgrounds, exposed to 11 genotoxins, including UV-B and ionizing radiation, alkylating compounds, aristolochic acid, aflatoxin B1, and cisplatin. Combined genotoxic exposure and DNA repair deficiency alters mutation rates or signatures in 41% of experiments, revealing how different DNA alterations induced by the same genotoxin are mended by separate repair pathways. Error-prone translesion synthesis causes the majority of genotoxin-induced base substitutions, but averts larger deletions. Nucleotide excision repair prevents up to 99% of point mutations, almost uniformly across the mutation spectrum. Our data show that mutational signatures are joint products of DNA damage and repair and suggest that multiple factors underlie signatures observed in cancer genomes.

Ionizing radiation (IR) is widely used in cancer therapy and accidental or environmental exposure is a major concern. However, little is known about the genome-wide effects IR exerts on germ cells and the relative contribution of DNA repair pathways for mending IR-induced lesions. Here, using C. elegans as a model system and using primary sequencing data from our recent high-level overview of the mutagenic consequences of 11 genotoxic agents, we investigate in detail the genome-wide mutagenic consequences of exposing wild-type and 43 DNA repair and damage response defective C. elegans strains to a Caesium (Cs-137) source, emitting γ-rays. Cs-137 radiation induced single nucleotide variants (SNVs) at a rate of ~1 base substitution per 3 Gy, affecting all nucleotides equally. In nucleotide excision repair mutants, this frequency increased 2-fold concurrently with increased dinucleotide substitutions. As observed for DNA damage induced by bulky DNA adducts, small deletions were increased in translesion polymerase mutants, while base changes decreased. Structural variants (SVs) were augmented with dose, but did not arise with significantly higher frequency in any DNA repair mutants tested. Moreover, 6% of all mutations occurred in clusters, but clustering was not significantly altered in any DNA repair mutant background. Our data is relevant for better understanding how DNA repair pathways modulate IR-induced lesions.

Genome integrity is particularly important in germ cells to faithfully preserve genetic information across generations. As yet little is known about the contribution of various DNA repair pathways to prevent mutagenesis. Using theC. elegansmodel we analyse mutational spectra that arise in wild-type and 61 DNA repair and DNA damage response mutants cultivated over multiple generations. Overall, 44% of lines show >2-fold increased mutagenesis with a broad spectrum of mutational outcomes including changes in single or multiple types of base substitutions induced by defects in base excision or nucleotide excision repair, or elevated levels of 50-400 bp deletions in translesion polymerase mutantsrev-3(pol ζ) andpolh-1(pol η). Mutational signatures associated with defective homologous recombination fall into two classes: 1) mutants lackingbrc-1/BRCA1orrad-51/RAD51 paralogs show elevated base substitutions, indels and structural variants, while 2) deficiency for MUS-81/MUS81 and SLX-1/SLX1 nucleases, and HIM-6/BLM, HELQ-1/HELQ and RTEL-1/RTEL1 helicases primarily cause structural variants. Genome-wide investigation of mutagenesis patterns identified elevated rates of tandem duplications often associated with inverted repeats inhelq-1mutants, and a unique pattern of ‘translocation’ events involving homeologous sequences inrip-1paralog mutants.atm-1/ATM DNA damage checkpoint mutants harboured complex structural variants enriched in subtelomeric regions, and chromosome end-to-end fusions. Finally, while inactivation of thep53-like genecep-1did not affect mutagenesis, combinedbrc-1 cep-1deficiency displayed increased, locally clustered mutagenesis. In summary, we provide a global view of how DNA repair pathways prevent germ cell mutagenesis.

