Emergency Medicine Research Directors and Research Programs: Characteristics and Factors Associated with Productivity

: Background: Periodic surveys of research directors (RDs) in emergency medicine (EM) are useful to assess the specialty's development and evolution of the RD role. Objectives: To assess associations between characteristics and research productivity of RDs and EM programs. Methods: A survey of EM RDs was developed using the nominal group technique and pilot tested. RDs or surrogate respondents at programs certified by the Accreditation Council for Graduate Medical Education were contacted by e-mail in early 2005. The survey assessed programs' research infrastructure and productivity, as well as RD characteristics, responsibilities, and career satisfaction. Three measures of research productivity were empirically defined: research publications, grant awards, and grant revenue. Results: Responses were received from 86% of 123 EM programs. Productivity was associated with the presence of nonclinical faculty, dedicated research coordinators, and reduced clinical hours for research faculty. Programs with an RD did not have greater research productivity, using any measure, than those without an RD. The majority of RDs cited pursuing their own studies, obtaining funding, research mentoring, and research administration to be major responsibilities. The majority characterized internal research funding, grant development support, and support from other faculty as inadequate. Most RDs are satisfied with their careers and expect to remain in the position for three or more years. Conclusions: Research productivity of EM residency programs is associated with the presence of dedicated research faculty and staff and with reduced clinical demands for research faculty. Despite perceiving deficiencies in important resources, most RDs are professionally satisfied.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72908/1/j.aem.2006.01.027.pd

Emergency Medicine Research Directors and Research Programs: Characteristics and Factors Associated with Productivity

: Background: Periodic surveys of research directors (RDs) in emergency medicine (EM) are useful to assess the specialty's development and evolution of the RD role. Objectives: To assess associations between characteristics and research productivity of RDs and EM programs. Methods: A survey of EM RDs was developed using the nominal group technique and pilot tested. RDs or surrogate respondents at programs certified by the Accreditation Council for Graduate Medical Education were contacted by e-mail in early 2005. The survey assessed programs' research infrastructure and productivity, as well as RD characteristics, responsibilities, and career satisfaction. Three measures of research productivity were empirically defined: research publications, grant awards, and grant revenue. Results: Responses were received from 86% of 123 EM programs. Productivity was associated with the presence of nonclinical faculty, dedicated research coordinators, and reduced clinical hours for research faculty. Programs with an RD did not have greater research productivity, using any measure, than those without an RD. The majority of RDs cited pursuing their own studies, obtaining funding, research mentoring, and research administration to be major responsibilities. The majority characterized internal research funding, grant development support, and support from other faculty as inadequate. Most RDs are satisfied with their careers and expect to remain in the position for three or more years. Conclusions: Research productivity of EM residency programs is associated with the presence of dedicated research faculty and staff and with reduced clinical demands for research faculty. Despite perceiving deficiencies in important resources, most RDs are professionally satisfied.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72908/1/j.aem.2006.01.027.pd

PPL2 translesion polymerase is essential for the completion of chromosomal DNA replication in the african trypanosome

Faithful copying of the genome is essential for life. In eukaryotes, a single archaeo-eukaryotic primase (AEP), DNA primase, is required for the initiation and progression of DNA replication. Here we have identified additional eukaryotic AEP-like proteins with DNA-dependent primase and/or polymerase activity. Uniquely, the genomes of trypanosomatids, a group of kinetoplastid protozoa of significant medical importance, encode two PrimPol-like (PPL) proteins. In the African trypanosome, PPL2 is a nuclear enzyme present in G2 phase cells. Following PPL2 knockdown, a cell-cycle arrest occurs after the bulk of DNA synthesis, the DNA damage response is activated, and cells fail to recover. Consistent with this phenotype, PPL2 replicates damaged DNA templates in vitro, including templates containing the UV-induced pyrimidine-pyrimidone (6-4) photoproduct. Furthermore, PPL2 accumulates at sites of nuclear DNA damage. Taken together, our results indicate an essential role for PPL2 in postreplication tolerance of endogenous DNA damage, thus allowing completion of genome duplication

RAB7 Controls Melanoma Progression by Exploiting a Lineage-Specific Wiring of the Endolysosomal Pathway

