PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1.

Mutations in the PTEN induced putative kinase 1 (PINK1) gene cause an autosomal recessive form of Parkinson disease (PD). So far, no substrates of PINK1 have been reported, and the mechanism by which PINK1 mutations lead to neurodegeneration is unknown. Here we report the identification of TNF receptor-associated protein 1 (TRAP1), a mitochondrial molecular chaperone also known as heat shock protein 75 (Hsp75), as a cellular substrate for PINK1 kinase. PINK1 binds and colocalizes with TRAP1 in the mitochondria and phosphorylates TRAP1 both in vitro and in vivo. We show that PINK1 protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria, and this protective action of PINK1 depends on its kinase activity to phosphorylate TRAP1. Moreover, we find that the ability of PINK1 to promote TRAP1 phosphorylation and cell survival is impaired by PD-linked PINK1 G309D, L347P, and W437X mutations. Our findings suggest a novel pathway by which PINK1 phosphorylates downstream effector TRAP1 to prevent oxidative-stress-induced apoptosis and implicate the dysregulation of this mitochondrial pathway in PD pathogenesis

A Method to Identify p62's UBA Domain Interacting Proteins

The UBA domain is a conserved sequence motif among polyubiquitin binding proteins. For the first time, we demonstrate a systematic, high throughput approach to identification of UBA domain-interacting proteins from a proteome-wide perspective. Using the rabbit reticulocyte lysate in vitro expression cloning system, we have successfully identified eleven proteins that interact with p62’s UBA domain, and the majority of the eleven proteins are associated with neurodegenerative disorders, such as Alzheimer’s disease. Therefore, p62 may play a novel regulatory role through its UBA domain. Our approach provides an easy route to the characterization of UBA domain interacting proteins and its application will unfold the important roles that the UBA domain plays

Departments of Defense and Agriculture team up to develop new insecticides for mosquito control

Mosquito-borne pathogens are among the most important sources of human disease that cause morbidity and mortality worldwide. They include the viruses responsible for deadly outbreaks of yellow fever, Rift Valley fever, eastern equine encephalitis, Japanese encephalitis and dengue, and an assortment of other serious illnesses caused by the etiological agents of West Nile fever, St Louis encephalitis, Murray Valley encephalitis, Venezuelan equine encephalitis and chikungunya disease. Dengue viruses, of which there are 4 serotypes, cause an estimated 50-100 million new illnesses each year (and 25,000 deaths) while the latest chikungunya epidemic has lasted longer, affected more people, and occurred over a wider geographic area than any previous outbreak of the disease. Yellow fever outbreaks continue to occur sporadically in South America and Africa when either vaccination or vector control are inadequate. These outbreaks have been controlled by creating barrier zones of vaccinated people and by increasing the intensity of vector control. The threat of devastating outbreaks of yellow fever remains, as illustrated by continuing quarantine and vaccination requirements for international travel. The most devastating of all mosquito-borne diseases is malaria, which kills an estimated 1 million people annually, while infecting another 500 million. Although public health efforts have been able to reduce or eliminate vector-borne pathogens in many situations, some parts of the world have actually suffered increases during the past 30 years. A number of agencies have responded to this problem with much increased levels of attention: World Health Organization, Bill and Melinda Gates Foundation, President’s Malaria Initiative, Institute Pasteur, US Centers for Disease Control and Prevention, and US National Institutes of Health. However, morbidity and mortality due to mosquito-borne diseases is increasing. Today, mosquito wars are being fought around the globe and on many fronts. Insecticide-treated bed nets are mass-produced and distributed to the hardesthit malarious regions in Africa, India and southern Asia. Vaccines have been developed to protect humans and domestic animals against Yellow fever, Japanese encephalitis, Rift Valley fever and eastern equine encephalitis, with intensive ongoing research targeting dengue, West Nile virus, and malaria vaccine development. New skin and clothing repellents for personal protection against all biting insects are being developed, and insecticide and related application technology development is in full swing. Of these, the key component for protecting humans from mosquito- borne illness is the use of effective insecticides that quickly kill millions of mosquitoes before they can pass their pathogens to sicken or kill humans. Mosquito adulticides and larvicides are a key component of our assault, along with indoor residual spraying and insecticide-treated bed nets. Unfortunately, mosquitoes are fighting back somewhat successfully by developing resistance to currently used mosquito adulticides. To date at least 100 species of pathogen-carrying mosquitoes have overcome the effects of today’s limited arsenal of adulticides. We now have only 2 chemical classes of adulticides available for adult mosquito control: organophosphates (OPs) and pyrethroids. Malathion is one of our oldest organophosphate adulticides and the workhorse of this class. It was developed in the early 1950s for agricultural pest control and has been used extensively around the world as a mosquito adulticide since 1953. It is a cholinesterase inhibitor that impairs nerve cell transmission. Resistant mosquitoes have at least 3 biochemical processes for detoxifying this class of insecticide. Pyrethroid insecticides were developed in the 1970s as analogs of pyrethrum, a natural product of chrysanthemum flowers, known for its insecticidal properties for hundreds of years. Pyrethroids provide rapid knockdown of mosquitoes by binding to sodium channels on nerve cells and subsequently depolarizing them to stop neural transmission. Resistant mosquitoes are now capable of detoxifying pyrethroids by the above 3 biochemical processes and target cell insensitivity. Larvicides offer more target sites for killing immature mosquitoes, but increased tolerance or resistance has also been reported among different larvicide classes including the stomach poison Bacillus sphaericus, insect growth regulator (methoprene), and a commonly used OP (temephos) among some mosquito species