Genome integrity is constantly challenged by exogenous and endogenous insults, and mutations are associated with inherited disease and cancer. Here we summarize recent studies that utilized C. elegans whole genome next generation sequencing to experimentally determine mutational signatures associated with mutagen exposure, DNA repair deficiency or a combination of both and discuss the implications of these results for the understanding of cancer genome evolution. The experimental analysis of wild-type and DNA repair deficient nematodes propagated under unchallenged conditions over many generations revealed increased mutagenesis in approximately half of all DNA repair deficient strains, its rate, except for DNA mismatch repair, only being moderately increased. The exposure of wild-type and DNA repair defective strains to selected genotoxins, including UV-B and ionizing radiation, alkylating compounds, aristolochic acid, aflatoxin-B1, and cisplatin enabled the systematic analysis of the relative contributions of redundant repair modalities that mend DNA damage. Combining genotoxin exposure with DNA repair deficiency can manifest as altered mutation rates and/or as a change in mutational profiles, and reveals how different DNA alterations induced by one genotoxin are repaired by separate DNA repair pathways, often in a highly redundant way. Cancer genomes provide a snapshot of all mutational events that happened prior to cancer detection and sequencing, necessitating computational models to deduce mutational signatures using mathematical best fit approaches. While computationally deducing signatures from cancer genomes has been tremendously successful in associating some signatures to known mutagenic causes, many inferred signatures lack a clear link to a known mutagenic process. Moreover, analytical signatures might not reflect any distinct mutagenic processes. Nonetheless, combined effects of mutagen exposure and DNA damage-repair deficiency are also present in cancer genomes, but cannot be as easily detected owing to the unknown histories of genotoxic exposures and because biallelic in contrast to monoallelic DNA repair deficiency is rare. The impact of damage-repair interactions also manifests through selective pressure for DNA repair gene inactivation during cancer evolution. Using these considerations, we discuss a theoretical framework that explains why minute mutagenic changes, possibly too small to manifest as change in a signature, can have major effects in oncogenesis. Overall, the experimental analysis of mutational processes underscores that the interpretation of mutational signatures requires considering both the primary DNA lesion and repair status and imply that mutational signatures derived from cancer genomes may be more variable than currently anticipated.

DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10(-13)). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in

Faithful chromosome segregation and genome maintenance requires the removal of all DNA bridges that physically link chromosomes before cells divide. Using C. elegans embryos we show that the LEM-3/Ankle1 nuclease defines a new genome integrity mechanism by processing DNA bridges right before cells divide. LEM-3 acts at the midbody, the structure where abscission occurs at the end of cytokinesis. LEM-3 localization depends on factors needed for midbody assembly, and LEM-3 accumulation is increased and prolonged when chromatin bridges are trapped at the cleavage plane. LEM-3 locally processes chromatin bridges that arise from incomplete DNA replication, unresolved recombination intermediates or the perturbance of chromosome structure. Proper LEM-3 midbody localization and function is regulated by AIR-2/Aurora B kinase. Strikingly, LEM-3 act cooperatively with the BRC-1/BRCA1 homologous recombination factor to promote genome integrity. These findings provide a molecular basis for the suspected role of the LEM-3 orthologue Ankle1 in human breast cancer.

Throughout their lifetime cells are subject to extrinsic and intrinsic mutational processes leaving behind characteristic signatures in the genome. DNA mismatch repair (MMR) deficiency leads to hypermutation and is found in different cancer types. While it is possible to associate mutational signatures extracted from human cancers with possible mutational processes the exact causation is often unknown. Here we useC. elegansgenome sequencing ofpms-2andmlh-1knockouts to reveal the mutational patterns linked toC. elegansMMR deficiency and their dependency on endogenous replication errors and errors caused by deletion of the polymerase ε subunitpole-4. Signature extraction from 215 human colorectal and 289 gastric adenocarcinomas revealed three MMR-associated signatures, one of which closely resembles theC. elegansMMR spectrum and strongly discriminates microsatellite stable and unstable tumors (AUC=98%). A characteristic difference between human andC. elegansMMR deficiency is the lack of elevated levels of NCG>NTG mutations inC. elegans, likely caused by the absence of cytosine (CpG) methylation in worms. The other two human MMR signatures may reflect the interaction between MMR deficiency and other mutagenic processes, but their exact cause remains unknown. In summary, combining information from genetically defined models and cancer samples allows for better aligning mutational signatures to causal mutagenic processes.

