DNA damage signals through differentially modified E2F1 molecules to induce apoptosis

E2F transcription can lead to cell proliferation or apoptosis, indicating that E2Fs control opposing functions. In a similar manner, DNA double-strand breaks can signal to induce cell cycle arrest or apoptosis. Specifically, pRB is activated following DNA damage, allowing it to bind to E2Fs and block transcription at cell cycle promoters; however, E2F1 is simultaneously activated, leading to transcription at proapoptotic promoters. We examined this paradoxical control of E2F transcription by studying how E2F1\u27s interaction with pRB is regulated following DNA damage. Our work reveals that DNA damage signals create multiple forms of E2F1 that contain mutually exclusive posttranslational modifications. Specifically, E2F1 phospho-serine 364 is found only in complex with pRB, while E2F1 phosphorylation at serine 31 and acetylation function to create a pRB-free form of E2F1. Both pRB-bound and pRB-free modifications on E2F1 are essential for the activation of TA-p73 and the maximal induction of apoptosis. Chromatin immunoprecipitation demonstrated that E2F1 phosphorylated on serine 364 is also present at proapoptotic gene promoters during the induction of apoptosis. This indicates that distinct populations of E2F1 are organized in response to DNA damage signaling. Surprisingly, these complexes act in parallel to activate transcription of proapoptotic genes. Our data suggest that DNA damage signals alter pRB and E2F1 to engage them in functions leading to apoptotic induction that are distinct from pRB-E2F regulation in cell cycle control. © 2012, American Society for Microbiology

Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment

AbstractInterleukin-2 receptor α chain (IL-2Rα) expression occurs at specific stages of early T and B lymphocyte development and is induced upon activation of mature lymphocytes. Young mice that lack IL-2Rα have phenotypically normal development of T and B cells. However, as adults, these mice develop massive enlargement of peripheral lymphoid organs associated with polyclonal T and B cell expansion, which, for T cells, is correlated with impaired activation-induced cell death in vivo. Older IL-2Rα-deficient mice also develop autoimmune disorders, including hemolytic anemia and inflammatory bowel disease. Thus, IL-2Rα is essential for regulation of both the size and content of the peripheral lymphoid compartment, probably by influencing the balance between clonal expansion and cell death following lymphocyte activation

Review of US GO-SHIP (Global Oceans Shipboard Hydrographic Investigations Program) An OCB and US CLIVAR Report

The following document constitutes a review of the US GO-SHIP program, performed under the auspices of US Climate Variability and Predictability (CLIVAR) and Ocean Carbon Biogeochemistry (OCB) Programs. It is the product of an external review committee, charged and assembled by US CLIVAR and OCB with members who represent the interests of the programs and who are independent of US GO-SHIP support, which spent several months gathering input and drafting this report. The purpose of the review is to assess program planning, progress, and opportunities in collecting, providing, and synthesizing high quality hydrographic data to advance the scientific research goals of US CLIVAR and OCB

High-throughput testing in head and neck squamous cell carcinoma identifies agents with preferential activity in human papillomavirus-positive or negative cell lines.

Head and neck squamous cell carcinoma (HNSCC) is a common cancer diagnosis worldwide. Despite advances in treatment, HNSCC has very poor survival outcomes, emphasizing an ongoing need for development of improved therapeutic options. The distinct tumor characteristics of human papillomavirus (HPV)-positive vs. HPV-negative disease necessitate development of treatment strategies tailored to tumor HPV-status. High-throughput robotic screening of 1,433 biologically and pharmacologically relevant compounds at a single dose (4 μM) was carried out against 6 HPV-positive and 20 HPV-negative HNSCC cell lines for preliminary identification of therapeutically relevant compounds. Statistical analysis was further carried out to differentiate compounds with preferential activity against cell lines stratified by the HPV-status. These analyses yielded 57 compounds with higher activity in HPV-negative cell lines, and 34 with higher-activity in HPV-positive ones. Multi-point dose-response curves were generated for six of these compounds (Ryuvidine, MK-1775, SNS-032, Flavopiridol, AZD-7762 and ARP-101), confirming Ryuvidine to have preferential potency against HPV-negative cell lines, and MK-1775 to have preferential potency against HPV-positive cell lines. These data comprise a valuable resource for further investigation of compounds with therapeutic potential in the HNSCC

