Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase.

Bacterial ClpB and yeast Hsp104 are homologous Hsp100 protein disaggregases that serve critical functions in proteostasis by solubilizing protein aggregates. Two AAA+ nucleotide binding domains (NBDs) power polypeptide translocation through a central channel comprised of a hexameric spiral of protomers that contact substrate via conserved pore-loop interactions. Here we report cryo-EM structures of a hyperactive ClpB variant bound to the model substrate, casein in the presence of slowly hydrolysable ATPγS, which reveal the translocation mechanism. Distinct substrate-gripping interactions are identified for NBD1 and NBD2 pore loops. A trimer of N-terminal domains define a channel entrance that binds the polypeptide substrate adjacent to the topmost NBD1 contact. NBD conformations at the seam interface reveal how ATP hydrolysis-driven substrate disengagement and re-binding are precisely tuned to drive a directional, stepwise translocation cycle

School Choice and Segregation by Race, Class, and Achievement

This chapter summarizes the empirical literature on the growth in school choice options, the increasing diversity of the school-aged population, and the segregation of America's schools by race, socioeconomic status, and student ability. Research findings suggest choice schools and programs are as segregated, and in some instances, more segregated by race and socioeconomic status than the other schools in their local community. Moreover, many forms of choice also segregate students by ability and achievement levels. The ways that school choice options are designed and implemented result in very little desegregation. The exceptions to this generalization are intradistrict full magnet programs that operate under conditions of controlled choice, interdistrict desegregation plans, and some secular private schools

Mining Disaggregase Sequence Space to Safely Counter TDP-43, FUS, and α-Synuclein Proteotoxicity.

Hsp104 is an AAA+ protein disaggregase, which can be potentiated via diverse mutations in its autoregulatory middle domain (MD) to mitigate toxic misfolding of TDP-43, FUS, and α-synuclein implicated in fatal neurodegenerative disorders. Problematically, potentiated MD variants can exhibit off-target toxicity. Here, we mine disaggregase sequence space to safely enhance Hsp104 activity via single mutations in nucleotide-binding domain 1 (NBD1) or NBD2. Like MD variants, NBD variants counter TDP-43, FUS, and α-synuclein toxicity and exhibit elevated ATPase and disaggregase activity. Unlike MD variants, non-toxic NBD1 and NBD2 variants emerge that rescue TDP-43, FUS, and α-synuclein toxicity. Potentiating substitutions alter NBD1 residues that contact ATP, ATP-binding residues, or the MD. Mutating the NBD2 protomer interface can also safely ameliorate Hsp104. Thus, we disambiguate allosteric regulation of Hsp104 by several tunable structural contacts, which can be engineered to spawn enhanced therapeutic disaggregases with minimal off-target toxicity

Examining the Effects of School Composition on North Carolina Student Achievement over Time

This study explores the effects of school-level characteristics on North Carolina students’ reading and math achievement from fourth through eighth grade, focusing on the relationships between achievement and the racial and poverty composition of schools. After creating race-by-poverty cohorts of schools, I use multilevel models to examine math and reading achievement for the same students in fourth, sixth, and eighth grades. The racial and poverty composition of schools affect student achievement after factoring in student, family, and other school influences. In addition, increasing teacher quality and school resources reduces but does not eliminate the effects of school racial and poverty composition on student achievement. Policies leading to reductions in racial and poverty isolation in schools and increases in teacher quality should be pursued to guarantee equality of educational opportunities to all children in North Carolina schools

Examining the relationship between vegetation decline and precipitation in the national parks of the Greater Limpopo Transfrontier Conservation Area during the 21st century