An improved five-step procedure has been applied to synthesize enantiopure l- and d-1,4-di-O-benzylthreitol out of readily available l- and d-tartaric acid. Through the use of modern reagents and enhanced work-up conditions these useful auxiliaries were obtained in quite perfect yields. In addition, accurate 1H and 13C NMR resonance assignments of all synthesized compounds were performed by 2D NMR spectroscopy.

Critically shortened telomeres can be subjected to DNA repair events that generate end-to-end chromosome fusions. The resulting dicentric chromosomes can enter breakage–fusion–bridge cycles, thereby impeding elucidation of the structures of the initial fusion events and a mechanistic understanding of their genesis. Current models for the molecular basis of fusion of critically shortened, uncapped telomeres rely on PCR assays that typically capture fusion breakpoints created by direct ligation of chromosome ends. Here we use independent approaches that rely on distinctive features of Caenorhabditis elegans to study the frequency of direct end-to-end chromosome fusion in telomerase mutants: (1) holocentric chromosomes that allow for genetic isolation of stable end-to-end fusions and (2) unique subtelomeric sequences that allow for thorough PCR analysis of samples of genomic DNA harboring multiple end-to-end fusions. Surprisingly, only a minority of end-to-end fusion events resulted from direct end joining with no additional genome rearrangements. We also demonstrate that deficiency for the C. elegans Ku DNA repair heterodimer does not affect telomere length or cause synthetic effects in the absence of telomerase.

Few original studies have described the prevalence and severity of clinical symptoms of primary ciliary dyskinesia (PCD). This systematic review and meta-analysis aimed to identify all published studies on clinical manifestations of PCD patients, and to describe their prevalence and severity stratified by age and sex.We searched PubMed, Embase and Scopus for studies describing clinical symptoms of ≥10 patients with PCD. We performed meta-analyses and meta-regression to explain heterogeneity.We included 52 studies describing a total of 1970 patients (range 10–168 per study). We found a prevalence of 5% for congenital heart disease. For the rest of reported characteristics, we found considerable heterogeneity (I2range 68–93.8%) when calculating the weighted mean prevalence. Even after taking into account the explanatory factors, the largest part of the between-studies variance in symptom prevalence remained unexplained for all symptoms. Sensitivity analysis including only studies with test-proven diagnosis showed similar results in prevalence and heterogeneity.Large differences in study design, selection of study populations and definition of symptoms could explain the heterogeneity in symptom prevalence. To better characterise the disease, we need larger, multicentre, multidisciplinary, prospective studies that include all age groups, use uniform diagnostics and report on all symptoms.

Aims: Limited data are available on lung function in paediatric and adult patients with Primary Ciliary Dyskinesia (PCD). Published studies typically included few patients and are difficult to compare because of methodological variations. We summarized the evidence in a systematic review. Methods: In a systematic search in Pubmed, Embase and Scopus we identified all studies reporting on lung function of ≥10 PCD patients, published since 1980. Results: We identified 588 studies, but only 44 met our inclusion criteria and allowed extraction of lung function data. 24 of them described overlapping populations. The diagnostic criteria varied from clinical diagnosis to full diagnostic testing. All studies presented spirometry results, with the majority (28) reporting on FEV1 expressed as %predicted. Only 5 studies included alternative techniques (e.g multiple-breath washout). Most studies found mild to moderate obstructive patterns, while few reported severe bronchial obstruction. Mean FEV1% was 73% (range: 51-93%). The 12 studies focusing on paediatric patients reported a mean FEV1% of 78% (range 73-88%); the 7 studies on adults reported a mean FEV1% of 58% (35-77%). Only 5 studies presented longitudinal results. Conclusion: These first results suggest reduced FEV1% in adult PCD patients, which will be further quantified in a meta-analysis. To study the natural history of lung function in PCD, we need standardized sensitive lung function measurements applied to representative patient populations covering a large age range. Funding: BESTCILIA FP7 grant 305404, Lungenliga Bern, Lungenliga St. Gallen, Ligue pulmonaire Vaudoise.

