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

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

The clinical potential of PARP-1 inhibitors has been recognized N10 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 problemfor 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 newnon-NAD-like inhibitors that block PARP-1 activity in cancer cellswith 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

Research on human skeletal biology in East Asia: a historical overview

In East Asia, interest in variation in human health and use of the human body as a source of knowledge on the human condition dates back to the earliest written texts. This chapter provides a particularly detailed overview of relevant research on human skeletal research starting from the end of the 19th century, emphasizing the role of interaction between different academic schools of thought for the development of physical anthropology in East Asia. The literature reviewed in this chapter illustrates a rich tradition of using the human skeleton to reconstruct the human past in East Asia

East Asian bioarchaeology: major trends in a temporally, genetically, and eco-culturally diverse region

This final synthesizing essay brings together the main threads that bind the various chapters in the volume in terms of human mobility and health. While appreciating the vast geographic area covered and the immense complexity (however measured) of the region, several overriding trends are evident. Regarding population mobility, more attention needs to be paid to Central China, a terribly under-researched area in terms of human biology in the past. A broad consensus emerges in terms of characterizing the northern zone (e.g. north and west of China), which experienced a great deal of biocultural flux over time. On the other hand, there is considerable controversy over characterization of the interaction zone between NE and SE Asia, with polarized views espousing either in situ evolution or demic diffusion to explain the emergence of modern SE Asians. Regarding the other main focus of this volume, human health, a clear pattern of declining community health is found to have accompanied the adoption/intensification of agriculture in both China and Japan

Paleopathological Research in Continental China: Introduction to the Special Section

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 present 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 constrains 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. The following sections are intended to contextualize this 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

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)、、。、，、。、。，，，，。，，

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

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