Susceptibility of \u3ci\u3eAedes aegypti, Culex quinquefasciatus\u3c/i\u3e Say, and \u3ci\u3eAnopheles quadrimaculatus\u3c/i\u3e Say to 19 Pesticides with Different Modes of Action

To access the relative potency of pesticides to control adult mosquitoes, 19 pesticides with various modes of action were evaluated against Aedes aegypti, Culex quinquefasciatus Say, and Anopheles quadrimaculatus Say. On the basis of 24-h LD50 values after topical application, the only pesticide that had higher activity than permethrin was fipronil, with LD50 values lower than permethrin for 107-, 4,849-, and 2-fold against Ae. aegypti, Cx. quinquefasciatus Say, and An. quadrimaculatus Say, respectively. Abamectin, imidacloprid, spinosad, diazinon, and carbaryl showed slightly lower activity than permethrin (\u3c20-fold). However, bifenazate showed very low activity against the three mosquito species tested, with LD50 values higher than permthrin for \u3e1000-fold. On the basis of 24-h LD50 values, Cx. quinquefasciatus was the least susceptible species to nine pesticides tested (DNOC, azocyclotin, chlorfenapyr, carbaryl, spinosad, imidaclorid, diazinon, abamectin, and permethrin), whereas Ae. aegypti was the least susceptible species to six pesticides tested (dicofol, amitraz, propargite, hydramethylnon, cyhexatin, and diafenthiuron), and An. quadrimaculatus was the least susceptible species to four pesticides tested (bifenazate, pyridaben, indoxacarb, and fipronil). Our results revealed that different species of mosquitoes had different susceptibility to pesticides, showing the need to select the most efficacious compounds for the least susceptible mosquito species to achieve successful mosquito control

Susceptibility of \u3ci\u3eAedes aegypti, Culex quinquefasciatus\u3c/i\u3e Say, and \u3ci\u3eAnopheles quadrimaculatus\u3c/i\u3e Say to 19 Pesticides with Different Modes of Action

To access the relative potency of pesticides to control adult mosquitoes, 19 pesticides with various modes of action were evaluated against Aedes aegypti, Culex quinquefasciatus Say, and Anopheles quadrimaculatus Say. On the basis of 24-h LD50 values after topical application, the only pesticide that had higher activity than permethrin was fipronil, with LD50 values lower than permethrin for 107-, 4,849-, and 2-fold against Ae. aegypti, Cx. quinquefasciatus Say, and An. quadrimaculatus Say, respectively. Abamectin, imidacloprid, spinosad, diazinon, and carbaryl showed slightly lower activity than permethrin (\u3c20-fold). However, bifenazate showed very low activity against the three mosquito species tested, with LD50 values higher than permthrin for \u3e1000-fold. On the basis of 24-h LD50 values, Cx. quinquefasciatus was the least susceptible species to nine pesticides tested (DNOC, azocyclotin, chlorfenapyr, carbaryl, spinosad, imidaclorid, diazinon, abamectin, and permethrin), whereas Ae. aegypti was the least susceptible species to six pesticides tested (dicofol, amitraz, propargite, hydramethylnon, cyhexatin, and diafenthiuron), and An. quadrimaculatus was the least susceptible species to four pesticides tested (bifenazate, pyridaben, indoxacarb, and fipronil). Our results revealed that different species of mosquitoes had different susceptibility to pesticides, showing the need to select the most efficacious compounds for the least susceptible mosquito species to achieve successful mosquito control

Susceptibility of \u3ci\u3eAedes aegypti, Culex quinquefasciatus\u3c/i\u3e Say, and \u3ci\u3eAnopheles quadrimaculatus\u3c/i\u3e Say to 19 Pesticides with Different Modes of Action