Meiotic recombination is essential for the repair of programmed double strand breaks (DSBs) to generate crossovers (COs) during meiosis. The efficient processing of meiotic recombination intermediates not only needs various resolvases but also requires proper meiotic chromosome structure. The Smc5/6 complex belongs to the structural maintenance of chromosome (SMC) family and is closely related to cohesin and condensin. Although the Smc5/6 complex has been implicated in the processing of recombination intermediates during meiosis, it is not known how Smc5/6 controls meiotic DSB repair. Here, using Caenorhabditis elegans we show that the SMC-5/6 complex acts synergistically with HIM-6, an ortholog of the human Bloom syndrome helicase (BLM) during meiotic recombination. The concerted action of the SMC-5/6 complex and HIM-6 is important for processing recombination intermediates, CO regulation and bivalent maturation. Careful examination of meiotic chromosomal morphology reveals an accumulation of inter-chromosomal bridges in smc-5; him-6 double mutants, leading to compromised chromosome segregation during meiotic cell divisions. Interestingly, we found that the lethality of smc-5; him-6 can be rescued by loss of the conserved BRCA1 ortholog BRC-1. Furthermore, the combined deletion of smc-5 and him-6 leads to an irregular distribution of condensin and to chromosome decondensation defects reminiscent of condensin depletion. Lethality conferred by condensin depletion can also be rescued by BRC-1 depletion. Our results suggest that SMC-5/6 and HIM-6 can synergistically regulate recombination intermediate metabolism and suppress ectopic recombination by controlling chromosome architecture during meiosis., Author Summary Meiosis is a special form of cell division needed for the formation of haploid gametes. During meiosis, DNA double-strand breaks are enzymatically induced and then repaired by the meiotic recombination pathway. Meiotic recombination is essential for genetic diversity and for accurate segregation of chromosomes during meiosis. Meiotic recombinational repair can either use the homolog or the sister chromatid as a template to generate different recombination intermediates. Recombination intermediates must be resolved or dissolved by specific endonucleases and the BLM helicase. Unresolved recombination intermediates lead to formation of chromatin bridges and perturb proper chromosome segregation. In this study we show that the concerted action of the BLM helicase HIM-6 and the evolutionarily conserved SMC-5/6 complex are important for the ordered processing of meiotic recombination intermediates, proper crossover (CO) formation and subsequent chromosome segregation in C. elegans. Notably, HIM-6 is required for the normal distribution of meiotic COs. We also propose that the interplay between SMC-5/6 and HIM-6 has a crucial role in the formation of a highly condensed and ordered chromosomal structure, which constrains BRC-1 dependent ectopic recombination.

Mutation is associated with developmental and hereditary disorders, aging, and cancer. While we understand some mutational processes operative in human disease, most remain mysterious. We used Caenorhabditis elegans whole-genome sequencing to model mutational signatures, analyzing 183 worm populations across 17 DNA repair-deficient backgrounds propagated for 20 generations or exposed to carcinogens. The baseline mutation rate in C. elegans was approximately one per genome per generation, not overtly altered across several DNA repair deficiencies over 20 generations. Telomere erosion led to complex chromosomal rearrangements initiated by breakage–fusion–bridge cycles and completed by simultaneously acquired, localized clusters of breakpoints. Aflatoxin B1 induced substitutions of guanines in a GpC context, as observed in aflatoxin-induced liver cancers. Mutational burden increased with impaired nucleotide excision repair. Cisplatin and mechlorethamine, DNA crosslinking agents, caused dose- and genotype-dependent signatures among indels, substitutions, and rearrangements. Strikingly, both agents induced clustered rearrangements resembling “chromoanasynthesis,” a replication-based mutational signature seen in constitutional genomic disorders, suggesting that interstrand crosslinks may play a pathogenic role in such events. Cisplatin mutagenicity was most pronounced in xpf-1 mutants, suggesting that this gene critically protects cells against platinum chemotherapy. Thus, experimental model systems combined with genome sequencing can recapture and mechanistically explain mutational signatures associated with human disease.

