Hit and run versus long-term activation of PARP-1 by its different domains fine-tunes nuclear processes.

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.

Raising girls and boys in early China: Stable isotope data reveal sex differences in weaning and childhood diets during the eastern Zhou era.

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 δ13 C and δ15 N isotope data from 23 individuals from two Eastern Zhou archaeological sites (Xiyasi and Changxinyuan ). 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 C3 foods, such as wheat and soybean, for almost all children, while later adulthood diets indicate greater incorporation of C4 foods (millets), particularly for males. DISCUSSION: Childhood diets included greater amounts of C3 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 (C4 foods) than girls. The findings suggest that feeding children was a significant aspect of socialization and cultural gendering of individuals in ancient China.

Shifting diets and the rise of male-biased inequality on the Central Plains of China during Eastern Zhou.

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.

Paleopathological research in continental China: Introduction to the Special Issue.

We set out to assemble this Special Issue of IJPP with three goals in mind: (1) to familiarize Anglophone readers with research on paleopathology conducted by Chinese scholars; (2) to enhance interest in paleopathological research among Chinese scholars, and to foster the use of differential diagnosis as the key mode of paleopathological analysis; and (3) to initiate integration of pathological analysis of human skeletal collections with historical records documenting early medical practices, epidemics, development and age-related diseases, and demographic records. The collection of papers that follows presents new data, from a range of time periods and geographic and social contexts, that we feel reflect the diversity, dynamism, and enormous scope of archaeology in China today. Themes such as infectious disease history, interpersonal violence, and comorbidity as a methodological issue are addressed by multiple papers. However, as the special issue developed, we also came to a slow appreciation of structural constraints that made our original goals difficult to attain within the current state of our discipline, of which the language barrier represents only a minor issue. This introductory paper is intended to contextualize the Special Issue, and help readers understand the intrinsic and extrinsic factors that influence paleopathological research in China and its interactions with similar research in other parts of the world. :IJPP，:(1);(2)，;(3)、、。、，、。、。，，，，。，，.

Growing up different in Neolithic China: A contextualised case study and differential diagnosis of a young adult with skeletal dysplasia.

This paper presents a case study of a young adult from the late Neolithic Yangshao cultural period site (∼3300-2900 years BC) of Guanjia () located in Henan Province on the Central Plains of China, who has evidence for skeletal dysplasia characterised by proportional stunting of the long bones and a small axial skeleton, generalised osteopenia, and non-fusion of epiphyses. We provide a detailed differential diagnosis of skeletal dysplasia with paediatric onset and conclude that this is likely a form of hypopituitarism or hypothyroidism, an extremely rare finding within the archaeological context. This paper highlights the issues of distinguishing the forms of proportional dwarfism in palaeopathology because of the considerable variation in manifestation of these conditions. Finally, we assess whether there were any health and social implications for this person and community through the consideration of a bioarchaeology of care approach across the lifecourse, burial context, and information on social perceptions of 'difference' in the community. ：： （3300～2900）。，，，，。，，。。，。，、、""，。.

What's that big thing on your head? Diagnosis of a large frontoparietal lesion on an Eastern Zhou skull from Henan, China.

We carried out a differential diagnosis of a large frontoparietal lesion on a human skull from a Late Bronze Age archaeological site located on the Central Plain of China, dating to between 771 and 476 BC. The head of this individual was covered in cinnabar, a mercury-based pigment that later was used for medicinal purposes in China. The lesion was well-circumscribed and involved the outer and inner tables of the skull, slight diploë thickening, and coarsening of bone trabeculae with expansion of intertrabecular spaces. We show that the observed changes are most consistent with cavernous hemangioma of the skull, a benign vascular malformation that preferentially affects older adults. Hemangiomas are often neglected in the paleopathological literature because of their benign nature - they tend to be asymptomatic and do not affect quality of life to a significant degree. Nevertheless, they produce characteristic lesions that can be confused with several other conditions with unrelated etiologies, including congenital hemoglabinopathies, traumas, malignant or benign neoplasms, and Paget's disease. We outline the diagnostic criteria that distinguish cavernous hemangioma from other conditions affecting the skull.

Cases of endocranial lesions on juvenile skeletons from Longshan cultural sites in Henan Province, China.

Endocranial lesions were recognized on eight out of the 31 juveniles (25.8%) that were recovered from three Neolithic archaeological sites in Henan province. The remains of juveniles were recovered from urn burials at the Jiazhuang site (2200-2030 BCE) and graves at the Pingliangtai (2300-2100 BCE) and Haojiatai sites (2448-1700 BCE). The presence of endocranial lesions on all eight of these juvenile skulls was associated with a range of lesions on other bones, including areas of abnormal porosity and subperiosteal new bone deposition on either the sphenoid, maxilla, mandibular ramus, or orbit, as well as subperiosteal lesions on the postcranial bones. Several plausible explanations for the formation of these endocranial lesions in our eight cases include scurvy, shaken baby syndrome, and intrathoracic disease (such as tuberculosis or pulmonary infection). We show that the presence of endocranial lesions had a strong correspondence with skeletal markers of dietary deficiency, i.e. scurvy, and in one case, anemia. Millet was a key component of the Longshan subsistence in the area, while paleobotanical evidence of fruit and leafy vegetables appears to be limited, likely resulting in a nutrient deficient diet. The coupling of endocranial lesions with skeletal signs of dietary deficiency can be direct, as scurvy favors hemorrhaging, or mediated by physiological or sociocultural factors, and thereby represents comorbidity.

Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivo.

The clinical potential of PARP-1 inhibitors has been recognized >10years 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.