Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells

Nucleotide excision repair (NER) is the most versatile DNA repair system that deals with the major UV photoproducts in DNA, as well as many other DNA adducts. The early steps of NER are well understood, whereas the later steps of repair synthesis and ligation are not. In particular, which polymerases are definitely involved in repair synthesis and how they are recruited to the damaged sites has not yet been established. We report that, in human fibroblasts, approximately half of the repair synthesis requires both polκ and polδ, and both polymerases can be recovered in the same repair complexes. Polκ is recruited to repair sites by ubiquitinated PCNA and XRCC1 and polδ by the classical replication factor complex RFC1-RFC, together with a polymerase accessory factor, p66, and unmodified PCNA. The remaining repair synthesis is dependent on polɛ, recruitment of which is dependent on the alternative clamp loader CTF18-RFC

Integrating DGSs and GATPs in an Adaptative and Collaborative Blended-Learning Web-Environment

The area of geometry with its very strong and appealing visual contents and its also strong and appealing connection between the visual content and its formal specification, is an area where computational tools can enhance, in a significant way, the learning environments. The dynamic geometry software systems (DGSs) can be used to explore the visual contents of geometry. This already mature tools allows an easy construction of geometric figures build from free objects and elementary constructions. The geometric automated theorem provers (GATPs) allows formal deductive reasoning about geometric constructions, extending the reasoning via concrete instances in a given model to formal deductive reasoning in a geometric theory. An adaptative and collaborative blended-learning environment where the DGS and GATP features could be fully explored would be, in our opinion a very rich and challenging learning environment for teachers and students. In this text we will describe the Web Geometry Laboratory a Web environment incorporating a DGS and a repository of geometric problems, that can be used in a synchronous and asynchronous fashion and with some adaptative and collaborative features. As future work we want to enhance the adaptative and collaborative aspects of the environment and also to incorporate a GATP, constructing a dynamic and individualised learning environment for geometry.Comment: In Proceedings THedu'11, arXiv:1202.453

Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome

A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be define

A Phase I/II Study of Crizotinib for Recurrent or Refractory Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma and a Phase I Study of Crizotinib for Recurrent or Refractory Neuroblastoma : Study Protocol for a Multicenter Single-arm Open-label Trial

Crizotinib is an inhibitor of multiple tyrosine kinases, including the anaplastic lymphoma kinase (ALK). Responses to crizotinib have also been reported in patients with ALK-positive anaplastic large-cell lymphoma (ALCL) and solid tumors with ALK-mutation, including neuroblastoma. Optimal treatment for patients with recurrent or refractory ALK-positive ALCL and neuroblastoma has not been established. There is a need to develop new drugs for these patients. The objectives of this trial are to evaluate the tolerability and safety of crizotinib in Japanese patients with recurrent/refractory ALK-positive ALCL or neuroblastoma (phase I) and its efficacy in recurrent/refractory ALK-positive ALCL (phase II)

A Multicenter, Open-label, Clinical Trial to Assess the Effectiveness and Safety of Allogeneic Hematopoietic Stem Cell Transplantation Using Reduced-intensity Conditioning in Relapsed/refractory Anaplastic Large-cell Lymphoma in Children

No standard treatment for relapsed or refractory anaplastic large-cell lymphoma (ALCL) has been established. This study is a multicenter, open-label trial to examine the effectiveness and safety of transplantation with reduced-intensity conditioning (RIC) for patients under 20 years old with relapsed or refractory ALCL. We defined RIC as the administration of fludarabine (30 mg/m2/day) for five days plus melphalan (70 mg/m2/day) for two days and total body irradiation at 4 Gy, followed by allogeneic hematopoietic stem cell transplantation

Postmortem and helminthological examination of seabirds killed by oil spilled at Ishikari, Hokkaido, Japan, in November 2004

Postmortems and helminthological examinations were performed on beached seabirds killed by oil spilled from a grounded freighter at Ishikari, Hokkaido, Japan in November 13, 2004. The carcasses were covered with crude oil, but they had adequate subcutaneous fat levels. Gross pathological findings consisting of gastric ulcers, pulmonary edema, enlarged spleens and blackish liquid contents in the digestive tracts suggested that they had a rapid progression to death caused by a loss of ascending force, hypothermia and dehydration. Although the visceral organs had degenerated, no direct evidence of mortality caused by ingesting oil was observed. However, extensive acute inflammatory reactions caused by large numbers of mature and immature nematodes (Contracaecum rudolphii) deeply penetrating the gastric walls was observed in two of the birds. Helminthological investigations were conducted on 21 birds from six species, namely: Phalacrocorax capillatus, Aythya marila, Cerorhinca monocerata, Synthliboramphus antiquus, Aethia cristatella, and Brachyramphus perdix. Thirteen helminth species were obtained and identified, including eight nematodes (Eucoleus contortus, Baruscapillaria mergi, B. rudolphii, Amidostomum acutum, C. rudolphii, Tetrameres fissispina, Cosmocephalus obvelatus and Stegophorus stercorarii), three trematodes (Aporchis sp., Hyptiasmus sp. and Renicola sp.), one cestode (Diorchis nyrocae) and one acanthocephalan species (Andracantha phalacrocoracis). Of these, B. rudolphii from S. antiquus, C. rudolphii and Renicola sp. from A. cristatella, and C. obvelatus and Renicola sp. from B. perdix were first host records. Additionally, B. rudolphii was the first geographical record of this species in Japan

Thermotomaculum hydrothermale gen. nov., sp. nov., a novel heterotrophic thermophile within the phylum Acidobacteria from a deep-sea hydrothermal vent chimney in the Southern Okinawa Trough

http://www.godac.jamstec.go.jp/darwin/cruise/natsushima/nt08-13/