To access the relative potency of pesticides to control adult mosquitoes, 19 pesticides with various modes of action were evaluated against Aedes aegypti, Culex quinquefasciatus Say, and Anopheles quadrimaculatus Say. On the basis of 24-h LD50 values after topical application, the only pesticide that had higher activity than permethrin was fipronil, with LD50 values lower than permethrin for 107-, 4,849-, and 2-fold against Ae. aegypti, Cx. quinquefasciatus Say, and An. quadrimaculatus Say, respectively. Abamectin, imidacloprid, spinosad, diazinon, and carbaryl showed slightly lower activity than permethrin (\u3c20-fold). However, bifenazate showed very low activity against the three mosquito species tested, with LD50 values higher than permthrin for \u3e1000-fold. On the basis of 24-h LD50 values, Cx. quinquefasciatus was the least susceptible species to nine pesticides tested (DNOC, azocyclotin, chlorfenapyr, carbaryl, spinosad, imidaclorid, diazinon, abamectin, and permethrin), whereas Ae. aegypti was the least susceptible species to six pesticides tested (dicofol, amitraz, propargite, hydramethylnon, cyhexatin, and diafenthiuron), and An. quadrimaculatus was the least susceptible species to four pesticides tested (bifenazate, pyridaben, indoxacarb, and fipronil). Our results revealed that different species of mosquitoes had different susceptibility to pesticides, showing the need to select the most efficacious compounds for the least susceptible mosquito species to achieve successful mosquito control

"It’s more like we want to come to this": Program Engagement in a Sexual Health Youth Leadership Council

Participants in the Looking Out for the Youth (L.O.F.T.Y) Crew, a sexual-health youth leadership council, reported and exhibited high engagement within the program. Understanding program characteristics that contribute to engagement is important because engagement is associated with positive outcomes for youth and program sustainability. According to self-determination theory (Ryan & Deci, 2000), programs that meet youth’s needs for autonomy, relatedness, and competence are more likely to facilitate sustained engagement. This qualitative study examined youth perceptions about the components of the program that contributed to engagement. We conducted focus group and interviews with L.O.F.T.Y Crew participants (N=42). With self-determination theory as a framework, we analyzed the data using a directed content analysis approach. Our analyses yielded five themes related to program engagement: ownership, youth voice, meaningful peer connection, adults as mentors, and increased knowledge and skills. Overall, the results provide support for self-determination theory. Importantly, by identifying specific action steps that can be implemented to increase youth engagement, this qualitative study can help practitioners translate theory to action

Toxicity Comparison Of Eight Repellents Against Four Species Of Female Mosquitoes

The relative toxicities of 8 repellents (DMP, Rutgers 612, DEET, IR3535, Picardin, PMD, AI3-35765, and AI3-37220) were evaluated by topical application against females of Aedes aegypti, Culex quinquefasciatus, Anopheles quadrimaculatus, and An. albimanus. Based on 24-h LD50 values, the most toxic repellent against all 4 mosquito species was AI3-37220, with values of 0.25, 0.20, 0.16, and 0.11 µg/mg for the listed 4 mosquito species, respectively. The least toxic of the 8 repellents tested was DMP, with LD50 values of 5.40, 4.72, 2.50, and 1.83 µg/mg, respectively. Based on the 24-h LD50 values, An. albimanus was the most susceptible species. The findings of the study reported herein provide a comprehensive examination of the toxicities of 4 currently used, 2 formerly used, and 2 experimental repellents against 4 mosquito species

Attenuation of a virulent \u3ci\u3eAeromonas hydrophila\u3c/i\u3e with novobiocin and pathogenic characterization of the novobiocin-resistant strain

Aim: To determine whether novobiocin resistance strategy could be used to attenuate a virulent Aeromonas hydrophila AH11P strain and to characterize the growth and pathogenic differences between the novobiocin-resistant strain and its virulent parent strain AH11P. Methods and Results: A novobiocin-resistant strain AH11NOVO was obtained from a virulent Aer. hydrophila strain AH11P through selection of resistance to novobiocin. AH11NOVO was found to be avirulent to channel catfish (Ictalurus punctatus), whereas AH11P was virulent. When AH11NOVO vaccinated channel catfish were challenged with AH11P at 14 days postvaccination, relative per cent of survival of vaccinated fish was 100%. The cell proliferation rate of AH11NOVO was found to be significantly (P \u3c 0•05) less than that of AH11P. In vitro motility assay revealed that AH11NOVO was nonmotile, whereas AH11P was motile. AH11NOVO had significantly (P \u3c 0•05) lower in vitro chemotactic response to catfish mucus than that of AH11P. Although the ability of AH11NOVO to attach catfish gill cells was similar to that of AH11P, the ability of AH11NOVO to invade catfish gill cells was significantly (P \u3c 0•05) lower than that of AH11P. Conclusions: The novobiocin-resistant AH11NOVO is attenuated and different from its parent AH11P in pathogenicity. Significance and Impact of the Study: The significantly lower chemotactic response and invasion ability of AH11NOVO compared with that of its virulent parent strain AH11P might shed light on the pathogenesis of Aer. hydrophila