Erioflorin stabilizes the tumor suppressor Pdcd4 by inhibiting its interaction with the E3-ligase β-TrCP1

Loss of the tumor suppressor Pdcd4 was reported for various tumor entities and proposed as a prognostic marker in tumorigenesis. We previously characterized decreased Pdcd4 protein stability in response to mitogenic stimuli, which resulted from p70S6K1-dependent protein phosphorylation, β-TrCP1-mediated ubiquitination, and proteasomal destruction. Following high-throughput screening of natural product extract libraries using a luciferase-based reporter assay to monitor phosphorylation-dependent proteasomal degradation of the tumor suppressor Pdcd4, we succeeded in showing that a crude extract from Eriophyllum lanatum stabilized Pdcd4 from TPA-induced degradation. Erioflorin was identified as the active component and inhibited not only degradation of the Pdcd4-luciferase-based reporter but also of endogenous Pdcd4 at low micromolar concentrations. Mechanistically, erioflorin interfered with the interaction between the E3-ubiquitin ligase β-TrCP1 and Pdcd4 in cell culture and in in vitro binding assays, consequently decreasing ubiquitination and degradation of Pdcd4. Interestingly, while erioflorin stabilized additional β-TrCP-targets (such as IκBα and β-catenin), it did not prevent the degradation of targets of other E3-ubiquitin ligases such as p21 (a Skp2-target) and HIF-1α (a pVHL-target), implying selectivity for β-TrCP. Moreover, erioflorin inhibited the tumor-associated activity of known Pdcd4- and IκBα-regulated αtranscription factors, that is, AP-1 and NF-κB, altered cell cycle progression and suppressed proliferation of various cancer cell lines. Our studies succeeded in identifying erioflorin as a novel Pdcd4 stabilizer that inhibits the interaction of Pdcd4 with the E3-ubiquitin ligase β-TrCP1. Inhibition of E3-ligase/target-protein interactions may offer the possibility to target degradation of specific proteins only as compared to general proteasome inhibition

Biting the bullet: a call for action on lead-contaminated meat in food-banks

Each year in the United States, food banks receive more than one million kilograms of donated hunted game meat. The National Rifle Association’s (NRA’s) Hunters for the Hungry initiative has established programs in more than 40 states for hunters to take their harvested game animal to a meat processing facility and indicate intent to donate the resulting processed and packaged meat to a local food bank. Most donated game meat is ground deer meat (venison); other donated game includes wild hog and goose. Even though the presence of ammunition-derived metallic lead fragments in donated firearms-hunted meat has been recognized for more than a decade, most of the donated hunted meat is not inspected to discard meat containing lead fragments. An underlying lack of food safety standards for adulterated donated food increases risks to low-income recipients, who are already disproportionately affected by elevated blood lead levels (BLLs).2 Primary prevention is needed for this overlooked source of lead exposure.publishedVersio

Symbiosis by Persons with Disabilities: Perspectives from Interviews

This study reports on an interview perspective on symbiosis by persons with disabilities. A main theme, Elements of Symbiotic Collaboration, emerged from the data, along with several subthemes. Symbioses described by participants are closely related to the concepts of independence and interdependence in the Disability Studies literature

Resolved Mid-IR Emission in the Narrow Line Region of NGC 4151

We present subarcsecond resolution mid infrared images of NGC 4151 at 10.8 micron and 18.2 micron. These images were taken with the University of Florida mid-IR camera/spectrometer OSCIR at the Gemini North 8-m telescope. We resolve emission at both 10.8 micron and 18.2 micron extending ~ 3.5" across at a P.A. of ~ 60 degrees. This coincides with the the narrow line region of NGC 4151 as observed in [OIII] by the Hubble Space Telescope. The most likely explanation for this extended mid-IR emission is dust in the narrow line region heated by a central engine. We find no extended emission associated with the proposed torus and place an upper limit on its mid-IR size of less than or equal to ~ 35 pc.Comment: accepted for publication in the Astrophysical Journal, 19 pages including 5 figure

Frequency distribution in intraoperative stimulation-evoked EMG responses during selective dorsal rhizotomy in children with cerebral palsy—part 1: clinical setting and neurophysiological procedure

Introduction: Selective dorsal rhizotomy (SDR) consists of microsurgical partial deafferentation of sensory nerve roots (L1-S2). It is primarily used today in decreasing spasticity in young cerebral palsy (CP) patients. Intraoperative monitoring (IOM) is an essential part of the surgical decision-making process, aimed at improving functional results. The role played by SDR-IOM is examined, while realizing that connections between complex EMG responses to nerve-root stimulation and a patient's individual motor ability remain to be clarified. Methods: We conducted this retrospective study, analyzing EMG responses in 146 patients evoked by dorsal-root and rootlet stimulation, applying an objective response-classification system, and investigating the prevalence and distribution of the assessed grades. Part1 describes the clinical setting and SDR procedure, reintroduced in Germany by the senior author in 2007. Results: Stimulation-evoked EMG response patterns revealed significant differences along the segmental levels. More specifically, a comparison of grade 3+4 prevalence showed that higher-graded rootlets were more noticeable at lower nerve root levels (L5, S1), resulting in a typical rostro-caudal anatomical distribution. Conclusions: In view of its prophylactic potential, SDR should be carried out at an early stage in all CP patients suffering from severe spasticity. It is particularly effective when used as an integral part of a coordinated, comprehensive spasticity program in which a team of experts pool their information. The IOM findings pertaining to the anatomical grouping of grades could be of potential importance in adjusting the SDR-IOM intervention to suit the specific individual constellation, pending further validation. Trial registration: ClinicalTrials.gov ID: NCT03079362

Frequency distribution in intraoperative stimulation-evoked EMG responses during selective dorsal rhizotomy in children with cerebral palsy—part 2: gender differences and left-biased asymmetry

Introduction: Spinal reflexes reorganize in cerebral palsy (CP), producing hyperreflexia and spasticity. CP is more common among male infants, and gender might also influence brain and spinal-cord reorganization. This retrospective study investigated the frequency of higher-graded EMG responses elicited by electrical nerve-root stimulation during selective dorsal rhizotomy (SDR), prior to partial nerve- root deafferentation, considering not only segmental level and body side, but also gender. Methods: Intraoperative neuromonitoring (IOM) was used in SDR to pinpoint the rootlets most responsible for exacerbated stimulation-evoked EMG patterns recorded from lower-limb muscle groups. Responses were graded according to an objective response-classification system, ranging from no abnormalities (grade 0) to highly abnormal (grade 4+), based on ipsilateral spread and contralateral involvement. Non-parametric analysis of data with repeated measures was primarily used in investigating the frequency distribution of these various EMG response grades. Over 7000 rootlets were stimulated, and the results for 65 girls and 81 boys were evaluated, taking changes in the composition of patient groups into account when considering GMFCS levels. Results: The distribution of graded EMG responses varied according to gender, laterality, and level. Higher-graded EMG responses were markedly more frequent in the boys and at lower segmental levels (L5, S1). Left-biased asymmetry in higher-graded rootlets was also more noticeable in the boys and in patients with GMFCS level I. A close link was observed between higher-grade assessments and left-biased asymmetry. Conclusions: Detailed insight into the patient's initial spinal-neurofunctional state prior to deafferentation suggests that differences in asymmetrical spinal reorganization might be attributable to a hemispheric imbalance