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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. PARG catalyzes the removal of poly(ADP-ribose) (PAR) from target proteins and executes critical functions in the DNA damage response. Here the authors provide structural and biological insight with small molecule PARG inhibitors and show that PARG inhibition sensitizes cells to ionizing radiation and kills cancer cells through replication fork defects.

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.

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.

The Persian Gulf war did not result in many injuries and the intervening years of relative peace between 1992 and the Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) conflicts permitted DVBIC centers to acquire experience evaluating and treating varied TBI populations, test the efficacy of several rehabilitation strategies (cognitive rehabilitation versus home program [6], cognitive versus functional rehabilitation treatments [analysis underway]) and pharmaceutical treatments (Exelon, sertraline), and implement strategies for providing inpatient and outpatient resources to individuals with TBI needing access to care across the country.

The Egyptian economy is typically described as redistributive, following the framework established by Karl Polanyi. In a redistributive system, the state supports its population by gathering goods from producers and redistributing them among the general population. Previous studies on the Egyptian economy support this theory with textual data from the New Kingdom (ca. 1550-1060 BC). In order to create a basis for an economic model for the Old Kingdom (ca. 2600-2200 BC) by using data internal to that period, this study analyzes ceramics, particularly beer jars and bd3 bread moulds. These two ceramic types were the main vessels used in the production and distribution of bread and beer, cornerstones in the Egyptian non-monetary economy. If the economy was truly state-run, one would expect these vessels to have a standardized volume throughout the country, allowing the government to control and measure the redistribution of resources. In order to assess standardization, this study focused on a sample of beer jars and bread moulds from fifteen sites throughout Egypt, both central and provincial. The volumes of these vessels were measured through a combination of filling on-site (when the author was able to work with the actual vessel) and calculation through Pot Utility v. 1.05 (when only the drawing was available for analysis). Standardization within a sample was then assessed by application of the Coefficient of Variation (CV). Through this method, standardization is shown to have been absent not only in the volumes of these samples when viewed as a unity across Egypt, but also when viewed at the level of a single site during a single period. Data from the iconographic, textual, and archaeological record supplement and support this finding. The study also addresses the few exceptions to this rule. This lack of standardization suggests that control of both ceramic production and distribution of goods did not rest in the hands of central or local governments. Local, informal economies appear to have been the norm in the Old Kingdom, not a large, state-controlled redistribution system.

While efficient methods of communication are known to be essential in conducting large multicenter clinical trials, very little information is provided on actual methods that can be implemented to improve communication. An integrated technology-based communication system was developed for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project, which prospectively defines treatments that are most effective for participants with a diagnosis of a nonpsychotic major depressive disorder (MDD) who report an unsatisfactory clinical outcome to an initial and, if necessary, subsequent treatment(s). This web-based communication system is comprised of a multi-faceted study Web site, including a help desk, document sharing, a project directory and reports. In addition, automated reporting via e-mail and an online data correction mechanism are also available. The STAR*D communication system improves communication between study personnel and improves the quality of the study's data through the integration of system elements, the integration of those elements with traditional forms of communication,, by filling the gaps not addressed by those traditional methods and by reducing the staff workload burden.