HPF1-dependent PARP activation promotes LIG3-XRCC1-mediated backup pathway of Okazaki fragment ligation

DNA ligase 1 (LIG1) is known as the major DNA ligase responsible for Okazaki fragment joining. Recent studies have implicated LIG3 complexed with XRCC1 as an alternative player in Okazaki fragment joining in cases where LIG1 is not functional, although the underlying mechanisms are largely unknown. Here, using a cell-free system derived from Xenopus egg extracts, we demonstrated the essential role of PARP1-HPF1 in LIG3-dependent Okazaki fragment joining. We found that Okazaki fragments were eventually ligated even in the absence of LIG1, employing in its place LIG3-XRCC1, which was recruited onto chromatin. Concomitantly, LIG1 deficiency induces ADP-ribosylation of histone H3 in a PARP1-HPF1-dependent manner. The depletion of PARP1 or HPF1 resulted in a failure to recruit LIG3 onto chromatin and a subsequent failure in Okazaki fragment joining in LIG1-depleted extracts. Importantly, Okazaki fragments were not ligated at all when LIG1 and XRCC1 were co-depleted. Our results suggest that a unique form of ADP-ribosylation signaling promotes the recruitment of LIG3 on chromatin and its mediation of Okazaki fragment joining as a backup system for LIG1 perturbation

トクシマ ダイガク ビョウイン ニオケル シュウジュツキ コウクウ キノウ カンリ ノ ゲンジョウ ト カダイ

It has been shown that oral hygiene affects the onset of perioperative complications. The usefulness of perioperative oral function management aiming at the outbreak decrease in treatment complications and an early discharge was recognized. As a result, perioperative oral function management fee was founded at revision of medical service fees in Fiscal year 2012. 　In this clinical study, we evaluated the implementation of perioperative oral function management in Tokushima University Hospital. We examined 781 patients, including 563 patients for surgery and 218 patients for chemotherapy and radiotherapy. The mean age of patients was 58.8 ± 12.4 years old. 　The implementation rate of perioperative oral function management was 9.7% in the patients of surgery, and 17.4% in those of chemotherapy and radiotherapy. The highly required medical department was neurosurgery in the patients of surgery, and hematology in those of chemotherapy and radiotherapy. The mean number of tooth present was 21.3 ± 7.1 in the patients of surgery, and 19.8 ± 7.2 in those chemotherapy and radiotherapy. The rate of dental treatment was required in 40.5% of total patients who received surgery, and in 51.4% of patients who received chemotherapy and radiotherapy. The rate of patients who received denture treatment attained to 11.9% of the whole patients receiving surgery, and 13.3% of patients receiving chemotherapy and radiotherapy. 　It was revealed that there were many patients required potential demands in perioperative oral function management, and that there were many patients who need dental or denture treatment. We would like to develop perioperative oral function management by the interprofessional collaboration in health and social care

Quark-gluon vertex in general kinematics

The original publication can be found at www.springerlink.com Submitted to Cornell University’s online archive www.arXiv.org in 2007 by Jon-Ivar Skullerud. Post-print sourced from www.arxiv.org.We compute the quark–gluon vertex in quenched lattice QCD in the Landau gauge, using an off-shell mean-field O(a)-improved fermion action. The Dirac-vector part of the vertex is computed for arbitrary kinematics. We find a substantial infrared enhancement of the interaction strength regardless of the kinematics.Ayse Kizilersu, Derek B. Leinweber, Jon-Ivar Skullerud and Anthony G. William

An Exploratory Journey into Sustainability Changemakers Learning Programs

Humanity is facing highly complex challenges at a global scale. A new sort of conscious sustainability changemakers is needed to face the sustainability challenge. However the mainstream entrepreneurship education tends to focus on business as usual skills, with a significant lack of comprehensive understanding of the whole system and the inner work needed to face the mental barriers to become sustainability changemakers. While the Framework for Strategic Sustainable Development was used as a structured approach to the topic, the research design was based on a dynamic research interactive model. Theory U guided the data gathering process that included participatory observation, dialogues with the organizers and participants through the seven progressive schools in Europe. The research aims to identify the common assumptions that guide the design of leading edge learning programs for sustainability changemakers. Building on the findings, the authors present a prototype of a learning tool in a form of self-reflection card game with the intention of helping the next generation of changemakers in their learning journey towards sustainability. Conclusions detail specific guidelines to design a learning program of changemakers towards sustainability