A universal and facile synthetic route for the preparation of enantiopure L- and D-1,4-di-O-benzylthreitols (IX) from easily accessible L- or D-tartaric acid, resp., is described.

Two roles for the Saccharomyces cerevisiae Cdc13 protein at the telomere have previously been characterized: it recruits telomerase to the telomere and protects chromosome ends from degradation. In a synthetic lethality screen with YKU70, the 70-kDa subunit of the telomere-associated Yku heterodimer, we identified a new mutation in CDC13, cdc13-4, that points toward an additional regulatory function of CDC13. Although CDC13 is an essential telomerase component in vivo, no replicative senescence can be observed in cdc13-4 cells. Telomeres of cdc13-4 mutants shorten for about 150 generations until they reach a stable level. Thus, in cdc13-4 mutants, telomerase seems to be inhibited at normal telomere length but fully active at short telomeres. Furthermore, chromosome end structure remains protected in cdc13-4 mutants. Progressive telomere shortening to a steady-state level has also been described for mutants of the positive telomere length regulator TEL1. Strikingly, cdc13-4/tel1Delta double mutants display shorter telomeres than either single mutant after 125 generations and a significant amplification of Y' elements after 225 generations. Therefore CDC13, TEL1, and the Yku heterodimer seem to represent distinct pathways in telomere length maintenance. Whereas several CDC13 mutants have been reported to display elongated telomeres indicating that Cdc13p functions in negative telomere length control, we report a new mutation leading to shortened and eventually stable telomeres. Therefore we discuss a key role of CDC13 not only in telomerase recruitment but also in regulating telomerase access, which might be modulated by protein-protein interactions acting as inhibitors or activators of telomerase activity.

Faithful recombination and chromosome segregation in meiosis require regulated steps of homolog recognition and association which are monitored by meiotic checkpoints. A recent study in the nematode Caenorhabditis elegans has identified a checkpoint mechanism that monitors chromosome pairing during meiosis.

The high affinity DNA binding factor (HDF) protein of Saccharomyces cerevisiae is composed of two subunits and specifically binds ends of double-stranded DNA. The 70-kDa subunit, HDF1, shows significant homology with the 70-kDa subunit of the human Ku protein. Like the Ku protein, HDF1 has been shown to be involved in recombination and double stranded DNA break repair. We have purified and cloned HDF2, the second subunit of the HDF protein. The amino acid sequence of HDF2 shows a 45.6% homology with the 80-kDa subunit of the Ku protein. HDF1 by itself does not bind DNA, while HDF2 protein on its own seems to displays DNA binding activity. Targeted disruption of the HDF2 gene causes a temperature-sensitive phenotype for growth comparable to the phenotype of hdf1(-) strains. The human Ku protein cannot complement this temperature-sensitive phenotype. hdf2(-) strains are sensitive to bleomycin and methyl methanesulfonate, but this sensitivity is reduced in comparison with hdf1(-) strains.

The telomerase reverse transcriptase adds de novo DNA repeats to chromosome termini. Here we define Caenorhabditis elegans MRT-1 as a novel factor required for telomerase-mediated telomere replication and the DNA-damage response. MRT-1 is composed of an N-terminal domain homologous to the second OB-fold of POT1 telomere-binding proteins and a C-terminal SNM1 family nuclease domain, which confer single-strand DNA-binding and processive 3 0 -to-5 0 exonuclease activity, respectively. Furthermore, telomerase activity in vivo depends on a functional MRT-1 OB-fold. We show that MRT-1 acts in the same telomere replication pathway as telomerase and the 9-1-1 DNA-damage response complex. MRT-1 is dispensable for DNA double-strand break repair, but functions with the 9-1-1 complex to promote DNA interstrand cross-link (ICL) repair. Our data reveal MRT-1 as a dualdomain protein required for telomerase function and ICL repair, which raises the possibility that telomeres and ICL lesions may share a common feature that plays a critical role in de novo telomere repeat addition.