Although common cancer hallmarks are well established, lineage-restricted oncogenes remain less understood. Here, we report an inherent dependency of melanoma cells on the small GTPase RAB7, identified within a lysosomal gene cluster that distinguishes this malignancy from over 35 tumor types. Analyses in human cells, clinical specimens, and mouse models demonstrated that RAB7 is an early-induced melanoma driver whose levels can be tuned to favor tumor invasion, ultimately defining metastatic risk. Importantly, RAB7 levels and function were independent of MITF, the best-characterized melanocyte lineage-specific transcription factor. Instead, we describe the neuroectodermal master modulator SOX10 and the oncogene MYC as RAB7 regulators. These results reveal a unique wiring of the lysosomal pathway that melanomas exploit to foster tumor progression.M.S.S. is funded by Projects SAF2011-28317 and Consolider RNAREG from the Spanish Ministry of Economy and Innovation, R01CA125017 from the NIH, and a Team Science Award by the Melanoma Research Foundation. J.L.R.-P. and P.O.-R. are funded by grants FIS 11/025685 and FIS 11/1759, respectively, from the Spanish Ministry of Health. J.L.R.-P. was also supported by grant FMM-2008-106 of Fundación Mutua Madrileña, and P.O.-R. by Red Tematica de Investigacion Cooperativa en Cancer. D.A.-C. and E.P.-G. are recipients of Scientists in Training predoctoral fellowships from the Spanish Ministry of Science and Innovation. M.C. and P.K. are funded by predoctoral fellowships of Fundación La Caixa. E.R.-F. is the recipient of a postdoctoral fellowship from Fundación Científica de la Asociación Española Contra el Cáncer, and J.A.J. and H.-W.W. are funded by the American Cancer Society (RSG-12-076-01-LIB)

The S phase checkpoint promotes the Smc5/6 complex dependent SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε

Replication fork stalling and accumulation of single-stranded DNA trigger the S phase checkpoint, a signalling cascade that, in budding yeast, leads to the activation of the Rad53 kinase. Rad53 is essential in maintaining cell viability, but its targets of regulation are still partially unknown. Here we show that Rad53 drives the hyper-SUMOylation of Pol2, the catalytic subunit of DNA polymerase ε, principally following replication forks stalling induced by nucleotide depletion. Pol2 is the main target of SUMOylation within the replisome and its modification requires the SUMO-ligase Mms21, a subunit of the Smc5/6 complex. Moreover, the Smc5/6 complex co-purifies with Pol ε, independently of other replisome components. Finally, we map Pol2 SUMOylation to a single site within the N-terminal catalytic domain and identify a SUMO-interacting motif at the C-terminus of Pol2. These data suggest that the S phase checkpoint regulate Pol ε during replication stress through Pol2 SUMOylation and SUMO-binding abilit

An Analysis of Enzyme Kinetics Data for Mitochondrial DNA Strand Termination by Nucleoside Reverse Transcription Inhibitors

Nucleoside analogs used in antiretroviral treatment have been associated with mitochondrial toxicity. The polymerase-γ hypothesis states that this toxicity stems from the analogs' inhibition of the mitochondrial DNA polymerase (polymerase-γ) leading to mitochondrial DNA (mtDNA) depletion. We have constructed a computational model of the interaction of polymerase-γ with activated nucleoside and nucleotide analog drugs, based on experimentally measured reaction rates and base excision rates, together with the mtDNA genome size, the human mtDNA sequence, and mitochondrial dNTP concentrations. The model predicts an approximately 1000-fold difference in the activated drug concentration required for a 50% probability of mtDNA strand termination between the activated di-deoxy analogs d4T, ddC, and ddI (activated to ddA) and the activated forms of the analogs 3TC, TDF, AZT, FTC, and ABC. These predictions are supported by experimental and clinical data showing significantly greater mtDNA depletion in cell culture and patient samples caused by the di-deoxy analog drugs. For zidovudine (AZT) we calculated a very low mtDNA replication termination probability, in contrast to its reported mitochondrial toxicity in vitro and clinically. Therefore AZT mitochondrial toxicity is likely due to a mechanism that does not involve strand termination of mtDNA replication

Does Size Matter? The Productivity of Government: Expenditures and the Size of States: Evidence from India

Some politicians argue for the splitting and combining of states to increase government productivity, but there is a dearth of empirical evidence on the optimal size of a state. Using data from Indian states, I test a model of the optimal size of the state. I find that size and preference heterogeneity do not significantly affect the productivity of a state government. However, when states are split up, the productivity of the root state's government is negatively affected. This suggests that there may be a readjustment phase after state reorganisation that brings about this negative effect. It is important to consider this effect when redrawing state borders