Inhibition of protein ubiquitination by paraquat and 1-methyl-4-phenylpyridinium impairs ubiquitin-dependent protein degradation pathways

Intracytoplasmic inclusions of protein aggregates in dopaminergic cells (Lewy bodies) are the pathological hallmark of Parkinson’s disease (PD). Ubiquitin (Ub), alpha [α]-synuclein, p62/sequestosome 1 and oxidized proteins are major components of Lewy bodies. However, the mechanisms involved in the impairment of misfolded/oxidized protein degradation pathways in PD are still unclear. PD is linked to mitochondrial dysfunction and environmental pesticide exposure. In this work, we evaluated the effect of the pesticide paraquat (PQ) and the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+) on Ub-dependent protein degradation pathways. No increase in the accumulation of Ub-bound proteins or aggregates was observed in dopaminergic cells (SK-N-SH) treated with PQ or MPP+, or in mice chronically exposed to PQ. PQ decreased Ub protein content, but not its mRNA transcription. Protein synthesis inhibition with cycloheximide depleted Ub levels and potentiated PQ–induced cell death. Inhibition of proteasomal activity by PQ was found to be a late event in cell death progression, and had no effect on either the toxicity of MPP+ or PQ, or the accumulation of oxidized sulfenylated, sulfonylated (DJ-1/PARK7 and peroxiredoxins) and carbonylated proteins induced by PQ. PQ- and MPP+-induced Ub protein depletion prompted the dimerization/inactivation of the Ub-binding protein p62 that regulates the clearance of ubiquitinated proteins by autophagic. We confirmed that PQ and MPP+ impaired autophagy flux, and that the blockage of autophagy by the overexpression of a dominant-negative form of the autophagy protein 5 (dnAtg5) stimulated their toxicity, but there was no additional effect upon inhibition of the proteasome. PQ induced an increase in the accumulation of α-synuclein in dopaminergic cells and membrane associated foci in yeast cells. Our results demonstrate that inhibition of protein ubiquitination by PQ and MPP+ is involved in the dysfunction of Ub-dependent protein degradation pathways

Colorectal Cancer Educational Intervention Targeting Latino Patients Attending a Community Health Center

Objective: Colorectal cancer (CRC) is the third leading cause of cancer death for Latino men and women; and Latinos are more likely to be diagnosed at a later stage, which is most likely due to underutilization of CRC preventive screening. The purpose of this study was to determine whether a brief, clinic-based intervention by a community health advisor (CHA) would increase CRC knowledge compared with traditional educational methodologies (eg, use of print materials). Methods: Latino adults 50 years and older attending a San Diego community health center were recruited while waiting for their primary care provider routine visit and were randomly assigned to receive 1 of 3 CRC educational interventions: community health advisor (CHA) plus CRC educational brochure (CHA intervention group), CRC educational brochure (minimal intervention group), or 5-a-day nutrition brochure (usual care). CRC knowledge was assessed before and after the primary care provider visit for 130 participants. Results: Results demonstrate that the CRC educational brochure (minimal intervention group) was effective at increasing CRC screening knowledge as compared to usual care. Conclusions: Future research is needed to explore innovative health education strategies that improve knowledge and subsequent CRC screening behaviors among low-income, low-literacy, unacculturated Latinos

Colorectal cancer in Mexico: should a middle income country invest in screening or in treatment?

Cancer, Mexico, Health systems, Middle income countries, Colorectal cancer, I11, I12, I18,

The 2016 M-w 7.8 Pedernales, Ecuador, earthquake : rapid response deployment

The April 2016 Pedernales earthquake ruptured a 100 km by 40 km segment of the subduction zone along the coast of Ecuador in an M-w 7.8 megathrust event east of the intersection of the Carnegie ridge with the trench. This portion of the subduction zone has ruptured on decadal time scales in similar size and larger earthquakes, and exhibits a range of slip behaviors, variations in segmentation, and degree of plate coupling along strike. Immediately after the earthquake, an international rapid response effort coordinated by the Instituto Geofisico at the Escuela Politecnica Nacional in Quito deployed 55 seismometers and 10 ocean-bottom seismometers above the rupture zone and adjacent areas to record aftershocks. In this article, we describe the details of the U.S. portion of the rapid response and present an earthquake cata-log from May 2016 to May 2017 produced using data recorded by these stations. Aftershocks focus in distinct clusters within and around the rupture area and match spatial patterns observed in long-term seismicity. For the first two and a half months, aftershocks exhibit a relatively sharp cutoff to the north of the mainshock rupture. In early July, an earthquake swarm occurred similar to 100 km to the northeast of the mainshock in the epicentral region of an M-w 7.8 earthquake in 1958. In December, an increase in seismicity occurred similar to 70 km to the northeast of the mainshock in the epicentral region of the 1906 earthquake. Data from the Pedernales earthquake and aftershock sequence recorded by permanent seismic and geodetic networks in Ecuador and the dense aftershock deployment provide an opportunity to examine the persistence of asperities for large to great earthquakes over multiple seismic cycles, the role of asperities and slow slip in subduction-zone megathrust rupture, and the relationship between locked and creeping parts of the subduction interface