Aims: Floral traits are frequently used in traditional plant systematics becauseof their assumed constancy. One potential reason for the apparent constancy of flower size is that effective pollen transfer between flowers depends on the accuracy of the physical fit betweenthe flower and pollinator. Therefore, flowers are likely to be under stronger stabilizing selection for uniform size than vegetative plant parts. Moreover, as predicted by the pollinator-mediated stabilizing selection (PMSS) hypothesis, an accurate fit between flowers andtheir pollinators is likely to be more important for specialized pollinationsystems as found in many species with bilaterally symmetric (zygomorphic) flowers than for species with radially symmetric (actinomorphic)flowers. Methods: In a comparative study of 15 zygomorphic and 13 actinomorphicspecies in Switzerland, we tested whether variation in flower size, among and within individuals, is smaller than variation in leaf size and whether variation in flower size is smaller in zygomorphic compared to actinomorphic species. Important findings: Indeed, variation in leaf length was significantly larger than variationin flower length and width. Within-individual variation in flower andleaf sizes did not differ significantly between zygomorphic and actinomorphicspecies. In line with the predictions of the PMSS, among-individual variation in flower length and flower width wassignificantly smaller for zygomorphic species than for actinomorphicspecies, while the two groups did not differ in leaf length variation.This suggests that plants with zygomorphic flowers have undergonestronger selection for uniform flowers than plants with actinomorphicflowers. This supports that the relative uniformity of flowers compared to vegetative structures within species, as already observed in traditional plant systematics, is, at least in part, a consequence of the requirement for effective pollination.

To design an artificial mouth in order to evaluate if a new diagnostic tool (Clinpro Cario Diagnosis) can be used for early detection of secondary caries at resin composite margins in vitro.32 intact human third molars received standardized Class-V resin composite restorations (Tetric Ceram bonded with Syntac SC). After storage for 4 weeks at 37 degrees C, teeth were subjected to 5,000 or 10,000 thermocycles (+/- 5 degrees C and +/- 55 degrees C) and polysiloxane impressions were taken. Streptococcus mutans 10449 (SM) was used in a nutrition medium to initiate a secondary caries process. Daily, the teeth were incubated for 2 x 2.5 hours in SM containing nutrition medium followed by 2 x 9.5 hours incubation in artificial saliva. Teeth were investigated after total incubation periods of 4, 6, and 8 weeks. After the different incubation protocols, the restoration margins were evaluated for infection and secondary caries processes in using Clinpro Cario Diagnosis which measures site-specifically the lactic acid production of SM in response to a sucrose challenge. The color signal was read 5 minutes after removal of the diagnostic impression. After thermocycling and biological load cycling, precision polysiloxane impressions were taken and replicas were investigated under a light microscope for gap widths at enamel and dentin margins. Demineralization was evaluated by fluorescence microscopy in using a special FITC filter. The demineralization depths at the cavity margin were calculated with Xpert for Windows using a pixel distance of 5 microm.After the different thermocycling protocols, no differences in gap widths and demineralization depths were found (P0.05). After SM incubation, gap widths and demineralization depths were significantly dependent on SM incubation time and previous number of thermocycles (P0.05). Lactic acid formations of SM were detectable by Clinpro Cario Diagnosis at dentin cavosurface margins formed after 6 weeks of incubation with SM (P0.05).

Der Begriff der Personalentwicklung ist mittlerweile weder aus Unternehmen noch aus der aktuellen Literatur, die sich mit den Bereichen Betriebswirtschaft oder Betriebspadagogik auseinandersetzt, wegzudenken. Zwar ist die Verzahnung der wissenschaftlichen Disziplinen — Betriebswirtschaft auf der einen Seite und Padagogik auf der anderen Seite — noch lange nicht zufriedenstellend in Hinblick auf ein gemeinsames Ziel gelungen, doch gerade im Bereich der Personalentwicklung bestehen gunstige Bedingungen dafur, dass diese sich oft auf den ersten Blick widersprechenden wissenschaftlichen Disziplinen sich einem gemeinsamen Ziel zuwenden: Der (Weiter-)Qualifizierung der Beschaftigten.

