Poly(ADP-ribose)ylation (PARylation) by PAR polymerase 1 (PARP1) and PARylation removal by poly(ADP-ribose) glycohydrolase (PARG) critically regulate DNA damage responses; yet, conflicting reports ...obscure PARG biology and its impact on cancer cell resistance to PARP1 inhibitors. Here, we found that PARG expression is upregulated in many cancers. We employed chemical library screening to identify and optimize methylxanthine derivatives as selective bioavailable PARG inhibitors. Multiple crystal structures reveal how substituent positions on the methylxanthine core dictate binding modes and inducible-complementarity with a PARG-specific tyrosine clasp and arginine switch, supporting inhibitor specificity and a competitive inhibition mechanism. Cell-based assays show selective PARG inhibition and PARP1 hyperPARylation. Moreover, our PARG inhibitor sensitizes cells to radiation-induced DNA damage, suppresses replication fork progression and impedes cancer cell survival. In PARP inhibitor-resistant A172 glioblastoma cells, our PARG inhibitor shows comparable killing to Nedaplatin, providing further proof-of-concept that selectively inhibiting PARG can impair cancer cell survival.
Settlement waste, especially in the form of fill layers within houses, is under-investigated by archaeologists. Yet fills constitute a large amount of excavated material in urban contexts. This paper ...investigates the ceramic assemblages from fill contexts from H169, a Middle Kingdom (c. 1850-1650 bc) house on Elephantine Island, Egypt. Using the Business Intelligence (BI) software Tableau to compare the ceramic assemblages from fill and floor contexts, I discuss Egyptian patterns of use and discard that highlight the need to study secondary waste in its depositional context to interpret past cultural activities.
Egyptian pottery—like the pottery from most excavations—is often prized as a chronological indicator above all else. Pottery thus becomes reified into apparently standard corpora by period, an ...impression reinforced by ceramic comparison and cross-dating across sites. Using data from select contexts at one Egyptian settlement site (Elephantine Island) and one specific ceramic form (the bread mold), this article argues that such an approach oversimplifies the ceramic record, ignoring localizing tendencies, continuities between periods, and the entanglement of the material record with long-lived social structures and patterns. Elephantine bread molds show technological continuity and change that does not move in lockstep with greater political changes, thus providing a window into local systems and the value of a regional approach to ceramics.
Studies were conducted from 2015 to 2018 to evaluate spotted lanternfly (SLF) distribution and developmental suitability of different plant species in the U.S. Tree bands on 283 trees spanning 33 ...species captured 21,006 SLF in 2 yr. More SLF per tree were trapped on tree-of-heaven Ailanthus altissima (Mill.) Swingle (Sapindales: Simaroubaceae) than on other species, on average, and most adults were captured on tree-of-heaven. Frequency of detection of adult SLF was higher on tree-of-heaven than on other species but was actually equal or lower on tree-of-heaven than on all other species combined for younger SLF stages in 2015.An enclosed choice test between tree-of-heaven and black walnut JuglansnigraL. (Fagales: Juglandaceae) revealed nymphs showed little consistent preference, whereas adults consistently and significantly preferred tree-of-heaven. No-choice field sleeve studies evaluated SLF survivorship on 26 host plant species in 17 families. Ten plant species supported SLF for an average of ≥45 d, with the rest unable to support SLF for >30 d. Eight species were able to support development from first instar to adult: black walnut, chinaberry Melia azedarach L. (Sapindales: Meliaceae), oriental bittersweet Celastrus orbiculatusThunb. (Celastrales: Celastraceae), tree-of-heaven, hops Humulus lupulus L. (Rosales: Cannabaceae), sawtooth oak Quercus acutissima Carruthers (Fagales: Fagaceae), butternut Juglans cinerea L, and tulip tree Liriodendron tulipifiera L. (Magnoliales: Magnoliaceae). The ability of SLF to develop to adult on hosts other than tree-of-heaven may impact pest management decisions.
Warden talks about the Old Kingdom which was the first major florescence of the Egyptian state. This period is often defined in both scholarship and the popular imagination as a time when powerful, ...pyramid-building pharaohs controlled Egypt and dictated social, religious, and economic affairs. The role of the general population in forming and supporting the Old Kingdom state is often overlooked, with one scholar even referring to the population simply as the undifferentiated masses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Primary blast injury of the central nervous system is described in a service-member exposed to a large ordinance explosion. Neuroimaging abnormalities are described together with normalization of the ...fractional anisotrophy on diffusion tensor imaging after follow-up imaging studies.
In Pottery and Economy in Old Kingdom Egypt, Leslie Anne Warden analyzes utilitarian ceramics to provide a framework for the Egyptian economy which is fluid, full of agents, and defined by small ...scale, face-to-face relationships rather than the state.
Purpose: To critically assess the accuracy and reproducibility of human epidermal growth factor receptor type 2 (HER-2) testing in
outside/local community-based hospitals versus two centralized ...reference laboratories and its effect on selection of women
for trastuzumab (Herceptin)–based clinical trials.
Experimental Design: Breast cancer specimens from 2,600 women were prospectively evaluated by fluorescence in situ hybridization (FISH) for entry into Breast Cancer International Research Group (BCIRG) clinical trials for HER-2-directed
therapies.
Results: HER-2 gene amplification by FISH was observed in 657 of the 2,502 (26%) breast cancers successfully analyzed. Among 2,243 breast
cancers with central laboratory immunohistochemistry (10H8-IHC) analysis, 504 (22.54%) showed overexpression (2+ or 3+). Outside/local
laboratories assessed HER-2 status by immunohistochemistry in 1,536 of these cases and by FISH in 131 cases. Overall, the
HER-2 alteration status determined by outside/local immunohistochemistry showed a 79% agreement rate κ statistic, 0.56; 95% confidence interval (95% CI), 0.52-0.60, with FISH done by the central laboratories. The agreement
rate comparing BCIRG central laboratory 10H8-IHC and outside/local laboratory immunohistochemistry was 77.5% ( κ statistic, 0.51; 95% CI, 0.46-0.55). Finally, HER-2 status, determined by unspecified FISH assay methods at outside/local
laboratories, showed a 92% agreement rate ( κ statistic, 0.83; 95% CI, 0.73-0.93), with FISH done at the BCIRG central laboratories.
Conclusions: Compared with the HER-2 status determined at centralized BCIRG reference laboratories, these results indicate superiority
of FISH to accurately and reproducibly assess tumors for the HER-2 alteration at outside/local laboratories for entry to clinical
trials.
The North Kharga Oasis Darb Ain Amur Survey (NKODAAS) has been exploring the extreme northern area and western extension of Kharga Oasis in order to locate and document hitherto undiscovered and ...unrecorded archaeological sites and material. The archaeological sites identified during the course of the survey are varied, including rock art, routes, mines, quarries, water dumps, wells, shelters, hamlets, and settlements. The site presented here is a Roman/“Late Antique” complex, including a church and several related areas of settlement and industrial activity devoted to alum mining and sandstone quarrying, that played a role in the history of the economy and landscape of Kharga Oasis.
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