Poly(ADP-ribose) polymerase 1 (PARP-1) is a multidomain multifunctional nuclear enzyme involved in the regulation of the chromatin structure and transcription. PARP-1 consists of three functional domains: the N-terminal DNA-binding domain (DBD) containing three zinc fingers, the automodification domain (A), and the C-terminal domain, which includes the protein interacting WGR domain (W) and the catalytic (Cat) subdomain responsible for the poly(ADP ribosyl)ating reaction. The mechanisms coordinating the functions of these domains and determining the positioning of PARP-1 in chromatin remain unknown. Using multiple deletional isoforms of PARP-1, lacking one or another of its three domains, as well as consisting of only one of those domains, we demonstrate that different functions of PARP-1 are coordinated by interactions among these domains and their targets. Interaction between the DBD and damaged DNA leads to a short-term binding and activation of PARP-1. This “hit and run” activation of PARP-1 initiates the DNA repair pathway at a specific point. The long-term chromatin loosening required to sustain transcription takes place when the C-terminal domain of PARP-1 binds to chromatin by interacting with histone H4 in the nucleosome. This long-term activation of PARP-1 results in a continuous accumulation of pADPr, which maintains chromatin in the loosened state around a certain locus so that the transcription machinery has continuous access to DNA. Cooperation between the DBD and C-terminal domain occurs in response to heat shock (HS), allowing PARP-1 to scan chromatin for specific binding sites.

Farming domesticated millets, tending pigs, and hunting constituted the core of human subsistence strategies during Neolithic Yangshao (5000–2900 BC). Introduction of wheat and barley as well as the addition of domesticated herbivores during the Late Neolithic (∼2600–1900 BC) led to restructuring of ancient Chinese subsistence strategies. This study documents a dietary shift from indigenous millets to the newly introduced cereals in northcentral China during the Bronze Age Eastern Zhou Dynasty (771–221 BC) based on stable isotope analysis of human and animal bone samples. Our results show that this change affected females to a greater degree than males. We find that consumption of the newly introduced cereals was associated with less consumption of animal products and a higher rate of skeletal stress markers among females. We hypothesized that the observed separation of dietary signatures between males and females marks the rise of male-biased inequality in early China. We test this hypothesis by comparing Eastern Zhou human skeletal data with those from Neolithic Yangshao archaeological contexts. We find no evidence of male–female inequality in early farming communities. The presence of male-biased inequality in Eastern Zhou society is supported by increased body height difference between the sexes as well as the greater wealth of male burials.

The clinical potential of PARP-1 inhibitors has been recognized > 10 years ago, prompting intensive research on their pharmacological application in several branches of medicine, particularly in oncology. However, natural or acquired resistance of tumors to known PARP-1 inhibitors poses a serious problem for their clinical implementation. Present study aims to reignite clinical interest to PARP-1 inhibitors by introducing a new method of identifying highly potent inhibitors and presenting the largest known collection of structurally diverse inhibitors. The majority of PARP-1 inhibitors known to date have been developed as NAD competitors. NAD is utilized by many enzymes other than PARP-1, resulting in a trade-off trap between their specificity and efficacy. To circumvent this problem, we have developed a new strategy to blindly screen a small molecule library for PARP-1 inhibitors by targeting a highly specific rout of its activation. Based on this screen, we present a collection of PARP-1 inhibitors and provide their structural classification. In addition to compounds that show structural similarity to NAD or known PARP-1 inhibitors, the screen identified structurally new non-NAD-like inhibitors that block PARP-1 activity in cancer cells with greater efficacy and potency than classical PARP-1 inhibitors currently used in clinic. These non-NAD-like PARP-1 inhibitors are effective against several types of human cancer xenografts, including kidney, prostate, and breast tumors in vivo. Our pre-clinical testing of these inhibitors using laboratory animals has established a strong foundation for advancing the new inhibitors to clinical trials.

Objectives Using stable isotope analysis of incremental dentin segments, we reconstruct breastfeeding, weaning, and childhood dietary patterns of Eastern Zhou period (771–221 BC) individuals from the Central Plains of China. Previous isotopic research on the Eastern Zhou demonstrated dietary difference between male and female diets in adulthood via bone collagen analysis. To understand the development of gendered dietary patterns we must examine the early life period. We aim to identify the timing of the weaning process, whether childhood diets were the same as adulthood diets, and if there were differences between the diets of boys and girls during childhood. Materials and Methods We present incremental dentin and bone collagen δ 13 C and δ 15 N isotope data from 23 individuals from two Eastern Zhou archaeological sites (Xiyasi 西亚斯and Changxinyuan 畅馨苑). Results Weaning was completed between ages 2.5 and 4 years. Females were weaned slightly earlier than males. Early childhood diets show significant incorporation of C 3 foods, such as wheat and soybean, for almost all children, while later adulthood diets indicate greater incorporation of C 4 foods (millets), particularly for males. Discussion Childhood diets included greater amounts of C 3 foods than expected, suggesting that grains such as wheat may have been adopted in these communities as foods for children. Nevertheless, dietary differentiation between females and males began in childhood, with boys eating more millets (C 4 foods) than girls. The findings suggest that feeding children was a significant aspect of socialization and cultural gendering of individuals in ancient China.

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