The Saccharomyces cerevisiae Ku heterodimer comprising Yku70p and Yku80p is involved in telomere maintenance and DNA repair by the pathway of non-homologous end joining. It is also a key regulator of transcriptional silencing of genes placed in close proximity to telomeres. Here, we describe the identification of separation-of-function mutants of Yku80p that exhibit defects in silencing but not DNA repair and show that these mutations map to an evolutionarily conserved domain within Yku80p. Furthermore, we reveal that Yku80p interacts with the silent information regulator protein Sir4p and that this interaction is mediated by the N-terminal 200 amino acid residues of Sir4p. Notably, this interaction also requires the region of Yku80p that contains the sites of the silencing defective mutations. Finally, we show that these mutations impair the Yku80p-Sir4p interaction and recruitment of Sir3p to telomeric regions in vivo. Taken together with other data, these findings indicate that the Yku80p-Sir4p interaction plays a vital role in the assembly of telomeric heterochromatin.

When meiotic cells complete S phase, homologous chromosomes pair, synapse and undergo recombination. A checkpoint protein is somehow required for meiotic chromosome pairing in C. elegans, thus providing a direct link between S phase and the rest of the meiotic program.

In nahezu allen Beitragen, die sich mit dem Themengebiet „Evaluation“ befassen, wird auf unterschiedliche Definitionsversuche des Begriffs verwiesen. Evaluation umfast eine Vielzahl moglicher Verhaltensweisen und entzieht sich damit einer einheitlichen Definition. Evaluation wird beispielsweise als Prozes der Beurteilung eines Wertes eines Produktes, Prozesses oder eines Programmes definiert (Wottawa & Thierau 1998). Wottawa und Thierau versuchen, allgemeine Kennzeichen wissenschaftlicher Evaluation herauszuarbeiten: Dabei dient Evaluation der Planungs- und Entscheidungshilfe, ist ziel- und zweckorientiert und soll dem aktuellen Stand wissenschaftlicher Forschung angepast sein. Zudem besteht laut Wottawa (1991) unabhangig von den zahlreichen verschiedenen Evaluationsdefinitionen Konsens, das die Evaluation zur Optimierung zielbezogener Handlungen beitragen soll.

Frankfurt am Main, im Grosen Hirschgraben, am 5. Juli 1947. Mitten in dem kaum geraumten Trummerfeld, das einmal die Innenstadt war, begeht man eine Feier des Wieder-Aufbaus: die “Grundsteinlegung” zum “neuen” Goethehaus, das als detailgetreue Nachbildung des alten Baus wiedererstehen soll. Oberburgermeister Walter Kolb nimmt von einem Zimmermann den Hammer entgegen, mit dem er dreimal auf die noch erhaltenen Turpfosten des Hauses schlagt. Dabei wiederholt er, was der ganz junge Johann Wolfgang Goethe 1775, bei der “eigentlichen” Grundsteinlegung, so oder so ahnlich gesprochen haben soll: “Ich wunsche, das dieses Haus bis zum Ende der Welt unverrucket stehen moge.”1 Nachdem dies von einem deutschen Madchen wiederholt wird, ergreift der franzosische Schriftsteller Andre Gide den Hammer, ihm folgen mehrere auslandische Jugendliche. Dann besichtigt man den Keller, wo der historische Grundstein auch den verheerenden Bombenangriff der alliierten Luftwaffe vom 22. Marz 1944 uberstanden hat, der das Goethehaus, das angrenzende Goethemuseum und weite Teile der Frankfurter Innenstadt in Trummer legte.

