The Importance of Therapeutically Targeting the Binary Toxin from Clostridioides difficile

Novel therapeutics are needed to treat pathologies associated with the Clostridioides difficile binary toxin (CDT), particularly when C. difficile infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell’s cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. Additionally, unique conformational assemblies of individual CDT components are highlighted herein to refine our mechanistic understanding of this deadly toxin as is needed to develop effective new therapeutic strategies for treating some of the most hypervirulent and lethal strains of CDT-containing strains of CDI.     

Impact of oral vitamin D supplementation on serum 25-hydroxyvitamin D levels in oncology

Background  

Serum 25-hydroxyvitamin D [25(OH)D] is the major circulating form of vitamin D and a standard indicator of vitamin D status. Emerging evidence in the literature suggests a high prevalence of suboptimal vitamin D (as defined by serum 25(OH)D levels of <32 ng/ml) as well as an association between lower serum levels and higher mortality in cancer. We investigated the effect of oral vitamin D supplementation as a means for restoring suboptimal levels to optimal levels in cancer.     

Terrain-derived measures for basin conservation and restoration planning

Centuries of human development have altered the connectivity of rivers, adversely impacting ecosystems and the services they provide. Significant investments in natural resource projects are made annually with the goal of restoring function to degraded rivers and floodplains and protecting freshwater resources. Yet restoration projects often fall short of their objectives, in part due to the lack of systems-based strategic planning. To evaluate channel-floodplain (dis)connectivity and erosion/incision hazard at the basin scale, we calculate Specific Stream Power (SSP), an estimate of the energy of a river, using a topographically based, low-complexity hydraulic model. Other basin-wide SSP modeling approaches neglect reach-specific geometric information embedded in Digital Elevation Models. Our approach leverages this information to generate reach-specific SSP-flow curves. We extract measures from these curves that describe (dis)connected floodwater storage capacity and erosion hazard at individual design storm flood stages and demonstrate how these measures may be used to identify watershed-scale patterns in connectivity. We show proof-of-concept using 25 reaches in the Mad River watershed in central Vermont and demonstrate that the SSP results have acceptable agreement with a well-calibrated process-based model (2D Hydraulic Engineering Center's River Analysis System) across a broad range of design events. While systems-based planning of regional restoration and conservation activities has been limited, largely due to computational and human resource requirements, measures derived from low-complexity models can provide an overview of reach-scale conditions at the regional level and aid planners in identifying areas for further restoration and/or conservation assessments.     

Effect of relocation on locomotion and cleanliness in dairy cows

This study was conducted to determine the effect that relocation to a new free stall barn had on locomotion and cleanliness of two breeds of dairy cows. The original facility before relocation had cows housed in an 8-row free stall barn. Cows were allocated in a new 4-row free stall facility: cows of two breeds (n=22 Holsteins and 22 Jerseys) were intermixed in the northwest section. Locomotion (scale 1-5) and cleanliness were scored (scale 1-4). Holsteins and Jerseys had no difference in locomotion score throughout 12 weeks following relocation. A lactation number by date interaction showed cows in third and greater lactations had significantly higher locomotion scores (more lameness) by day 86. Locomotion scores increased across breeds during the 86-d observation period, suggesting cows became lamer. Jerseys had cleaner lower legs than Holsteins (2.9+/-0.1 v. 3.5+/-0.1, respectively). Lactation number affected lower leg cleanliness, with scores decreasing as lactation number increased (3.4 v. 3.3 v. 2.9+/-0.10 for first, second and third and greater lactations, respectively; P<0.01). All cows were cleaner (lower scores) after relocation, suggesting that the new facility improved hygiene.     

Flexible and light weight copper indium diselenide solar cells on polyimide substrates

Thin film flexible CuInSe₂ (CIS) solar cells have been fabricated for the first time on light-weight polymeric substrates. Evaporated Cu---In alloy precursors were selenized in H₂Se atmosphere at around 400°C to grow the CIS absorber layers. Low temperature techniques which are compatible with the polymeric substrates were used to deposit the window layers of CdS and ZnO. The demonstrated active area conversion efficiency of 9.3% makes this light-weight device very attractive for many terrestrial and space power generation applications where high specific power and mechanical flexibility are needed.     