The Greater Limpopo Transfrontier Conservation Area (GLTFCA) of southeastern Southern Africa is home to five large national parks and is an important protected area crossing different geopolitical borders, but with the same conservation goals. However, even with similar management techniques, there have been concerning declines in vegetation observed across the last few decades. This study proposes that a larger driver, climate, is linked to this decline over time, and raises the point that these conservation areas are more important now than ever. Precipitation (annual and seasonal), the Normalized Difference Vegetation Index (NDVI, indicator of vegetation health), and Directional Persistence data (D, metric to measure trends in vegetation health over time compared to a baseline value) from 2000 to 2020 are used. Overall, there was a negative trend in precipitation during the 21st century in all seasons except the beginning of the wet season. Linked to this were negative trends in vegetation health both in absolute Normalized Difference Vegetation Index values and resultant D values. Overall, this study found a decline in precipitation, which was significantly linked to a decline in vegetation health across the majority of the year in the Greater Limpopo Transfrontier Conservation Area. This study supports literature on browning in sub-Saharan Africa and gives managers even more reason to work together towards a unified conservation strategy for this important region

Sources of Mercury to East Fork Poplar Creek Downstream from the Y-12 National Security Complex: Inventories and Export Rates

East Fork Poplar Creek (EFPC) in Oak Ridge, Tennessee, has been heavily contaminated with mercury (also referred to as Hg) since the 1950s as a result of historical activities at the U.S. Department of Energy (DOE) Y-12 National Security Complex (formerly the Oak Ridge Y-12 Plant and hereinafter referred to as Y-12). During the period from 1950 to 1963, spills and leaks of elemental mercury (Hg{sup 0}) contaminated soil, building foundations, and subsurface drainage pathways at the site, while intentional discharges of mercury-laden wastewater added 100 metric tons of mercury directly to the creek (Turner and Southworth 1999). The inventory of mercury estimated to be lost to soil and rock within the facility was 194 metric tons, with another estimated 70 metric tons deposited in floodplain soils along the 25 km length of EFPC (Turner and Southworth 1999). Remedial actions within the facility reduced mercury concentrations in EFPC water at the Y-12 boundary from > 2500 ng/L to about 600 ng/L by 1999 (Southworth et al. 2000). Further actions have reduced average total mercury concentration at that site to {approx}300 ng/L (2009 RER). Additional source control measures planned for future implementation within the facility include sediment/soil removal, storm drain relining, and restriction of rainfall infiltration within mercury-contaminated areas. Recent plans to demolish contaminated buildings within the former mercury-use areas provide an opportunity to reconstruct the storm drain system to prevent the entry of mercury-contaminated water into the flow of EFPC. Such actions have the potential to reduce mercury inputs from the industrial complex by perhaps as much as another 80%. The transformation and bioaccumulation of mercury in the EFPC ecosystem has been a perplexing subject since intensive investigation of the issue began in the mid 1980s. Although EFPC was highly contaminated with mercury (waterborne mercury exceeded background levels by 1000-fold, mercury in sediments by more than 2000-fold) in the 1980s, mercury concentrations in EFPC fish exceeded those in fish from regional reference sites by only a little more than 10-fold. This apparent low bioavailability of mercury in EFPC, coupled with a downstream pattern of mercury in fish in which mercury decreased in proportion to dilution of the upstream source, lead to the assumption that mercury in fish would respond to decreased inputs of dissolved mercury to the stream's headwaters. However, during the past two decades when mercury inputs were decreasing, mercury concentrations in fish in Lower EFPC (LEFPC) downstream of Y-12 increased while those in Upper EFPC (UEFPC) decreased. The key assumption of the ongoing cleanup efforts, and concentration goal for waterborne mercury were both called into question by the long-term monitoring data. The large inventory of mercury within the watershed downstream presents a concern that the successful treatment of sources in the headwaters may not be sufficient to reduce mercury bioaccumulation within the system to desired levels. The relative importance of headwater versus floodplain mercury sources in contributing to mercury bioaccumulation in EFPC is unknown. A mercury transport study conducted by the Tennessee Valley Authority (TVA) in 1984 estimated that floodplain sources contributed about 80% of the total annual mercury export from the EFPC system (ORTF 1985). Most of the floodplain inputs were associated with wet weather, high flow events, while much of the headwater flux occurred under baseflow conditions. Thus, day-to-day exposure of biota to waterborne mercury was assumed to be primarily determined by the Y-12 source. The objective of this study was to evaluate the results of recent studies and monitoring within the EFPC drainage with a focus on discerning the magnitude of floodplain mercury sources and how long these sources might continue to contaminate the system after headwater sources are eliminated or greatly reduced