Wie die Huter des Frankfurter Hauses waren offensichtlich auch die Verantwortlichen in der Weimarer Goethe-Gesellschaft um den Erhalt des Hauses am Frauenplan bzw. dessen Wiederaufbau im Falle eines Unglucks- oder Kriegsfalles besorgt. So berichtet Elisabeth Wedekind, das die Wiederherstellung des Goethehauses in Weimar „nach vorhandenen Planen und Zeichnungen“ durchgefuhrt wurde.1 Wann diese Plane erstellt wurden, last sich allerdings nicht feststellen. Wie in Frankfurt hatte man auch in Weimar das wertvolle Inventar des Hauses vor den Bombenangriffen „durch Auslagerung in Sicherheit gebracht“.2 Am 9. Februar 1945 sollte sich zeigen, das diese Vorsichtsmasnahmen begrundet waren, denn an diesem Tag wurde ein groser Teil des Hauptgebaudes wahrend eines Luftangriffes von einer Sprengbombe schwer beschadigt. Bei dem Angriff wurden mehrere Hauser der historischen Innenstadt Weimars — Kulturdenkmaler wie das Nationaltheater, die Herderkirche oder das Wittumspalais sowie das Schillerhaus und andere Goethestatten wie Garten- und Jagerhaus — ganz oder teilweise zerstort.3

Wie konnte es geschehen, das der international geachtete Nobelpreistrager Thomas Mann — der burgerliche Schriftsteller par excellence — 1949 in Westdeutschland in dieser Form zum Unruhestifter werden konnte? Diese Frage mag sich dem heutigen Betrachter aufdrangen. Die Heftigkeit der Reaktionen und der vorwiegend emotionale Charakter der Auseinandersetzungen um Thomas Mann, die durch seine demonstrative Hochschatzung in der SBZ noch angeheizt wurden, lassen darauf schliesen, das es nicht (nur) um den Schriftsteller Thomas Mann ging. Es ging offensichtlich um den Emigranten Mann, der sich nach 1945 weigerte, die jungste Vergangenheit einfach zu vergessen und zu einer vorgeblich neuen Tagesordnung uberzugehen. Mann glaubte nicht an eine uber Nacht erfolgte Wandlung der Deutschen zu einem Volk von Humanisten, wie sie allenthalben proklamiert wurde. Schon wahrend des Krieges hatte er die Uberzeugung vertreten, das nur eine tiefgreifende Auseinandersetzung der Bevolkerung mit ihren Taten bzw. den in ihrem Namen verubten Verbrechen die Voraussetzung fur eine wirkliche Veranderung der Menschen sein kann.

In einer Tagebucheintragung vom Mai 1946 beschreibt Max Frisch den Anblick der Ruine des Goethehauses inmitten des zerstorten Frankfurt am Main: „Wenn man in Frankfurt steht, zumal in der alten Innenstadt, und wenn man an Munchen zuruckdenkt: Munchen kann man sich vorstellen, Frankfurt nicht mehr. Eine Tafel zeigt, wo das Goethehaus stand. Das man nicht mehr auf dem alten Strasenboden geht, entscheidet den Eindruck: die Ruinen stehen nicht, sondern versinken in ihrem eigenen Schutt, und oft erinnert es mich an die heimatlichen Berge, schmale Ziegenwege fuhren uber die Hugel von Geroll, und was noch steht, sind die bizarren Turme eines verwitterten Grates; …“1 Das Geburtshaus Johann Wolfgang von Goethes wurde am 22. Marz 1944 wahrend eines Bombenangriffs der Royal Air Force endgultig zerstort, nachdem es zuvor schon durch zwei Angriffe schwer beschadigt worden war. Drei Jahre spater beschlos der Magistrat der Stadt Frankfurt auf Antrag des Freien Deutschen Hochstifts — dem die Verwaltung des Goethehauses obliegt — den Wiederaufbau des Hauses. Der Grundstein des neuen Hauses wurde am 5. Juli 1947 gelegt; die Einweihung erfolgte am 10. Mai 1951. Der Antrag des Hochstifts und die Entscheidung des Magistrats hatten allerdings eine offentliche Auseinandersetzung zur Folge, deren Verlauf die zeitgeschichtlichen und ideologischen Hintergrunde des Wiederaufbaus erhellt.