Cyanobacterial blooms in the central basin of Lake Erie: Potentials for cyanotoxins and environmental drivers

Lake Erie western basin (WB) cyanobacterial blooms are a yearly summer occurrence; however, blooms have also been reported in the offshore waters of the central basin (CB), and very little is known about what drives these blooms or their potential for cyanobacterial toxins. Cyanobacteria Index was quantified using MODIS and MERIS data for the CB between 2003 and 2017, and water samples were collected between 2013 and 2017. The goals were to 1) quantify cyanobacteria, 2) determine environmental drivers of CB blooms, and 3) determine the potential for cyanobacterial toxins in the CB. Dolichospermum (Anabaena) occurred in the CB during July before the onset of the WB bloom, and then in August and September, the cyanobacteria community shifted towards Microcystis. The largest Dolichospermum blooms (2003, 2012, 2013, and 2015) were associated with reduced water clarity (Secchi disk depth?<?4?m), whereas large CB Microcystis blooms (2011 and 2015) were associated with large WB blooms. Dolichospermum blooms occurred in high nitrate concentrations (>20?μmol/L) and high nitrogen-to?phosphorus ratios (>100), which indicate nutrient concentrations or ratios did not select for Dolichospermum. Additionally, the sxtA gene, but not mcyE or microcystins, were detected in the CB during July 2016 and 2017. The mcyE gene and microcystins were detected in the CB during August 2016 and 2017. The results indicate the CB's potential for cyanotoxins shifts from saxitoxins to microcystins throughout the summer. Continued monitoring of cyanobacteria and multiple cyanobacterial toxins is recommended to ensure safe drinking water for CB coastal communities.     

The Lake Ontario zooplankton community before (1987–1991) and after (2001–2005) invasion-induced ecosystem change

We assessed changes in Lake Ontario zooplankton biomass, production, and community composition before (1987–1991) and after (2001–2005) invasion-induced ecosystem changes. The ecosystem changes were associated with establishment of invasive dreissenid mussels and invasive predatory cladocerans (Bythotrephes and Cercopagis). Whole-lake total epilimnetic plus metalimnetic zooplankton production declined by approximately half from 42.45 (g dry wt?m⁻²? year⁻¹) during 1987–1991 to 21.91 (g dry wt?m⁻²? year⁻¹) in 2003 and averaged 21.01 (g dry wt?m⁻²? year⁻¹) during 2001–2005. Analysis of two independent data sets indicates that the mean biomass and biomass proportion of cyclopoid copepods declined while the same measures increased for the invasive predatory cladocerans. Changes in means and proportions of all other zooplankton groups were not consistent between the data sets. Cyclopoid copepod biomass and production declined by factors ranging from 3.6 to 5.7. Invasive predatory cladoceran biomass averaged from 5.0% to 8.0% of the total zooplankton biomass. The zooplankton community was otherwise resilient to the invasion-induced disruption as zooplankton species richness and diversity were unaffected. Zooplankton production was likely reduced by declines in primary productivity but may have declined further due to increased predation by alewives and invasive predatory cladocerans. Shifts in zooplankton community structure were consistent with increased predation pressure on cyclopoid copepods by alewives and invasive predatory cladocerans. Predicted declines in the proportion of small cladocerans were not evident. This study represents the first direct comparison of changes in Lake Ontario zooplankton production before and after the invasion-induced disruption and will be important to food web-scale investigations of invasion effects.     

An overview of FDA medical device regulation as it relates to deep brain stimulation devices.

The United States Food and Drug Administration (FDA) is charged with assuring the safety and effectiveness of a variety of medical products and the FDA's Center for Devices and Radiological Health is responsible for premarket and postmarket regulation of medical devices. In this paper, we review--from device classification and clinical studies to the final marketing application--FDA's premarket requirements and postmarket requirements as they relate to deep brain stimulation devices.