Long‐lived Snell dwarf mice display increased proteostatic mechanisms that are not dependent on decreased mTORC1 activity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111144/1/acel12329.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/111144/2/acel12329-sup-0001-SuppInfo.pd

Impact of endoscopic versus open saphenous vein harvest technique on late coronary artery bypass grafting patient outcomes in the ROOBY (Randomized On/Off Bypass) Trial

ObjectiveIn the Randomized On/Off Bypass (ROOBY) Trial, the efficacy of on-pump versus off-pump coronary artery bypass grafting was evaluated. This ROOBY Trial planned subanalysis compared the effects on postbypass patient clinical outcomes and graft patency of endoscopic vein harvesting and open vein harvesting.MethodsFrom April 2003 to April 2007, the technique used for saphenous vein graft harvesting was recorded in 1471 cases. Of these, 894 patients (341 endoscopic harvest and 553 open harvest) also underwent coronary angiography 1 year after coronary artery bypass grafting. Univariate and multivariable analyses were used to compare patient outcomes in the endoscopic and open groups.ResultsPreoperative patient characteristics were statistically similar between the endoscopic and open groups. Endoscopic vein harvest was used in 38% of the cases. There were no significant differences in both short-term and 1-year composite outcomes between the endoscopic and open groups. For patients with 1-year catheterization follow-up (n = 894), the saphenous vein graft patency rate for the endoscopic group was lower than that in the open harvest group (74.5% vs 85.2%, P < .0001), and the repeat revascularization rate was significantly higher (6.7% vs 3.4%, P < .05). Multivariable regression documented no interaction effect between endoscopic approach and off-pump treatment.ConclusionsIn the ROOBY Trial, endoscopic vein harvest was associated with lower 1-year saphenous vein graft patency and higher 1-year revascularization rates, independent of the use of off-pump or on-pump cardiac surgical approach

G2019S mutation in the leucine-rich repeat kinase 2 gene is not associated with multiple system atrophy

Multiple system atrophy (MSA) is characterized clinically by Parkinsonism, cerebellar dysfunction, and autonomic impairment. Multiple mutations in the LRRK2 gene are associated with parkinsonian disorders, and the most common one, the G2019S mutation, has been found in ∼1% of sporadic cases of Parkinsonism. In a well-characterized cohort of 136 subjects with probable MSA and 110 neurologically evaluated control subjects, none carried the G2019S mutation. We conclude that the G2019S mutation in the LRRK2 gene is unlikely to be associated with MSA. © 2007 Movement Disorder SocietyPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56014/1/21343_ftp.pd

Research conference summary from the 2014 International Task Force on

OBJECTIVE: METHODS: In 2014, the Alternating Hemiplegia of Childhood Foundation hosted a multidisciplinary workshop intended to address fundamental challenges surrounding the diagnosis and management of individuals with RESULTS: Workshop attendees were charged with the following: (1) to achieve consensus on expanded diagnostic criteria to facilitate the identification of additional patients, intended to supplement existing syndrome-specific diagnostic paradigms; (2) to standardize definitions for the broad range of paroxysmal manifestations associated with AHC to disseminate to families; (3) to create clinical recommendations for common recurrent issues facing families and medical care providers; (4) to review data related to the death of individuals in the Alternating Hemiplegia of Childhood Foundation database to guide future efforts in identifying at-risk subjects and potential preventative measures; and (5) to identify critical gaps where we most need to focus national and international research efforts. CONCLUSIONS: This report summarizes recommendations of the workshop committee, highlighting the key phenotypic features to facilitate the diagnosis of possibl

Cracking and Corrosion of Composite Tubes in Black Liquor Recovery Boiler Primary Air Ports

Black liquor recovery boilers are an essential part of kraft mills. Their design and operating procedures have changed over time with the goal of providing improved boiler performance. These performance improvements are frequently associated with an increase in heat flux and/or operating temperature with a subsequent increase in the demand on structural materials associated with operation at higher temperatures and/or in more corrosive environments. Improvements in structural materials have therefore been required. In most cases the alternate materials have provided acceptable solutions. However, in some cases the alternate materials have solved the original problem but introduced new issues. This report addresses the performance of materials in the tubes forming primary air port openings and, particularly, the problems associated with use of stainless steel clad carbon steel tubes and the solutions that have been identified