Multispectral quantification of tissue types in a RIF-1 tumor model with histological validation. Part I

Accurate assessments of therapeutic efficacy are confounded by intra- and intertumor heterogeneity. To address this issue we employed multispectral (MS) analysis using the apparent diffusion coefficient (ADC), T(2), proton density (M(0)), and k-means (KM) clustering algorithm to identify multiple compartments within both viable and necrotic tissue in a radiation-induced fibrosarcoma (RIF-1) tumor model receiving single-dose (1000 cGy) radiotherapy. Optimization of the KM method was achieved through histological validation by hematoxylin-eosin (Hand and E) staining and hypoxia-inducible factor-1alpha (HIF-1alpha) immunohistochemistry. The optimum KM method was determined to be a two-feature (ADC, T(2)) and four-cluster (two clusters each of viable tissue and necrosis) segmentation. KM volume estimates for both viable (r = 0.94, P \u3c 0.01) and necrotic (r = 0.69, P = 0.07) tissue were highly correlated with their HandE counterparts. HIF-1alpha immunohistochemistry showed that the intensity of HIF-1alpha expression tended to be concentrated in perinecrotic regions, supporting the subdivision of the viable tissue into well-oxygenated and hypoxic regions. Since both necrosis and hypoxia have been implicated in poor treatment response and reduced patient survival, the ability to quantify the degree of necrosis and the severity of hypoxia with this method may aid in the planning and modification of treatment regimens

Multispectral tissue characterization in a RIF-1 tumor model: monitoring the ADC and T2 responses to single-dose radiotherapy. Part II

A multispectral (MS) approach that combines apparent diffusion coefficient (ADC) and T(2) parameter maps with k-means (KM) clustering was employed to distinguish multiple compartments within viable tumor tissue (V1 and V2) and necrosis (N1 and N2) following single-dose (1000 cGy) radiotherapy in a radiation-induced fibrosarcoma (RIF-1) tumor model. The contributions of cell kill and tumor growth kinetics to the radiotherapy-induced response were investigated. A larger pretreatment V1 volume was correlated with decreased tumor growth delay (TGD) (r = 0.68) and cell kill (r = 0.71). There was no correlation for the pretreatment V2 volume. These results suggest that V1 tissue is well oxygenated and radiosensitive, whereas V2 tissue is hypoxic and therefore radioresistant. The relationship between an early ADC response and vasogenic edema and formation of necrosis was investigated. A trend for increased ADC was observed prior to an increase in the necrotic fraction (NF). Because there were no changes in T(2), these observations suggest that the early increase in ADC is more likely based on a slight reduction in cell density, rather than radiation-induced vasogenic edema. Quantitative assessments of individual tissue regions, tumor growth kinetics, and cell kill should provide a more accurate means of monitoring therapy in preclinical animal models because such assessments can minimize the issue of intertumor variability

Distinct contribution of IL-6, TNF-α, IL-1, and IL-10 to T cell–mediated spontaneous autoimmune arthritis in mice

Cytokines play key roles in spontaneous CD4(+) T cell–mediated chronic autoimmune arthritis in SKG mice, a new model of rheumatoid arthritis. Genetic deficiency in IL-6 completely suppressed the development of arthritis in SKG mice, irrespective of the persistence of circulating rheumatoid factor. Either IL-1 or TNF-α deficiency retarded the onset of arthritis and substantially reduced its incidence and severity. IL-10 deficiency, on the other hand, exacerbated disease, whereas IL-4 or IFN-γ deficiency did not alter the disease course. Synovial fluid of arthritic SKG mice contained high amounts of IL-6, TNF-α, and IL-1, in accord with active transcription of these cytokine genes in the afflicted joints. Notably, immunohistochemistry revealed that distinct subsets of synovial cells produced different cytokines in the inflamed synovium: the superficial synovial lining cells mainly produced IL-1 and TNF-α, whereas scattered subsynovial cells produced IL-6. Thus, IL-6, IL-1, TNF-α, and IL-10 play distinct roles in the development of SKG arthritis; arthritogenic CD4(+) T cells are not required to skew to either Th1 or Th2; and the appearance of rheumatoid factor is independent of joint inflammation. The results also indicate that targeting not only each cytokine but also each cell population secreting distinct cytokines could be an effective treatment of rheumatoid arthritis